Hyperimmune immunoglobulin for people with COVID‐19

Abstract

Background

Hyperimmune immunoglobulin (hIVIG) contains polyclonal antibodies, which can be prepared from large amounts of pooled convalescent plasma or prepared from animal sources through immunisation. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID‐19). This review was previously part of a parent review addressing convalescent plasma and hIVIG for people with COVID‐19 and was split to address hIVIG and convalescent plasma separately.

Objectives

To assess the benefits and harms of hIVIG therapy for the treatment of people with COVID‐19, and to maintain the currency of the evidence using a living systematic review approach.

Search methods

To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID‐19 Research Database, the Cochrane COVID‐19 Study Register, the Epistemonikos COVID‐19 L*OVE Platform and Medline and Embase from 1 January 2019 onwards. We carried out searches on 31 March 2022.

Selection criteria

We included randomised controlled trials (RCTs) that evaluated hIVIG for COVID‐19, irrespective of disease severity, age, gender or ethnicity.

We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies that evaluated standard immunoglobulin.

Data collection and analysis

We followed standard Cochrane methodology.

To assess bias in included studies, we used RoB 2. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all‐cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), quality of life, adverse events, and serious adverse events.

Main results

We included five RCTs with 947 participants, of whom 688 received hIVIG prepared from humans, 18 received heterologous swine glyco‐humanised polyclonal antibody, and 241 received equine‐derived processed and purified F(ab’)₂ fragments. All participants were hospitalised with moderate‐to‐severe disease, most participants were not vaccinated (only 12 participants were vaccinated). The studies were conducted before or during the emergence of several SARS‐CoV‐2 variants of concern.

There are no data for people with COVID‐19 with no symptoms (asymptomatic) or people with mild COVID‐19. We identified a further 10 ongoing studies evaluating hIVIG.

Benefits of hIVIG prepared from humans

We included data on one RCT (579 participants) that assessed the benefits and harms of hIVIG 0.4 g/kg compared to saline placebo. hIVIG may have little to no impact on all‐cause mortality at 28 days (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.43 to 1.44; absolute effect 77 per 1000 with placebo versus 61 per 1000 (33 to 111) with hIVIG; low‐certainty evidence). The evidence is very uncertain about the effect on worsening of clinical status at day 7 (RR 0.85, 95% CI 0.58 to 1.23; very low‐certainty evidence). It probably has little to no impact on improvement of clinical status on day 28 (RR 1.02, 95% CI 0.97 to 1.08; moderate‐certainty evidence). We did not identify any studies that reported quality‐of‐life outcomes, so we do not know if hIVIG has any impact on quality of life.

Harms of hIVIG prepared from humans

hIVIG may have little to no impact on adverse events at any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study 579 participants; low‐certainty evidence). Patients receiving hIVIG probably experience more adverse events at grade 3‐4 severity than patients who receive placebo (RR 4.09, 95% CI 1.39 to 12.01; moderate‐certainty evidence). hIVIG may have little to no impact on the composite outcome of serious adverse events or death up to day 28 (RR 0.72, 95% CI 0.45 to 1.14; moderate‐certainty evidence).

We also identified additional results on the benefits and harms of other dose ranges of hIVIG, not included in the summary of findings table, but summarised in additional tables.

Benefits of animal‐derived polyclonal antibodies

We included data on one RCT (241 participants) to assess the benefits and harms of receptor‐binding domain‐specific polyclonal F(ab´)₂ fragments of equine antibodies (EpAbs) compared to saline placebo. EpAbs may reduce all‐cause mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; absolute effect 114 per 1000 with placebo versus 68 per 1000 (30 to 156) ; low‐certainty evidence). EpAbs may reduce worsening of clinical status up to day 28 (RR 0.67, 95% CI 0.38 to 1.18; absolute effect 203 per 1000 with placebo versus 136 per 1000 (77 to 240); low‐certainty evidence). It may have some effect on improvement of clinical status on day 28 (RR 1.06, 95% CI 0.96 to 1.17; low‐certainty evidence). We did not identify any studies that reported quality‐of‐life outcomes, so we do not know if EpAbs have any impact on quality of life.

Harms of animal‐derived polyclonal antibodies

EpAbs may have little to no impact on the number of adverse events at any grade up to 28 days (RR 0.99, 95% CI 0.74 to 1.31; low‐certainty evidence). Adverse events at grade 3‐4 severity were not reported. Individuals receiving EpAbs may experience fewer serious adverse events than patients receiving placebo (RR 0.67, 95% CI 0.38 to 1.19; low‐certainty evidence).

We also identified additional results on the benefits and harms of other animal‐derived polyclonal antibody doses, not included in the summary of findings table, but summarised in additional tables.

Authors' conclusions

We included data from five RCTs that evaluated hIVIG compared to standard therapy, with participants with moderate‐to‐severe disease. As the studies evaluated different preparations (from humans or from various animals) and doses, we could not pool them. hIVIG prepared from humans may have little to no impact on mortality, and clinical improvement and worsening. hIVIG may increase grade 3‐4 adverse events. Studies did not evaluate quality of life. RBD‐specific polyclonal F(ab´)₂ fragments of equine antibodies may reduce mortality and serious adverse events, and may reduce clinical worsening. However, the studies were conducted before or during the emergence of several SARS‐CoV‐2 variants of concern and prior to widespread vaccine rollout.

As no studies evaluated hIVIG for participants with asymptomatic infection or mild disease, benefits for these individuals remains uncertain.

This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence.

Plain language summary

Are concentrated antibodies from people who have recovered from COVID‐19 or animals an effective treatment for people with COVID‐19?

Key messages

• We do not know whether hyperimmune immunoglobulin (a preparation made with antibodies from people who have recovered from COVID‐19) reduces deaths or serious unwanted effects in people with moderate to severe COVID‐19. But a similar preparation made by injecting animals with certain antibodies may reduce deaths, and serious unwanted effects and may stop people’s condition getting worse.

• We found no studies that investigated people with COVID‐19 but without symptoms or people with mild COVID‐19, so we do not know how effective human or animal hyperimmune immunoglobulin is for them.

• We found 10 ongoing studies. We will update this review when their results become available.

What is hyperimmune immunoglobulin?

The body produces antibodies as one of its defences against infection. Antibodies, or 'immunoglobulins', are found in blood plasma. They act as a critical part of the immune response.

Plasma from people who have recovered from COVID‐19 contains COVID‐19 antibodies, and can be used to make two preparations. Firstly, it can be used to make convalescent plasma, which is plasma that contains these antibodies. Secondly, it can be used to make hyperimmune immunoglobulin, which is more concentrated, and therefore contains more antibodies. The manufacturing process of hyperimmune immunoglobulin is complex and requires large pools of human plasma.

Similar antibodies can be made from animal sources and used in humans.

Why is hyperimmune immunoglobulin a possible treatment for COVID‐19?

Hyperimmune immunoglobulin products contain high levels of antibodies that target SARS‐CoV‐2, the virus that causes COVID‐19. The products are thought to inactivate the virus particles.

What did we want to find out?

We wanted to know if hyperimmune immunoglobulin is an effective and helpful treatment for people with suspected or confirmed COVID‐19 in any setting (for example, home or hospital).

We were interested in:

• death from any cause up 30 days after treatment, 60 days, or longer if reported;

• improvement or worsening of symptoms;

• quality of life;

• unwanted effects.

What did we do?

We searched for studies that investigated hyperimmune immunoglobulin and usual care compared to usual care only, or in addition to a dummy medicine that did not contain any active ingredients (placebo).

To make a fair comparison, patients in the studies must all have had the same random chance (like the flip of a coin) to receive the hyperimmune immunoglobulin or the other treatment. The studies could include people of any age, sex, or ethnicity.

We compared and summarised the results of the studies. We used a standardised method to rate our confidence in the evidence. The confidence is based on study features such as how it was designed and the number of people in them.

What did we find?

We found five studies with 957 people. Studies took place in Pakistan, India, France, and Argentina, and one study was conducted in multiple countries, including Denmark, Greece, Japan, Nigeria, Spain, the UK and the USA. The studies took place before or during the emergence of several new COVID‐19 variants and prior to widespread vaccine rollout. All the participants in four studies were unvaccinated. In one study, 12 from 579 participants were vaccinated.

We also found 10 ongoing studies.

Main results

All studies compared hyperimmune immunoglobulin from human or animal sources with usual care or placebo. The studies included only hospitalised people with moderate to severe disease. No studies looked at people without COVID‐19 symptoms or mild COVID‐19. No studies reported on quality of life.

We are uncertain whether or not hyperimmune immunoglobulin prepared from humans affects risk of death from any cause up to 28 days after treatment. It may have little to no impact on improvement or worsening of symptoms up to 28 days after treatment. We are uncertain about a possible difference in unwanted or serious unwanted effects. The individual studies decided which events to classify as serious unwanted effects, but this usually means something that may cause hospitalisation or permanent harm.

Hyperimmune immunoglobulin from animals may reduce deaths up to 28 days after treatment, may reduce worsening of symptoms, may improve patients' condition and may reduce serious unwanted events.

What are the limitations of the evidence?

We are uncertain whether hyperimmune immunoglobulin is an effective treatment for people hospitalised with COVID‐19, and whether it affects the number of unwanted or serious unwanted effects because the studies were small and did not all provide evidence on all our points of interest. The studies were conducted predominantly in people from wealthy countries, before the widespread rollout of COVID‐19 vaccines and the emergence of the omicron variant, so the results may not apply to people with omicron variant infection, or people who were vaccinated before falling ill.

There was no evidence for people without symptoms or with mild COVID‐19.

How up to date is this evidence?

Our evidence is up‐to‐date to 31st March 2022.

Summary of findings

Summary of findings 1. Hyperimmune immunoglobulin from human plasma compared to saline placebo.

Patient or population: individuals with moderate or severe COVID‐19 Setting: inpatient Intervention: hyperimmune immunoglobunin (hIVIG) Comparison: placebo (saline)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo alone	Risk with hIVIG
All‐cause mortality at day 28	77 per 1000	61 per 1000 (33 to 111)	RR 0.79 (0.43 to 1.44)	579 (1 RCT)	⨁⨁◯◯ Lowa	hIVIG may have little to no impact on mortality at 28 days.
Worsening of clinical status at day 28 (data only available for clinical status worsened on day 7)	176 per 1000	149 per 1000 (102 to 216)	RR 0.85 (0.58 to 1.23)	579 (1 RCT)	⨁◯◯◯ Very lowb	The evidence is very uncertain about the effect on clinical worsening at day 7.
Improvement of clinical status (number of people discharged from hospital, or reaching category 1 on a 7‐point ordinal scale)	887 per 1000	908 per 1000 (860 to 958)	RR 1.02 (0.97 to 1.08)	579 (1 RCT)	⨁⨁⨁◯ Moderatec	hIVIG probably has little to no impact on the number of people discharged at 28 days.
Quality of life	This study did not report any quality‐of‐life outcomes					We do not know if hIVIG has any impact on quality‐of‐life outcomes.
Adverse events of any grade up to 28 days (data only available for adverse events up to day 1)	440 per 1000	431 per 1000 (356 to 519)	RR 0.98 (0.81 to 1.18)	579 (1 RCT)	⨁⨁◯◯ Lowd	hIVIG may have little to no effect on adverse events.
Adverse events at grades 3 to 4 up to 28 days	14 per 1000	58 per 1000 (19 to 169)	RR 4.09 (1.39 to 12.01)	579 (1 RCT)	⨁⨁⨁◯ Moderatec	hIVIG probably increases adverse events at grades 3 to 4.
Serious adverse events up to day 28 (data available only as a composite of serious adverse events or death up to day 28)	133 per 1000	96 per 1000 (60 to 152)	RR 0.72 (0.45 to 1.14)	572 (1 RCT)	⨁⨁◯◯ Lowa	hIVIG may have little to no effect on serious adverse events
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; hIVIG: hyperimmune immunoglobulin; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^aCertainty of evidence downgraded twice for imprecision, because of wide confidence intervals, and because the result is based on a single, small study
^bCertainty of evidence downgraded twice for imprecision, because of wide confidence intervals, and because the result is based on a single, small study; certainty downgraded once for indirectness, as the result only includes worsening that was ongoing on day 7
^cCertainty of evidence downgraded once for imprecision, because the result is based on a single, small study
^dCertainty of evidence downgraded once for indirectness, because the outcome only includes adverse events that occurred on day 1; and once for imprecision, as the result is based on a single, small study.

Summary of findings 2. RBD‐specific polyclonal F(ab') ₂ fragments of equine antibodies (EpAbs) compared to saline placebo.

Patient or population: individuals with moderate or severe COVID‐19 Setting: inpatient Intervention: RBD‐specific polyclonal F(ab')2 fragments of equine antibodies (EpAbs) Comparison: placebo (saline)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE	Comments
	Risk with placebo alone	Risk with EpAbs
All‐cause mortality (by day 28)	114 per 1000	68 per 1000 (30 to 156)	RR 0.60 (0.26 to 1.37)	241 (1 RCT)	⨁⨁◯◯ Lowa	EpAbs may reduce mortality at 28 days
Worsening of clinical status (expressed as new need for IMV, admission to ICU, or death by day 28)	203 per 1000	136 per 1000 (77 to 240)	RR 0.67 (0.38 to 1.18)	241 (1 RCT)	⨁⨁◯◯ Lowa	EpAbs may reduce clinical worsening
Improvement of clinical status (number of participants discharged from hospital by day 28)	837 per 1000	890 per 1000 (804 to 979)	RR 1.06 (0.96 to 1.17)	241 (1 RCT)	⨁⨁◯◯ Lowa	EpAbs may have some effect on the number of patients discharged at 28 days
Quality of life	This study did not report on quality of life.					We do not know if EpAbs have any impact on quality of life
Adverse events of any grade (by day 28)	444 per 1000	437 per 1000 (329 to 582)	RR 0.99 (0.74 to 1.31)	243 (1 RCT)	⨁⨁◯◯ Lowa	EpAbs may have little to no impact on adverse events at 28 days
Adverse events at grade 3 or 4 (by day 28)	Grade 3 or 4 adverse events were not reported.
Serious adverse events (by day 28)	202 per 1000	134 per 1000 (77 to 240)	RR 0.67 (0.38 to 1.19)	243 (1 RCT)	⨁⨁◯◯ Lowa	EpAbs may reduce serious adverse events
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; EpAbs: equine antibodies; ICU: intensive care unit; IMV: invasive mechanical ventilation; RCT: randomised controlled trial; RBD: receptor‐binding domain; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

^aCertainty of evidence downgraded twice for imprecision, because of wide confidence intervals, and because the result is based on a single small study.

Background

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Description of the condition

This review was previously part of a parent review addressing convalescent plasma and hyperimmune intravenous immunoglobulins (hereafter referred to as hyperimmune immunoglobulins (hIVIG)) for people with COVID‐19 (Piechotta 2021). The review was split to address hIVIG and convalescent plasma separately. Therefore, parts of this background text are shared between the two reviews. We made specific adaptations related to hIVIG in this review.

The clinical syndrome coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2; WHO 2020a), is a major, ongoing challenge for health systems worldwide. On 22 March 2020, the World Health Organization (WHO) declared the current COVID‐19 outbreak to be a pandemic, with the outbreak resulting in more than 479 million confirmed cases, and over 6 million deaths worldwide (WHO 2020b; WHO 2021). Although there are similarities with historic coronavirus epidemics, with severe acute respiratory syndrome (SARS) responsible for 813 deaths and Middle East respiratory syndrome (MERS) responsible for 858 deaths, the scale and impact of the COVID‐19 pandemic present unprecedented challenges to health facilities and healthcare workers all over the world (WHO 2007; WHO 2019).

Approximately 5% of people with COVID‐19, and 20% of those hospitalised, experience severe disease requiring intensive care (Wiersinga 2020). Early reports suggested case fatality rates between 0.7% and 4% (WHO 2020a; WHO 2020c). More recent reports estimate wide‐ranging case fatality rates, as low as 0.0% in Singapore and up to 9.0% in Mexico (Johns Hopkins 2021). However, these numbers should be interpreted with great care due to testing availability, underreporting of cases, and delays between confirmation of a case and time of death (Kim 2020), and factors associated with ethnicity, underlying health conditions, access to health care, and socioeconomic status (Williamson 2020). A more recent publication, using data gathered before the emergence of variants, shows a strong relation between the case fatality rate and the person's age, geographic location, and time, with mortality decreasing between 15 April 2020 and 1 January 2021 (COVID‐19 Forecasting Team 2022). Changes in case fatality rates have also been reported for different variants, with the case fatality rate also declining over time in more recent reports (Grint 2021; Haider 2022).

The median incubation period of SARS‐CoV‐2 was reported to be five days, with 97.5% of cases developing symptoms within 11.5 days of infection (Lauer 2020). Common signs and symptoms can include fever, dry cough, fatigue, and sputum production (WHO 2020a). Post‐viral olfactory dysfunction is reported in 5% to 85% of cases, with loss of both smell and taste reported (Izquierdo‐Dominguez 2020). Other less commonly reported signs and symptoms are shortness of breath, sore throat, headache, myalgia or arthralgia, chills, nausea or vomiting, nasal congestion, diarrhoea, haemoptysis, and conjunctival congestion (WHO 2020a). Of the reported cases, 80% are estimated to have a mild or asymptomatic course of infection, and an estimated 5% of cases are admitted to an intensive care unit (ICU) with acute respiratory distress syndrome (ARDS), septic shock, multiple organ failure, or all three conditions (NCPERE 2020; WHO 2020a). A risk factor for developing infection and progressing to severe disease is old age, with people aged over 80 years at the highest risk of mortality. Other risk factors are cardiovascular disease, obesity, hypertension, diabetes, chronic respiratory disease, cancer, and compromised immune status (Chen 2020a; Huang 2020; Liang 2020; WHO 2020a; Wu 2020a). Early reports have suggested that people who are immune‐compromised may not have an increased risk of being hospitalised with severe COVID‐19 symptoms (D'Antiga 2020). However, evidence has been conflicting, with people with malignancy and recipients of solid organ and allogeneic stem cell transplants reported to have an increased risk of severe COVID‐19 disease (Fung 2020; Sharma 2021).

Description of the intervention

Hyperimmune immunoglobulin (hIVIG) has been used to treat infections when no vaccine or pharmacological intervention is available. hIVIG is made from pools of human or animal donor serum with high neutralising titres (da Costa 2021). These hyperimmune sera contain polyclonal antibodies, which are concentrates of heterologous immunoglobulins, formed by intact IgG (immunoglobulin G, one of the five major classes of immunoglobulins) molecules, or antigen‐binding antibody fragments (da Costa 2021).

hIVIG provides passive immunisation with a level of therapeutic antibody that is more concentrated than convalescent plasma alone. Following an infection, antibodies are produced within B cell lineages exposed to antigens from the virus. These cells then produce immunoglobulins specific to different viral components. Preparations of hIVIG can be extracted from large amounts of pooled convalescent plasma, collected from people previously infected or vaccinated against the virus. Plasma may be obtained by separation of whole blood or by plasmapheresis. Alternatively, viral‐specific antibodies can be injected with an adjuvant into a genetically modified animal, engineered to generate antibodies similar to those made naturally in humans.

Plasma from either source is then fractionated, or extracted and purified to obtain the hIVIG preparation. Measures are undertaken for viral inactivation or removal, which can include pasteurisation, solvent, or detergent, and low pH incubation and filtration. Regulatory oversight stipulates minimum viral reduction steps in the manufacturing process, which vary across countries (Bloch 2021). In 2020, a group of large plasma industry companies formed a plasma alliance to work together to develop hIVIG to be used in the treatment of COVID‐19 (Farrugia 2020).

There is conflicting evidence about the effect of hIVIG for treating severe acute respiratory infections. Studies investigating the effectiveness of hIVIG for influenza have been contradictory, with at least one randomised controlled trial (RCT) showing effectiveness (Hung 2013), while another shows no benefit (Davey 2019). hIVIG has also been used in the treatment of coronaviruses (including SARS‐CoV‐1 and MERS‐CoV; da Costa 2021). In a systematic review, hIVIG has been found to be effective against cytomegalovirus in solid organ recipients (Bonaros 2008).

Apart from use in the treatment of infections, hIVIG is also used to prevent infections in high‐risk individuals, or used as pre‐exposure or post‐exposure prophylaxis; for example, for varicella‐zoster virus (UK HSA 2022).

A potential benefit of hIVIG over monoclonal antibody therapy is the diversity of antibodies obtained from a pool of donors. hIVIG may provide a wider range of specificity than monoclonal antibodies, be more effective in the setting of emerging variants, and provide a wide range of antiviral actions at relatively cheaper costs (Vandeberg 2021).

Benefits of hIVIG in comparison to convalescent plasma include lower volume, a higher concentration of antibody titre, the possibility of administration as an intramuscular injection (instead of intravenous infusion), and more convenience in storage and shipping conditions, allowing for more ease of transport (Bloch 2021). When compared to convalescent plasma, hIVIG also has the advantage of preventing the transfer of potentially harmful coagulation factors that are present in plasma products. The amount and antibody concentration can be more accurately dosed compared to convalescent plasma, and hIVIG can be prepared consistently (Hung 2013).

Not many studies have reported on adverse effects of hIVIG, but the safety profile of standard intravenous immunoglobulin is known, and the adverse events reported here are also likely to occur in hIVIG therapy. These include infusion site pain, swelling and erythema, and immediate systemic reactions such as head and body aches, chills, and fever ​​​​(Stiehm 2013). Other, less common, early adverse reactions to immunoglobulin therapy are pulmonary complications, such as pulmonary embolism, pulmonary oedema, and pleural effusion, with transfusion‐related acute lung injury (TRALI) also reported (Baudel 2020; Stiehm 2013). Anaphylactic and anaphylactoid reactions to immunoglobulin therapy are rare (Brennan 2003; Stiehm 2013). Delayed adverse events of immunoglobulin therapy, which occur within hours to days of initiation of immunoglobulin therapy, are persistent headaches (common), aseptic meningitis, renal failure, thromboembolic events, and haemolytic reactions (Sekul 1994; Stiehm 2013). Transmission of infectious agents ​​has been described after administration of intravenous immunoglobulin, but this risk is considered to be low (Stiehm 2013). Other severe adverse events that occur late after administration are lung disease, enteritis, and dermatological disorders (Stiehm 2013).

A theoretical risk related to virus‐specific antibodies, which are transferred with hIVIG administration, is an antibody‐dependent enhancement (ADE) of infection (Morens 1994). Here, virus‐binding antibodies facilitate the entry and replication of virus particles into monocytes, macrophages, and granulocytic cells, and thereby, increase the risk of more severe disease in the infected host. ADE has not been demonstrated in people who have recovered and become reinfected with COVID‐19, and there have been no reports of ADE in studies on monoclonal antibodies, convalescent plasma, or following COVID‐19 vaccination. However, ADE has been seen with previous coronavirus infections, when the antibodies given targeted a different serotype of the virus (Wan 2020; Wang 2014). The circulation of COVID‐19 variants could increase the risk of ADE when the intervention contains antibodies targeting parts of the virus that are different from the original strain. Therefore, antibody‐dependent enhancement is a potentially harmful consequence of hIVIG therapy for COVID‐19.

Further definitions of the terms used in this description can be found in the glossary of abbreviations and medical terms (Appendix 1).

In summary, the benefits of the intervention should be carefully considered in view of the risks of adverse events.

How the intervention might work

Hyperimmune immunoglobulin (hIVIG) contains pathogen‐specific neutralising antibodies, which can neutralise viral particles; treatment with hIVIG confers passive immunity to recipients. The duration of conferred protection can differ, depending on the timing of administration, ranging from weeks to months after treatment (Casadevall 2020).

It has been postulated that neutralising SARS‐CoV‐2 particles, in the form of early treatment with convalescent plasma, and by extension hIVIG, might increase an individual's capacity to clear the initial infection (Casadevall 2020; Robbins 1995). This could lead to a reduction in mortality and fewer hospitalised people progressing to the ICU, thus helping to lift pressure from global healthcare systems and increasing ICU capacity.

Preliminary evidence has shown that reinfection with SARS‐CoV‐2 is possible, particularly since the emergence of new variants (Pulliam 2022); however, most (but not all) people who recover from COVID‐19 produce sufficient amounts of neutralising antibodies to protect against reinfection (Bao 2020; Wu 2020b). This implies that hIVIG made from convalescent plasma of people who have recovered from SARS‐CoV‐2 infection may be capable of conferring passive immunity. Retrospective studies also observed a potential correlation between the level of antibody titres in convalescent plasma and recovery after treatment (Joyner 2021; Shen 2020). However, it is important to note that research in other coronavirus species has shown that immunity may not be long‐lasting, with two to three years of protection estimated from work with SARS and MERS (Mo 2006; Payne 2016). Studies in SARS‐CoV‐2 indicate that immunity may wane more quickly, over a timeframe of about six months (Steenhuis 2021). Furthermore, there are indications that the severity of infection has an impact on antibody titres, with less severe disease leading to lower neutralising antibody response in people with SARS and COVID‐19 (Ho 2005; Zhao 2020a). It is unclear exactly how often reinfection occurs. The burden of reinfection is likely to be underestimated, while at the same time, a number of case reports of severe reinfection have been published (Iwasaki 2021).

Why it is important to do this review

Although mass vaccination programmes have been underway since late 2020, there is a continued need to treat people with COVID‐19 (WHO 2020b). Even with effective vaccines, not everyone can be effectively vaccinated; for example, people who are temporarily or permanently immune‐compromised, and very young children. Pharmacological treatment options have been investigated in many clinical trials, some of which are still ongoing (WHO 2022). Despite the treatment options now available, people hospitalised with COVID‐19 are still at a high risk of mortality. hIVIG could potentially be used alongside these treatments in ambulatory or hospitalised settings, if it proves to be effective and safe. hIVIG can be prepared and made available when enough potential donors have recovered from the infection, using readily available materials and methods (Bloch 2020). However, its benefits and harms are not well characterised, and there are costs associated with pursuing the use of hIVIG to treat COVID‐19.

While our last systematic review showed that convalescent plasma for the treatment of moderate to severe COVID‐19 does not reduce mortality, and has little to no impact on measures of clinical improvement, we remain very uncertain about the benefit of convalescent plasma in people with asymptomatic or mild disease (Piechotta 2021). SARS‐CoV‐2‐neutralising monoclonal antibodies are prescribed in select patient populations, but their effectiveness against new variants can diminish for these specific therapies (Copin 2021; Kreuzberger 2021). Therefore, it is important to continue to assess the possible effect of hIVIG and other antibody therapies on people with COVID‐19, particularly in the early phase, and their potential role in specific population subgroups.

Several clinical trials investigating the safety and effectiveness of hIVIG were conducted, and their results must be interpreted with care. Thus, we must thoroughly understand the current body of evidence regarding the use of hIVIG for people with COVID‐19; an extensive review of the available literature is required.

Objectives

To assess the benefits and harms of hyperimmune immunoglobulin therapy for the treatment of people with COVID‐19, and to maintain the currency of the evidence using a living systematic review approach.

Methods

Criteria for considering studies for this review

Types of studies

The main description of methods is based on Cochrane Haematology's standard template, and is in line with the parent review of this series that addressed convalescent plasma and hyperimmune immunoglobulins for people with COVID‐19 (Piechotta 2021). We made specific adaptations related to the research question, and we updated the methods slightly in light of the evolving research knowledge.

To assess the benefits and harms of hIVIGs for the treatment of COVID‐19, we included RCTs, as these studies, if performed appropriately, give the best evidence for experimental therapies in highly controlled therapeutic settings. For RCT data, we used the methods recommended by the Cochrane Handbook for Systematic Reviews of Interventions, as specified in the description of the methods (Higgins 2022a). If we had identified non‐standard RCT designs, such as cluster‐randomised trials and cross‐over trials, we had planned to include those, applying the methods recommended in Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022b). We would have considered only the results from the first cycle of cross‐over RCTs.

We included full‐text publications, preprint articles, abstract publications, and results published in trials registries, if sufficient information was available on study design, characteristics of participants, interventions, and outcomes. We did not apply any limitation to the length of follow‐up.

Types of participants

We included participants with a suspected or confirmed diagnosis of COVID‐19, with no age, gender, or ethnicity restrictions.

We included trials that included participants with any disease severity. We performed separate analyses for ambulatory populations with mild disease, and for hospitalised participants with moderate to severe disease, according to the latest WHO clinical progression score (see Table 3; WHO 2020d).

1. World Health Organization clinical progression scale ^a.

Patient state	Descriptor	Score
Uninfected	Uninfected; no viral RNA detected	0
Ambulatory mild disease	Asymptomatic; viral RNA detected	1
	Symptomatic; independent	2
	Symptomatic; assistance needed	3
Hospitalised: moderate disease	Hospitalised; no oxygen therapyb	4
	Hospitalised; oxygen by mask or nasal prongs	5
Hospitalised: severe disease	Hospitalised; oxygen by non‐invasive mechanical ventilation or high‐flow oxygen	6
	Intubation and mechanical ventilation; pO2/FiO2 ≥ 150 or SpO2/FiO2 ≥ 200	7
	Invasive mechanical ventilation; pO2/FiO2 < 150 (SpO2/FiO2 < 200) or vasopressors	8
	Invasive mechanical ventilation; pO2/FiO2 < 150 and vasopressors, dialysis or ECMO	9
Dead	Dead	10
ECMO: extracorporeal membrane oxygenation; FiO2:fraction of inspired oxygen; pO2: partial pressure of oxygen; RNA: ribonucleic acid; SpO2: oxygen saturation; WHO: World Health Organization

^aWorld Health Organization (WHO) clinical progression scale from (WHO 2020d).
^bIf hospitalised for isolation only, record status as for ambulatory patient.

We excluded studies that included populations with other coronavirus diseases (SARS or MERS). We also excluded studies of populations with mixed viral diseases (e.g. influenza), unless the study authors provided subgroup data for people with COVID‐19.

Types of interventions

We included the following interventions.

• hIVIG therapy

• Hyperimmune animal sera containing polyclonal antibodies

These include polyclonal immunoglobulin therapies containing full‐length antibodies or fragment antibodies, and may be sourced from convalescent humans or immunised animals (including bovine, equine, rabbit, chicken, or other animal sources).

We did not include studies on standard immunoglobulin (from non‐convalescent donors) except as comparator, monoclonal antibodies, nanobodies or microbodies.

We did not include studies of hIVIG used in healthy individuals to prevent COVID‐19.

We included the following comparisons for studies with a control arm.

• hIVIG therapy versus control treatment, for example, drug treatments (including but not limited to hydroxychloroquine and remdesivir). Co‐interventions were allowed but had to be comparable between intervention groups.

• hIVIG therapy versus standard care or placebo (i.e. saline solution)

Types of outcome measures

We evaluated core outcomes, as predefined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative for people with COVID‐19 (COMET 2020), and additional outcomes that were prioritised by consumer representatives, referees of previous versions of this review (Piechotta 2021), and the German guideline panel for inpatient therapy of people with COVID‐19.

We defined outcome sets for two populations, according to the WHO clinical progression scale (WHO 2020d):

• people with a confirmed diagnosis of COVID‐19 and moderate to severe disease; and

• people with a confirmed diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease,

Primary outcomes

We included these critical outcomes in the summary of findings tables for the most important comparisons.

Participants with a confirmed diagnosis of COVID‐19 and moderate to severe disease

• All‐cause mortality by day 28 (dichotomous)

• Clinical status, at day 28, day 60, and up to the longest follow‐up, including:

• worsening of clinical status: participants with clinical deterioration (new need for invasive mechanical ventilation (IMV) or death;

• improvement of clinical status: participants discharged from hospital. Participants should be discharged without clinical deterioration.

• Quality of life, including fatigue, functional independence and neurological status, assessed with standardised scales (e.g. WHOQOL‐100, a standardised scale for assessing quality of life) by 7 days, by 28 days, and longest follow‐up available

• Adverse events (any grade, grades 1 to 2, grades 3 to 4), defined as the number of participants with any event, including the potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, transfusion‐associated circulatory overload (TACO), transfusion‐associated dyspnoea (TAD), acute transfusion reactions, headache, thromboembolic events)

• Serious adverse events, defined as the number of participants with any event

Participants with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild disease

We had planned to include these critical outcomes for participants with asymptomatic or mild disease.  However, we did not find any studies for this population.  In future updates of this living systematic review, these outcomes will be presented in summary of findings tables for this population:

• All‐cause mortality by day 28 (dichotomous)

• Admission to hospital or death within 28 days

• Symptom resolution:

  • all initial symptoms resolved (asymptomatic) by day 14, day 28, and up to the longest follow‐up;

  • duration to symptom resolution

• Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) by 7 days, by 28 days, and longest follow‐up available

• Adverse events (any grade, grades 1 to 2, grades 3 to 4), defined as the number of participants with any event, including the potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events)

• Serious adverse events, defined as the number of participants with any event

Secondary outcomes

We did not not include these important outcomes in the summary of findings tables.

Participants with a confirmed diagnosis of COVID‐19 and moderate to severe disease

• All‐cause mortality by day 60 (dichotomous), and at hospital discharge (dichotomous), and mortality (time to event)

• Need for dialysis by 28 days

• Admission to the ICU by day 28

• Duration of hospitalisation

• Viral clearance, assessed with reverse transcription polymerase chain reaction (RT‐PCR) test for SARS‐CoV‐2 at baseline, up to day 3, day 7, and day 14

Participants with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild disease

We had planned to include these important outcomes for participants with asymptomatic or mild disease. However, we did not find any studies for this population. In future updates of this living systematic review, these outcomes will be presented in summary of findings tables for this population:

• All‐cause mortality by day 60 (dichotomous), and at hospital discharge (dichotomous), and mortality (time to event)

• Clinical status by day 28 and up to the longest follow‐up, including worsening of clinical status (moderate to severe COVID‐19 symptoms):

  • need for IMV

  • need for non‐IMV or high‐flow oxygen

  • need for hospitalisation requiring oxygen by mask or nasal prongs

  • need for hospitalisation without oxygen therapy

• Viral clearance, assessed with RT‐PCR for SARS‐CoV‐2 at baseline, up to day 3, day 7, and day 14

Timing of outcome measurement

For time‐to‐event outcomes, such as mortality and discharge from hospital, we included outcome measures that represented the longest follow‐up time available.

We included all other outcome categories for the observational periods that the study publications reported. We included adverse events that occurred during active treatment, and long‐term adverse events. If sufficient data were available, we planned to group the measurement time points of eligible outcomes — for example, adverse events and serious adverse events — into those measured directly after treatment (up to 7 days after treatment), medium‐term outcomes (15 days after treatment), and longer‐term outcomes (more than 30 days after treatment).

Search methods for identification of studies

Electronic searches

We searched electronic databases according to methods suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2022). Studies reported in all languages were eligible, in order to limit language bias. If studies were published in languages other than those our review team could accommodate (English, Dutch, German, French, Italian, Malay, and Spanish), we planned to ask Cochrane Task Exchange to identify people within Cochrane to translate these studies.

As publication bias might influence all subsequent analyses and conclusions, we searched all potentially relevant trials registries in detail to detect ongoing as well as completed, but not yet published studies. If outcome data were not available elsewhere, we planned to extract any outcome data found in the trial registry entry.

We searched the following databases and sources from 1 January 2019 to 31 March 2022; see Appendix 2 for search strategies.

Databases of medical literature

• MEDLINE (via Ovid; 1 January 2019 to 31 March 2022);

• Embase (via Ovid; 1 January 2019 to 31 March 2022);

• Cochrane COVID‐19 Study Register* (inception to 31 March 2022; covid-19.cochrane.org);

• PubMed (for e‐publications ahead of print only; 1 January 2019 to 31 March 2022);

• World Health Organization (WHO) COVID‐19 Global literature on coronavirus disease (inception to 31 March 2022;bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/);

• Epistemonikos, L*OVE List Coronavirus disease (COVID‐19; inception to 31 March 2022; app.iloveevidence.com/loves).

*The Cochrane COVID‐19 Study Register is a specialised register built within the Cochrane Register of Studies (CRS), and is maintained by Cochrane Information Specialists. Complete data sources and search methods for the register are available at: community.cochrane.org/about-covid-19-study-register. The register contains study reports from several sources, including:

• weekly searches of PubMed;

• weekly searches of ClinicalTrials.gov;

• weekly searches of Embase.com;

• weekly searches of the WHO International Clinical Trials Registry Platform (ICTRP);

• monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL).

Living systematic review considerations

We carried out monthly searches for completed and ongoing studies. We checked monthly for newly emerging hyperimmune immunoglobulins, and reviewed search methods and strategies approximately monthly, to ensure they reflected any terminology changes in the topic area, or in the databases. We adapted the strategy where necessary.

Searching other resources

We handsearched the reference lists of all identified studies. We also contacted experts in the field, drug manufacturers, and regulatory agencies in an effort to retrieve information on unpublished studies.

Living systematic review considerations

The signal for updating this review stemmed from monthly monitoring of the published relevant RCTs via the database search, as described under Electronic searches. Once we had decided to update the review, we incorporated the methods mentioned in this section of the protocol into the review update.

Data collection and analysis

Selection of studies

Using Covidence software, two review authors (from amongst SJV, KLC, VP, CK, CI, and NS) independently screened the results of the search strategies for eligibility, by reading the abstracts. We coded the abstracts as either 'retrieve' or 'do not retrieve'. In the case of disagreement, or if it was unclear whether we should retrieve the abstract or not, we obtained the full‐text publication for further discussion. Two review authors assessed the full‐text articles of selected studies. If the two review authors were unable to reach a consensus, we consulted a third review author to reach a final decision.

We documented the study selection process in a flow chart, as recommended in the PRISMA statement, and show the total numbers of retrieved references and the numbers of included and excluded studies (Moher 2009). We listed all studies excluded after full‐text assessment, and the reasons for their exclusion, in the Characteristics of excluded studies table.

Living systematic review considerations

Two review authors screened records derived from weekly searches to identify new studies.

Data extraction and management

Two review authors (from amongst SJV, KLC, VP, CK, and CI) independently assessed eligible studies obtained in the process of study selection (described above) for methodological quality and risk of bias. If the review authors were unable to reach a consensus, we consulted a third review author to reach a final decision.

Two review authors (from amongst SJV, KLC, CK, CI, and VP) extracted data using a customised data extraction form, developed in Microsoft Excel (Microsoft Corporation 2018). Another review author (CI, VP, or NS) verified the accuracy and, where applicable, the plausibility of extractions and assessment. We conducted data extraction according to the guidelines proposed by Cochrane (Li 2022). If the review authors were unable to reach a consensus, we consulted a third review author. We summarised all extracted data in tables or appendices.

We collated multiple reports of one study so that the study, and not the report, was the unit of analysis.

We extracted the following information.

• General information: author, title, source, publication date, country, language, duplicate publications

• Quality assessment: study design, confounding, definition of risk estimates, bias arising from:

  • the randomisation process;

  • deviations from the intended interventions;

  • missing outcome data;

  • measurement of the outcome; and

  • selection of the reported results.

• Study characteristics: trial design, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, treatment cross‐overs, compliance with assigned treatment, length of follow‐up

• Participant characteristics: age, gender, ethnicity, number of participants recruited/allocated/evaluated, disease, severity of disease, additional diagnoses, baseline serostatus, previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation), whether the donors were tested by nasal swabs or whether the plasma was tested

• Interventions: hyperimmune immunoglobulin therapy, concomitant therapy, duration of follow‐up, donors' disease severity, methods of hIVIG preparation, whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels

  • For studies including a control group: comparator (type)

• Outcomes: as specified in Types of outcome measures.

Living systematic review considerations

Two review authors extracted, evaluated, and integrated studies identified through the monthly searches.

Assessment of risk of bias in included studies

We used RoB 2 to analyse the risk of bias in the underlying study results (Sterne 2019). Of interest for this review is the effect of the assignment on the intervention (the intention‐to‐treat (ITT) effect), and we performed all assessments with RoB 2 to this effect. The outcomes that we addressed are those specified for inclusion in the Summary of findings and assessment of the certainty of the evidence section.

Two review authors (from among SJV, KLC, VP, CK, CI, and NS) independently assessed the risk of bias for each study result. In cases of discrepancies between their judgements or inability to reach consensus, we consulted a third review author to reach a final decision. We assessed the following types of bias, as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022c).

• Bias arising from the randomisation process

• Bias due to deviations from the intended interventions

• Bias due to missing outcome data

• Bias in measurement of the outcome

• Bias in selection of the reported result

For cluster‐RCTs, we planned to add a domain to assess bias arising from the timing of identification and recruitment of participants in relation to the timing of randomisation, as recommended in the archived RoB 2 guidance for cluster‐randomised trials (Eldridge 2016), and in Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022b).

To address these types of bias, we used the signalling questions recommended in RoB 2 and made a judgement using the following options.

• Yes: if there is firm evidence that the question is fulfilled in the study (i.e. the study is at low or high risk of bias given the direction of the question)

• Probably yes: a judgement has been made that the question is fulfilled in the study (i.e. the study is at low or high risk of bias given the direction of the question)

• No: if there is firm evidence that the question is unfulfilled in the study (i.e. the study is at low or high risk of bias for the given direction of the question)

• Probably no: a judgement has been made that the question is unfulfilled in the study (i.e. the study is at low or high risk of bias given the direction of the question)

• No information: if the study report does not provide sufficient information to allow any judgement

We used the algorithms proposed by RoB 2 to assign each domain one of these levels of bias:

• low risk of bias;

• some concerns;

• high risk of bias.

Subsequently, we derived a risk of bias rating for each prespecified outcome in each study, in accordance with the following suggestions.

• Low risk of bias: we judged the trial to be at low risk of bias for all domains for this result.

• Some concerns: we judged the trial to raise some concerns in at least one domain for this result, but not to be at high risk of bias for any domain.

• High risk of bias: we judged the trial to be at high risk of bias in at least one domain for the result, or we judged the trial to have some concerns for multiple domains in a way that substantially lowered confidence in the results.

We used the RoB 2 Excel tool to implement RoB 2 (available at riskofbiasinfo.org); we added our judgements to the analysis for each assessed study and outcome, and we stored our detailed RoB 2 assessments as supplementary online material. We used the overall risk of bias judgement, derived from the RoB 2 Excel tool, to inform our GRADE decision (Balshem 2011) on downgrading for risk of bias.

Measures of treatment effect

For continuous outcomes, we recorded the mean, standard deviation, and total number of participants in both the treatment and control groups. For dichotomous outcomes, we recorded the number of events and total number of participants in both the treatment and control groups.

For continuous outcomes using the same scale, we planned to perform analyses using the mean difference (MD) with 95% confidence interval (CI). For continuous outcomes measured with different scales, we planned to perform analyses using the standardised mean difference (SMD). For interpreting SMDs, we planned to re‐express SMDs in the original units of a particular scale with the most clinical relevance and impact.

If available, we extracted and reported hazard ratios (HRs) for time‐to‐event outcomes. If HRs were not available, we made every effort to estimate the HR as accurately as possible using the available data and a purpose‐built method based on the Parmar and Tierney approach (Parmar 1998; Tierney 2007). Had sufficient studies provided HRs, we would have used HRs rather than risk ratios (RRs) or MDs in a meta‐analysis.

For dichotomous outcomes, we reported the pooled RR with the associated 95% CIs (Deeks 2022). If the number of observed events was small (less than 5% of sample per group), and if studies had balanced treatment groups, we reported the Peto odds ratio (OR) with 95% CI (Deeks 2022).

Unit of analysis issues

For studies with multiple treatment groups, we planned to combine arms if they could be regarded as subtypes of the same intervention, as recommended in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022d).

When arms could not be pooled this way, we planned to compare each arm with the common comparator separately. For the pair‐wise meta‐analysis, we planned to split the ‘shared’ group into two or more groups with smaller sample sizes, and include two or more (reasonably independent) comparisons. For this purpose, for dichotomous outcomes, we planned to divide both the number of events and the total number of participants; for continuous outcomes, we planned to divide the total number of participants, but use the original (unchanged) means and standard deviations (SDs).

However, in this update of the review, we were unable to pool dose arms or meta‐analyse studies, so we presented results singly, with the control group results given in full, alongside each intervention result.

Dealing with missing data

When we identified missing data at the study level, we contacted principal investigators to request these data. If, after this, data were still missing, we consulted with content experts to judge whether data were missing at random (e.g. if missing outcomes were balanced across study arms, and reasons for loss to follow‐up were common and reasonable). If we judged data to be missing at random, we performed a complete case analysis and excluded the participants with missing outcome data from the analysis (Guyatt 2017). When we judged data to be not missing at random, and we identified no supporting evidence that the results were not biased by missing outcome data, we did not make any assumptions about the missing outcome data. We had planned to conduct sensitivity analyses to assess the impact of missing data on the overall effect (excluding studies with more than 10% missing outcome data), however, none of the included studies had more than 10% of missing outcome data. In future updates, we will discuss the potential impact of missing data on results.

Assessment of heterogeneity

We assessed heterogeneity of treatment effects between trials using a Chi² test with a significance level at P less than 0.1, and visual examination. We used the I² statistic (Higgins 2003), to quantify possible heterogeneity (I² > 30% to signify moderate heterogeneity, I² > 75% to signify considerable heterogeneity (Deeks 2022)). If heterogeneity was above 80%, we planned to explore potential causes through subgroup analyses. If we found a reason for heterogeneity, we did not perform a meta‐analysis, but we did comment on results from all studies and present these in tables.

Assessment of reporting biases

As mentioned above, we searched trials registries to identify completed studies that had not been published elsewhere, to minimise or determine publication bias. We included studies irrespective of their publication status, as recommended in Chapter 3 of the Cochrane Handbook for systematic reviews of interventions (McKenzie 2022).

We planned to explore potential publication bias by generating a funnel plot, and testing this statistically by conducting a linear regression test for meta‐analyses involving at least 10 studies (Page 2022). We would have considered a P value of less than 0.1 as significant for this test.

Data synthesis

If the clinical and methodological characteristics of individual studies were sufficiently homogeneous, we planned to pool the data in meta‐analysis, including all eligible studies. We planned to perform separate analyses for ambulatory populations with mild disease and for hospitalised participants with moderate to severe disease, according to the latest WHO clinical progression score (WHO 2020d). We planned to perform analyses according to the recommendations in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2022). We would not have conducted meta‐analyses that included different study designs. We planned to conduct separate meta‐analyses for each comparison.

We used Review Manager Web software for analyses (RevMan Web 2022). One review author entered the data into the RevMan Web file, and a second review author checked the data for accuracy.

We planned to use the random‐effects model for all analyses, as we anticipated that true effects would be related in included studies, but would not be the same. For binary outcomes, we planned to base the estimation of the between‐study variance using the Mantel‐Haenszel method. We planned to use the inverse variance method for continuous outcomes, outcomes that include data from cluster‐RCTs, or outcomes where HRs were available. We planned to explore heterogeneity above 80% with subgroup analyses. If we could not find a cause for the heterogeneity, or if study outcomes were too clinically heterogeneous to be combined, we did not perform a meta‐analysis, but commented on the results in narrative analysis, with the results from all studies presented in tables.

Living systematic review considerations

Whenever we identified new evidence (studies, data, or information) that met the review inclusion criteria, we immediately assessed the risk of bias, extracted the data, and incorporated it into the synthesis, as appropriate. We did not adjust the meta‐analyses to account for multiple testing, given that the methods related to frequent updating of meta‐analyses are under development (Simmonds 2017).

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses of the following characteristics for the outcome of mortality.

• Severity of condition, divided into:

  • moderate and severe disease; and

  • participants receiving IMV at baseline or not

• Duration since symptom onset, divided into:

  • up to 7 days; and

  • more than 7 days

• Antibodies in recipients detected at baseline; that is, seropositive or seronegative, divided into:

  • detected in a maximum of 20% of recipients; versus

  • detected in at least 80% of recipients

• Age of participants, divided into applicable age groups, for example:

  • children;

  • 18 to 65 years;

  • 65 years and older

• Pre‐existing conditions (diabetes, respiratory disease, hypertension, immunosuppression)

• SARS‐CoV‐2 variants (e.g. B1.1.7, B.1.351, P.1, and other variants that may occur in the future)

• Concentration of neutralising antibodies in the therapy (i.e. with known concentration of neutralising antibodies, by taking into account batch‐dependent neutralising antibody levels, or with unknown concentration)

We planned to use the tests for interaction to test for differences between subgroup results.

Sensitivity analysis

We planned to perform sensitivity analyses for the following.

• Risk of bias assessment components (studies with a low risk of bias or some concerns versus studies with a high risk of bias)

• Impact of completed, but not published, studies

• Impact of premature termination of studies

• Impact of studies that include individuals with suspected COVID‐19

• Fixed‐effect model meta‐analysis

• Impact of missing outcome data (exclude studies with more than 10% missing data)

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach to assess the certainty of the evidence for the following outcomes. We prepared summary of findings tables for each critical outcome, with the important outcomes summarised in additional tables. We planned to present results separately for moderate to severe disease, and asymptomatic or mild disease. However, in this version of the review, we present summary of findings table for moderate to severe disease only as no studies on asymptomatic or mild disease were identified.  We did not combine results from studies using different preparations and doses of hIVIG, but presented them as separate comparisons. We presented the results for the most important comparisons in the summary of findings tables.

Hyperimmune immunoglobulin from human plasma compared to saline placebo

• All‐cause mortality at day 28 (dichotomous)

• Worsening of clinical status at day 28: participants with clinical deterioration (new need for invasive mechanical ventilation (IMV) or death by day 28;

• Improvement of clinical status: participants discharged from hospital. Participants should be discharged without clinical deterioration.

• Quality of life, including fatigue, functional independence and neurological status, assessed with standardised scales (e.g. WHOQOL‐100, a standardised scale for assessing quality of life) by 7 days, by 28 days, and longest follow‐up available

• Adverse events of any grade up to 28 days, defined as the number of participants with any event, including the potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, transfusion‐associated circulatory overload (TACO), transfusion‐associated dyspnoea (TAD), acute transfusion reactions, headache, thromboembolic events)

• Adverse events at grades 3 to 4 up to 28 days, defined as the number of participants with any event.

• Serious adverse events up to day 28, defined as the number of participants with any event.

RBD‐specific polyclonal F(ab') ₂ fragments of equine antibodies (EpAbs) compared to saline placebo

• All‐cause mortality by day 28 (dichotomous)

• Worsening of clinical status: participants with clinical deterioration (new need for invasive mechanical ventilation (IMV) or death by day 28.

• Improvement of clinical status: participants discharged from hospital by day 28. Participants should be discharged without clinical deterioration.

• Quality of life, including fatigue, functional independence and neurological status, assessed with standardised scales (e.g. WHOQOL‐100, a standardised scale for assessing quality of life) by 7 days, by 28 days, and longest follow‐up available

• Adverse events of any grade up to 28 days defined as the number of participants with any event, including the potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, transfusion‐associated circulatory overload (TACO), transfusion‐associated dyspnoea (TAD), acute transfusion reactions, headache, thromboembolic events)

• Adverse events at grades 3 to 4 up to 28 days.

• Serious adverse events up to day 28, defined as the number of participants with any event.

We followed the current GRADE guidance in its entirety for these assessments, as recommended in Chapter 14 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2022). We used GRADEpro GDT software to create the summary of findings tables (Schünemann 2022). For RCTs, we used the overall risk of bias judgement, derived from the RoB 2 Excel tool, to inform our decision on downgrading for risk of bias. For time‐to‐event outcomes, we calculated absolute effects at specific time points, as recommended in the GRADE guidance 27 (Skoetz 2020). We phrased the findings and certainty of the evidence as suggested in the informative statement guidance (Santesso 2020). For binary data, we reported relative and absolute effects.

Methods for future updates — living systematic review considerations

We will update our searches to monitor newly published results of RCTs on hIVIGs on monthly basis. Two review authors will screen, extract, evaluate, and integrate information following the guidance for Cochrane living systematic reviews (Brooker 2019).

We will manually check platform trials that have previously been identified and listed as Characteristics of studies awaiting classification for additional treatment arms.

We will wait until the accumulating evidence changes one or more of the following components of the review before republishing the review.

• The findings of one or more of the critical outcomes

• The credibility (e.g. GRADE rating) of one or more of the critical outcomes

• New settings, populations, interventions, comparisons, or outcomes studied

Review methods

We will check the review scope and methods approximately monthly, or more frequently if appropriate, in light of potential changes in COVID‐19 research (for example, when additional comparisons, interventions, subgroups or outcomes, or new review methods, become available).

The conditions under which we will no longer maintain the review as a living systematic review

We will regularly review the scope of the review to decide whether to continue or stop updating the review. Decisions to stop may be based on the premise that the conclusions for our main outcomes and populations of interest are unlikely to change with future studies included in the review, no new evidence is expected, or the review question is no longer a priority for policy and practice.

Results

Description of studies

Results of the search

This review used the same search strategies for which results were previously described in the parent review (Piechotta 2021). For this review, we identified 7906 new records, in addition to the 22,570 potentially relevant records from the most recent version of the parent review (altogether 30,476 references). After removing duplicates, we screened 7906 new records for this update (altogether 21,078 records) based on their titles and abstracts, and we excluded 20,253 records that did not meet the prespecified inclusion criteria. We evaluated the remaining 825 records and screened the full texts, or if these were not available, abstract publications, or trials registry entries. See Figure 1 for the study flow diagram (Moher 2009).

1.

PRISMA flow diagram

We identified 15 potentially eligible studies within 19 citations: five completed studies from seven records (Ali 2021; Gaborit 2021; ITAC 2022; Lopardo 2021; Parikh 2021), and 10 ongoing studies (see Ongoing studies). See PRISMA flow diagram (Figure 1; Moher 2009).

Included studies

Design and sample size

We included five RCTs that reported on 947 participants. Of these, 688 received hIVIG prepared from humans (Ali 2021; ITAC 2022; Parikh 2021), 18 received heterologous swine glyco‐humanised polyclonal antibody (Gaborit 2021), and 241 received equine‐derived processed and purified F(ab’)₂ fragments (Lopardo 2021). We presented results from animal‐derived and human derived hIVIG preparations separately and we did not combine different doses of hIVIG.  We selected the most important comparisons to present in summary of findings tables. Please refer to Characteristics of included studies for more detailed information.

Setting

The included studies varied in their settings.

One study was conducted in multiple countries, including Denmark, Greece, Japan, Nigeria, Spain, the UK, and the USA (ITAC 2022). The remaining four studies took place in one country each: Ali 2021was conducted in Pakistan (Ali 2021), Gaborit 2021 in France, Lopardo 2021 in Argentina, and Parikh 2021 in India.

One study was a single‐centre study (Ali 2021), and four were multi‐centre studies, with a minimum of four centres for Gaborit 2021, and a maximum of 63 centres for ITAC 2022.

All the RCTs were performed in inpatient settings.

Participants

One RCT included participants with severe disease (Ali 2021), and four RCTs included participants with either moderate or severe disease (Gaborit 2021; ITAC 2022; Lopardo 2021; Parikh 2021), according to the latest WHO clinical progression score (WHO 2020d).

Interventions

All included RCTs evaluated hIVIGs compared to a control arm; three studies compared hIVIG to placebo (Gaborit 2021; ITAC 2022; Lopardo 2021), and two studies compared hIVIG to standard care (Ali 2021; Parikh 2021). All the included studies administered different doses of hIVIG, and all had different methods of preparation. Three studies used human‐donor, plasma‐derived hIVIG (Ali 2021; ITAC 2022; Parikh 2021), and two studies used animal‐derived polyclonal antibodies (Gaborit 2021; Lopardo 2021).

Source of hIVIG

Ali 2021 combined plasma with variable titres to produce a pooled plasma product with a maximum anti‐SARS‐CoV‐2 antibody level of 104 ± 30 cut‐off index (COI), measured with an electrochemiluminescence immunoassay analyser (ECLIA). Donors in this study were individuals who had recovered from COVID‐19 and had been asymptomatic for 15 days or more. No further details of the donors' characteristics or eligibility criteria were reported. Four doses of hIVIG were administered (0.15 g/kg, 0.2 g/kg, 0.25 g/kg, and 0.3 g/kg) in addition to standard care.

Gaborit 2021 used a heterologous swine glyco‐humanised polyclonal antibody (GH‐pAb), which was developed to target multiple epitopes on the receptor‐binding domain of the spike protein of the SARS‐CoV‐2 original Wuhan strain, using serum from multiple immunised donor animals. This publication reports on findings from the phase IIa pharmacokinetics and safety component of the study. Doses administered were 0.5 mg/kg at days 1 and 5, 2 mg/kg at days 1 and 5, and 2 mg/kg at day 1.

ITAC 2022 used four hIVIG products (Emergent BioSolutions, Grifols Therapeutics, Inc., Takeda Pharmaceuticals, and CSL Behring), prepared from plasma collected from either fractionated whole blood, or by plasmapheresis from healthy adult volunteers in North America and Europe, who had recovered from COVID‐19. Donors and plasma units were selected based on neutralisation antibody titres against SARS‐CoV‐2. Each lot of hIVIG underwent central testing, and was required to meet a prespecified range of neutralising activity, measured by a sero‐neutralisation validated assay, calibrated against the WHO International standard. The median Texcell potency levels was reported to be 1220 IU/mL. The hIVIG product was administered at a dose of 0.4 g/kg bodyweight, capped at 40 g.

Lopardo 2021 used equine‐derived processed and purified F(ab’)₂ fragments. This was prepared from horses immunised with the receptor‐binding domain (RBD) domain of the viral spike protein. This intervention was administered in two doses of 0.04 g/kg: at baseline and at 48 hours.

Parikh 2021 used an hIVIG product that was manufactured by Intas Pharmaceuticals Ltd., India, using plasma from people who had recovered from COVID‐19. Neutralising antibody titres observed in the serum microneutralisation assay for final purified samples were > 1:2560 to < 1:5120, and > 1:640, using the plaque reduction neutralisation test (PRNT90). hIVIG was administered as a 30 mL infusion on day 1 and day 2.

Outcomes

We evaluated the benefits and harms of treatment from five RCTs (Ali 2021; Gaborit 2021; ITAC 2022; Lopardo 2021; Parikh 2021).

Benefits

We prioritised different outcomes relating to benefits of treatment, based on the setting and the disease severity in participants of the included RCTs (see Types of outcome measures).

Amongst the RCTs that included individuals with moderate to severe disease, four studies reported 28‐day mortality (Ali 2021; ITAC 2022; Lopardo 2021; Parikh 2021), and one study reported 60‐day mortality (Gaborit 2021). Two studies reported time to mortality (ITAC 2022; Lopardo 2021).

One RCT assessed clinical worsening as a worsening clinical status on day 7 (ITAC 2022). One RCT assessed clinical worsening as a new need for IMV, or as a composite outcome of admission to the ICU, need for IMV, or death by day 28 (Lopardo 2021).

Two RCTs assessed clinical improvement as the number of participants discharged from hospital on day 28 (Ali 2021; Lopardo 2021). One RCT assessed clinical improvement as the number of participants discharged or reaching category 1 on the WHO scale on day 28 (ITAC 2022). One RCT assessed clinical improvement as the number of participants discharged from hospital on day 60 (Gaborit 2021).

Two RCTs reported on admission to ICU on day 28 (Gaborit 2021; Lopardo 2021).

One RCT reported viral clearance at days 3, 7, and 15 (Parikh 2021).

None of the included RCTs reported on quality of life or the need for dialysis.

We did not identify any completed studies evaluating individuals with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild disease.

Harms

Four RCTs reported harms as any grade of an adverse event (Ali 2021; Gaborit 2021; ITAC 2022; Lopardo 2021); two RCTs reported grade 3 or 4 adverse events (Gaborit 2021; ITAC 2022); three RCTs reported serious adverse events (defined by study authors; ITAC 2022; Lopardo 2021; Parikh 2021); and one RCT reported grade 1 or 2 adverse events (Gaborit 2021).

Ongoing studies

We identified 10 ongoing studies investigating the effect of hyperimmune immunoglobulin (see Table 4). One was scheduled to complete in 2021 but according to the trial registry, it is still recruiting participants. The number of intended participants was not reported. Four are due to be completed in 2022, reporting on between 30 and 722 participants. Two are due to complete in 2023, reporting on 180 and 820 participants respectively. Three studies do not report an intended completion date, but report an intended number of participants between 72 and 160.

2. Summary of ongoing hyperimmune immunoglobulin studies: design and planned completion date.

Study ID	Title	Design	Planned number of participants	Planned completion date	Results available
CTRI/2020/11/028779 (pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/en/ictrp-CTRI202011028779)	Effect of SARS‐CoV‐2 equine antiserum immunoglobulin (purified F(ab)2 fragment) in hospitalised COVID‐19 patients with moderate disease	RCT	72	NR	No
CTRI/2021/02/031566 (pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/en/ictrp-CTRI202106034359) NCT04834908 (clinicaltrials.gov/ct2/show/NCT04834908)	Evaluation of equine antibody treatment in patient with COVID 19 infection	RCT	160	NR	No
IRCT20200508047346N1 (www.irct.ir/trial/47953)	Evaluation of the efficacy and safety of rabbit polyclonal antibody (CoviGlobulin) in patients with coronavirus COVID‐19 virus moderate to severe − more options	RCT	124	NR	No
Gaborit 2021 NCT04453384 (clinicaltrials.gov/show/NCT04453384) EUCTR2020‐002574‐27 (clinicaltrialsregister.eu/ctr-search/trial/2020-002574-27/FR)	A randomized, double‐blind, placebo‐controlled phase 2a and 2b study to evaluate the safety and efficacy of XAV‐19 in patients with COVID‐19 induced moderate pneumonia	RCT	414	31 December 2021	No
NCT04514302 (clinicaltrials.gov/show/NCT04514302)	Safety and efficacy of anti‐SARS‐CoV‐2 equine antibody fragments (INOSARS) for hospitalized patients with COVID‐19	RCT	30	20 February 2022	No
NCT04891172 (clinicaltrials.gov/ct2/show/NCT04891172)	Anti COVID 19 hyperimmune intravenous immunoglobulin (C‐IVIG) therapy for severe COVID‐19 patients	RCT	310	2 August 2022	No
NCT04910269 (clinicaltrials.gov/ct2/show/NCT04910269)	Outpatient treatment with anti‐coronavirus immunoglobulin (OTAC)	RCT	820	1 August 2023	No
NCT04928430 (clinicaltrials.gov/ct2/show/NCT04928430)	An international, placebo‐controlled, double‐blind, randomized clinical trial to evaluate the efficacy and safety of 150 mg XAV‐19 infusion, in patients with moderate to severe COVID‐19: the EUROXAV study	RCT	722	1 April 2022	No
NCT05173441 (clinicaltrials.gov/ct2/show/NCT05173441)	Human COVID‐19 immunoglobulin (COVID‐HIG) therapy for COVID‐19 patients	RCT	180	30 November 2023	No
RPCEC000000379 (rpcec.sld.cu/en/trials/RPCEC00000379-En)	Exploratory, controlled, randomized, open and monocentric clinical trial to evaluate the safety and explore the antiviral effect of anti‐SARSCoV‐2 gamma globulin in Sars‐Cov‐2 adult serious with COVID‐19	RCT	NR	31 January 2022	No
NCT04838821 (clinicaltrials.gov/ct2/show/NCT04838821)	Efficacy and safety of three different doses of an anti SARS‐CoV‐2 hyperimmune equine serum in COVID‐19 patients (SECR‐02)	RCT	156	29 September 2021	No
NR: not reported; RCT: randomised controlled trial

Please refer to Characteristics of ongoing studies and Table 4 for more detailed information.

Studies awaiting assessment

Three studies are completed according to the trial registry, but no results have yet been published, therefore, we decided to record them under Characteristics of studies awaiting classification (NCT04366245; NCT04610502; Gaborit 2020). Three studies are active but not yet recruiting according to the trial registry, and therefore, we included them here (NCT04395170; NCT04469179; NCT04573855). One study describes its intervention as hyperimmune plasma obtained from convalescent antibodies of COVID‐19 infection, and we are unclear if this intervention will meet our inclusion criteria, therefore, we will keep it here until results are published (NCT04366245).

Excluded studies

We excluded 33 studies after full‐text assessment. Of these, 21 used an ineligible intervention, five were reviews, one was a report, and four had an ineligible study design, that is, they were not randomised controlled trials. Two studies included an ineligible population, that is, healthy people who had not tested positive for COVID‐19. Of the 21 studies with an ineligible intervention, one was a convalescent plasma study, and 20 were using normal intravenous immunoglobulin (IVIG).

Risk of bias in included studies

We assessed methodological quality and risk of bias for the five RCTs (Ali 2021; Gaborit 2021; ITAC 2022; Lopardo 2021; Parikh 2021), using RoB 2, recommended in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022c).

Please refer to the risk of bias table at the end of the Characteristics of included studies table for more details. The completed RoB 2 tool with responses to all assessed signalling questions is available at https://doi.org/10.5281/zenodo.7402252.

Overall judgements for studies including participants with a confirmed diagnosis of COVID‐19 and moderate to severe disease

All‐cause mortality

Amongst the studies reporting a mortality outcome, we rated the overall risk of bias to be of some concern in Parikh 2021, and low in Ali 2021, Gaborit 2021, ITAC 2022, and Lopardo 2021. We assessed this outcome on a study level at day 28, day 60, time‐to‐event, and at hospital discharge.

For Parikh 2021, the available preprint gave no clear information on allocation concealment, which led to a risk of bias of some concerns (see risk of bias table for Analysis 10.1).

10.1. Analysis.

Comparison 10: hIVIG 350 AU/mL versus standard care, Outcome 1: All‐cause mortality at 28 days

Clinical worsening

Amongst the studies reporting at least one of the outcomes addressing clinical worsening, we rated the overall risk of bias to be low for ITAC 2022 and Lopardo 2021. We assessed clinical status on a study level, in accordance with the WHO Clinical Progression Scale (WHO 2020d).

Clinical improvement

Amongst the studies reporting at least one of the outcomes addressing clinical improvement, we rated the overall risk of bias to be low for Ali 2021, Gaborit 2021, ITAC 2022, and Lopardo 2021. We assessed clinical status on a study level, in accordance with the WHO Clinical Progression Scale (WHO 2020d).

Quality of life

We could not assess the risk of bias for quality of life, as none of the studies reported this outcome.

Adverse events

Amongst the studies reporting at least one of the safety outcomes, we rated the overall risk of bias to be of some concern in Parikh 2021, and low in Ali 2021, Gaborit 2021, ITAC 2022, and Lopardo 2021. We assessed safety outcomes on a study level and included any adverse events, grades 1 to 2 adverse events, grades 3 to 4 adverse events, and serious adverse events.

For Parikh 2021, the available preprint gave no clear information on allocation concealment, which led to a risk of bias judgement of some concerns (see risk of bias table for Analysis 10.2).

10.2. Analysis.

Comparison 10: hIVIG 350 AU/mL versus standard care, Outcome 2: Serious adverse events

Need for dialysis

We could not assess the risk of bias for the need for dialysis, as none of the studies reported this outcome.

Admission to ICU

Amongst the studies reporting admission to ICU, we rated the overall risk of bias to be of some concern in Gaborit 2021, and low for Lopardo 2021.

In Gaborit 2021, the produced result analysed was not in accordance with the prespecified analysis plan, as the time point of measuring admission to ICU was not specified in the publication (see risk of bias table for Analysis 7.6; Analysis 8.6; Analysis 9.6).

7.6. Analysis.

Comparison 7: Swine glyco‐humanised polyclonal antibody 0.5 mg/kg days 1 to 5 versus placebo, Outcome 6: Admission to ICU on day 28

8.6. Analysis.

Comparison 8: Swine glyco‐humanised polyclonal antibody 2 mg/kg days 1 to 5 versus placebo, Outcome 6: Admission to ICU on day 28

9.6. Analysis.

Comparison 9: Swine glyco‐humanised polyclonal antibody 2 mg/kg day 1 only versus placebo, Outcome 6: Admission to ICU on day 28

Duration of hospitalisation

Amongst the studies reporting duration of hospital stay, we rated the the overall risk of bias to be low for Ali 2021, and low for ITAC 2022.

Viral clearance

Amongst the studies reporting at least one of the viral clearance outcomes, we rated the overall risk of bias to be of some concern for Parikh 2021.

For Parikh 2021, the available preprint gave no clear information on allocation concealment, and viral clearance was not reported as an outcome in the trial registration, which led to a risk of bias of some concern for randomisation process and selection of the reported result (see risk of bias table for Analysis 10.3; Analysis 10.4; Analysis 10.5).

10.3. Analysis.

Comparison 10: hIVIG 350 AU/mL versus standard care, Outcome 3: Negative RT‐PCR test on day 3

10.4. Analysis.

Comparison 10: hIVIG 350 AU/mL versus standard care, Outcome 4: Negative RT‐PCR test on day 7

10.5. Analysis.

Comparison 10: hIVIG 350 AU/mL versus standard care, Outcome 5: Negative RT‐PCR on day 15

Overall judgements for studies including participants with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild disease

We did not identify any completed studies evaluating participants with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild disease.

Effects of interventions

See: Table 1; Table 2

Participants with a confirmed diagnosis of COVID‐19 and moderate to severe disease

All the studies we identified were on people hospitalised with moderate to severe disease. We identified the two most important comparisons, and presented them in summary of findings tables: Table 1 describes hIVIG versus saline placebo and Table 2 describes equine antibodies versus saline placebo. We identified three smaller‐ studies, which we analysed in separate comparisons; the results are presented in Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12; Table 13 and Table 14)

3. hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline) − outcomes not included in Summary of findings table 1.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: hIVIG 0.4 mg/kg Comparison: placebo
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with hIVIG
28‐day mortality	See Table 1
60‐day mortality	There were no data for 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	77 per 1000	61 per 1000 (33 to 98)	HR 0.80 (0.42‐1.51)	579 (1 RCT)	⨁⨁◯◯ lowa	hIVIG may have little to no impact on mortality
Clinical worsening	See Table 1
Clinical improvement (number of participants discharged from hospital by day 60)	See Table 1
Time to hospital discharge	Study authors report a recovery rate ratio (RRR) of participants discharged from hospital or reaching ordinal scale category 1 (return to normal activities; RRR: 1.07 (95% CI 0.92 to 1.26))
Quality of life	There were no data for quality of life
Any adverse events	See Table 1
Grades 1 to 2 adverse events	There were no data for grades 1 to 2 adverse events
Grades 3 to 4 adverse events (by day 28)	See Table 1
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	There were no data for admission to ICU
Viral clearance	There were no data for viral clearance
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; HR: hazard ratio; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^a Certainty of evidence downgraded twice for imprecision, owing to very wide confidence intervals, and the result being based on a single study.

4. Equine polyclonal antibodies (EpAbs) versus placebo − outcomes not included in Summary of findings table 2.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: equine antibodies (EpAbs) Comparison: placebo
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with hIVIG
28‐day mortality	See Table 2
60‐day mortality	There were no data for 60‐day mortality
90 day mortality	There were no data for 90‐day mortality
Mortality (time to event)	114 per 1000	68 per 1000 (30 to 156)	HR 0.58 (0.24 to 1.37)	241 (1 RCT)	⨁⨁◯◯a Low	EpAbs may have little to no impact on mortality at 28 days
Clinical worsening	See Table 2
Clinical improvement (number of people discharged from hospital by day 60)	See Table 2
Time to hospital discharge	Time to discharge could not be analysed because death was a competing event.
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	See Table 2
Grades 1 to 2 adverse events	There were no data for grades 1 to 2 adverse events
Grades 3 to 4 adverse events (by day 28)	See Table 2
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	187 per 1000	127 per 1000 (69 to 232)	RR 0.68 (0.37 to 1.24)	241 (1 RCT)	⨁⨁◯◯a Low	People receiving EpAbs may be less likely to be admitted to ICU by day 28
Viral clearance	Viral clearance was reported in a figure, but we were unable to extract data in a format that we could analyse
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; HR: hazard ratio; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aWe downgraded the certainty of evidence twice for imprecision, because of very wide confidence intervals, and because the result is based on a single study.

5. hIVIG 0.15 g/kg versus standard care − all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: hIVIG 0.15 g/kg Comparison: standard care
Outcomes	Number with event (n/N)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard care	Risk with hIVIG
28‐day mortality	6/10	2/10	RR 0.33 (0.09 to 1.27)	20 (1 study)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on mortality at 28 days
60‐day mortality	There were no data for 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	There were no data for mortality
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event.
Clinical improvement (number of people discharged from hospital by day 28)	4/10	8/10	RR 2.00 (0.88 to 4.54)	20 (1 study)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on clinical improvement
Time to hospital discharge	Time to discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	7/10	7/10	RR 1.00 (0.56 to 1.78)	20 (1 study)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on adverse events
Grades 3 to 4 adverse events (by day 28 )	There were no data for grades 3 to 4 adverse events
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	There were no data for admission to ICU
Time to hospital discharge	Time to discharge could not be analysed because mortality was a competing event
Viral clearance	Data were presented as time to viral clearance, but we could not analyse this outcome as death was a competing event
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small.

6. hIVIG 0.2 g/kg versus standard care − all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: hIVIG 0.2 g/kg Comparison: standard care
Outcomes	Number with event (n/N)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard care	Risk with hIVIG
28‐day mortality	6/10	3/10	RR 0.50 (0.17 to 1.46)	20 (1 RCT)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on mortality at 28 days
60‐day mortality	There were no data for 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	There were no data formortality
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event
Clinical improvement (number of people discharged by day 28)	4/10	7/10	RR 1.75 (0.74 to 4.14)	20 (1 RCT)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on clinical improvement
Time to hospital discharge	Time to discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	7/10	8/10	RR 1.14 (0.69 to 1.90)	20 (1 RCT)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on adverse events
Grades 3 to 4 adverse events (by day 28)	There were no data for grades 3 to 4 adverse events
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	There were no data for admission to ICU
Time to hospital discharge	Time to discharge could not be analysed because mortality was a competing event
Viral clearance	Data were presented as time to viral clearance, but this outcome could not be analysed as death was a competing event
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small.

7. hIVIG 0.25 g/kg versus standard care − all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: 0.25 mg/kg hIVIG Comparison: standard care
Outcomes	Number with event (n/N)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard care	Risk with hIVIG
28‐day mortality	6/10	1/10	RR 0.17 (0.02 to 1.14)	20 (1 RCT)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on mortality at 28 days
60‐day mortality	There were no data for 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	There were no data for mortality
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event
Clinical improvement (number of people discharged from hospital by day 28)	4/10	9/10	RR 2.25 (1.02 to 4.94)	20 (1 RCT)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on clinical improvement at 28 days
Time to hospital discharge	Time to discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life outcomes
Any adverse events (by day 28)	7/10	5/10	RR 0.71 (0.34 to 1.50)	20 (1 RCT)	⨁◯◯◯ Very lowa	hIVIG may have little to no impact on adverse events
Grades 1 to 2 adverse events (by day 28)	There were no data for grades 1 to 2 adverse events
Grades 3 to 4 adverse events (by day 28)	There were no data for grades 3 to 4 adverse events
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	There were no data for admission to ICU
Time to hospital discharge	Time to hospital discharge could not be analysed because mortality was a competing event
Viral clearance	Data were presented as time to viral clearance, but this outcome could not be analysed as death was a competing event
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small.

8. hIVIG 0.3 g/kg versus standard care − all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: 0.3 mg/kg hIVIG Comparison: standard care
Outcomes	Number with event (n/N)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard care	Risk with hIVIG
28‐day mortality	6/10	4/10	RR 0.67 (0.27 to 1.66)	20 (1 RCT)	⨁◯◯◯ very lowa	hIVIG may have little to no impact on mortality at 28 days
60‐day mortality	There were no data for 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	There were no data for mortality
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event
Clinical improvement (number of people discharged, or reaching category 1 on a 7‐point ordinal scale)	4/10	6/10	RR 1.50 (0.60 to 3.74)	20 (1 RCT)	⨁◯◯◯ very lowa	hIVIG may have little to no impact on clinical improvement
Time to hospital discharge	Time to discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	7/10	8/10	RR 1.14 (0.69 to 1.90)	20 (1 RCT)	⨁◯◯◯ very lowa	hIVIG may have little to no impact on any adverse events of any grade
Grades 1 to 2 adverse events (by day 28)	There were no data for grades 1 to 2 adverse events
Grades 3 to 4 adverse events (by day 28)	There were no data for grades 3 to 4 adverse events
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	There were no data for admission to ICU
Time to hospital discharge	Time to discharge could not be analysed because mortality was a competing event
Viral clearance	Data were presented as time to viral clearance, but this outcome could not be analysed as death was a competing event
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small.

9. hIVIG 350 AU/mL versus standard care – all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: hIVIG 350 AU/mL Comparison: standard care
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard care	Risk with hIVIG
28‐day mortality	34 per 1000	33 per 1000 (2 to 508)	RR 0.97 (0.06 to 14.74)	59 (1 RCT)	⨁◯◯◯ Very lowa	We do not know if hIVIG has any impact on 28‐day mortality
60‐day mortality	There were no data for 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	There were no data for mortality: time to event
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event
Clinical improvement (number of people discharged from hospital by day 60)	Clinical improvement data could not be analysed because clinical status was reported as mean change on a clinical ordinal score: the number of participants showing improvement was not reported
Time to hospital discharge	Time to hospital discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	Only serious adverse events were reported
Grades 1 to 2 adverse events (by day 28)	Only serious adverse events were reported
Grades 3 to 4 adverse events (by day 28)	Only serious adverse events were reported
Serious adverse events	34 per 1000	33 per 1000 (2 to 508)	RR 0.97 (0.06 to 14.74)	59 (1 RCT)	⨁◯◯◯ Very lowa	We do not know if hIVIG has any impact on serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	There were no data for admission to ICU on day 28
Viral clearance (number of participants with negative RT‐PCR test on day 3)	379 per 1000	467 per 1000 (254 to 853)	RR 1.23 (0.67 to 2.25)	59 (1 RCT)	⨁◯◯◯ Very lowa	We do not know if hIVIG has any impact on viral clearance
Viral clearance (number of participants with negative RT‐PCR test on day 7)	690 per 1000	667 per 1000 (469 to 945)	RR 0.97 (0.68 to 1.37)	59 (1 RCT)	⨁◯◯◯ Very lowa	We do not know if hIVIG has any impact on viral clearance
Viral clearance (number of participants with negative RT‐PCR test on day 15)	828 per 1000	767 per 1000 (596 to 994)	RR 0.93 (0.72 to 1.20)	59 (1 RCT)	⨁⨁◯◯ Lowb	We are uncertain if hIVIG has any impact on viral clearance
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio; RT‐PCR: reverse transcription polymerase chain reaction

^aWe downgraded the result once for risk of bias in the domains of randomisation and allocation to intervention; and twice for imprecision because of very wide confidence intervals.
^bWe downgraded the result once for risk of bias in the domains of randomisation and allocation to intervention; and once for imprecision because of wide confidence intervals.

10. Swine glyco‐humanised polyclonal antibody 0.5 mg/kg on days 1 to 5 versus placebo − all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: hIVIG 0.5 mg/kg days 1 to 5 (swine glyco‐humanised polyclonal antibody) Comparison: placebo
Outcomes	Number with event (n/N)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with hIVIG
28‐day mortalitya	0/5	0/6	Not estimable	11 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on 28‐day mortality
60‐day mortality	0/5	1/6	RR 2.57 (0.13 to 52.12)	11 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	Hazard ratio was not available for this outcome. One participant died on day 58 in the hIVIG group; none died in the control arm.
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event
Clinical improvement (number of people discharged on day 60)	5/5	5/6	RR 0.86 (0.54 to 1.35)	11 (1 RCT)	⨁◯◯◯ Very lowc	We do not know if swine glyco‐humanised polyclonal antibody has any impact on clinical improvement
Time to hospital discharge	Time to discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	5/5	7/7	RR 1.00 (0.74 to 1.35)	12 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on any adverse events
Grades 1 to 2 adverse events (by day 28)	5/5	7/7	RR 1.00 (0.74 to 1.35)	12 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on grades 1 to 2 adverse events
Grades 3 to 4 adverse events (by day 28)	3/5	2/7	RR 0.48 (0.12 to 1.88)	12 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on grades 3 to 4 adverse events
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	0/5	0/6	Not estimable	11 (1 RCT)	⨁◯◯◯ Very lowd	We do not know if swine glyco‐humanised polyclonal antibody has any impact on admission to ICU
Viral clearance	There were no data for viral clearance
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aResults for 28‐day mortality were inferred, because only one participant in the study died, at day 58.
^bThe certainty of evidence was downgraded three times for imprecision because the number of participants was very small.
^cThe certainty of evidence was downgraded three times for imprecision because the number of participants was very small; and was downgraded once for indirectness because the result was only available at the 60‐day time point.
^dThe certainty of evidence was downgraded three times for imprecision because the number of participants was very small; and was downgraded once for risk of bias in the selection of the reported result domain.

11. Swine glyco‐humanised polyclonal antibody 2 mg/kg days on 1 to 5 versus placebo – all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: hIVIG 2 mg/kg days 1 to 5 (swine glyco‐humanised polyclonal antibody) Comparison: placebo
Outcomes	Number with event (n/N)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with hIVIG
28‐day mortalitya	0/5	0/1	Not estimable	6 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on 28‐day mortality
60‐day mortality	0/5	0/1	Not estimable	6 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	Hazard ratio was not available for this outcome. No participants died in either arm of this comparison.
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event
Clinical improvement (number of people discharged from hospital by day 60)	5/5	1/1	RR 1.00 (0.43 to 2.31)	6 (1 RCT)	⨁◯◯◯ Very lowc	We do not know if swine glyco‐humanised polyclonal antibody has any impact on clinical improvement
Time to hospital discharge	Time to hospital discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	5/5	1/1	RR 1.00 (0.43 to 2.31)	6 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on any adverse events
Grades 1 to 2 adverse events (by day 28)	5/5	1/1	RR 1.00 (0.43 to 2.31)	6 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on grades 1 to 2 adverse events
Grades 3 to 4 adverse events (by day 28)	3/5	0/1	RR 0.43 (0.04 to 5.19)	6 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on grades 3 to 4 adverse events
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	0/5	0/1	RR 1.00 (0.06 to 15.99)	6 (1 RCT)	⨁◯◯◯ Very lowd	We do not know if swine glyco‐humanised polyclonal antibody has any impact on admission to ICU
Viral clearance	There were no data for viral clearance
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aResults for 28‐day mortality were inferred, because only one participant in the study died, at day 58.
^bWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small.
^cWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small; and downgraded once for indirectness because the result was only available at the 60‐day time point.
^dWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small; and once for risk of bias in the selection of the reported result domain.

12. Swine glyco‐humanised polyclonal antibody 2 mg/kg on day 1 only versus placebo – all outcomes.

Patient or population: people with moderate or severe COVID‐19 Setting: inpatient Intervention: hIVIG 2 mg/kg day 1 only (swine glyco‐humanised polyclonal antibody) Comparison: placebo
Outcomes	Number with event (n/N)		Relative effect (95% CI)	Number of particpants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with hIVIG
28‐day mortalitya	0/5	0/5	Not estimable	10 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on 28‐day mortality
60‐day mortality	0/5	0/5	Not estimable	10 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on 60‐day mortality
90‐day mortality	There were no data for 90‐day mortality
Mortality (time to event)	Hazard ratio was not available for this outcome. No participants died in either arm in this comparison.
Clinical worsening	Clinical worsening data could not be analysed because mortality was a competing event
Clinical improvement (number of people discharged by day 60)	5/5	5/5	RR 1.00 (0.71 to 1.41)	10 (1 RCT)	⨁◯◯◯ Very lowc	We do not know if swine glyco‐humanised polyclonal antibody has any impact on clinical improvement
Time to hospital discharge	Time to discharge could not be analysed because death was a competing outcome
Quality of life	There were no data for quality of life
Any adverse events (by day 28)	5/5	4/5	RR 0.82 (0.49 to 1.38)	10 (1 RCT)	⨁◯◯◯ very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on any adverse events
Grades 1 to 2 adverse events (by day 28)	5/5	4/5	RR 0.82 (0.49 to 1.38)	10 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on grades 1 to 2 adverse events
Grades 3 to 4 adverse events (by day 28)	3/5	2/5	RR 0.67 (0.18 to 2.42)	10 (1 RCT)	⨁◯◯◯ Very lowb	We do not know if swine glyco‐humanised polyclonal antibody has any impact on grades 3 to 4 adverse events
Serious adverse events	There were no data for serious adverse events
Need for dialysis	There were no data for the need for dialysis
Admission to ICU (by day 28)	0/5	0/5	RR 2.00 (0.26 to 15.62)	10 (1 RCT)	⨁◯◯◯ Very lowd	We do not know if swine glyco‐humanised polyclonal antibody has any impact on admission to ICU
Viral clearance	There were no data for viral clearance
CI: confidence interval; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; RCT: randomised controlled trial; RR: risk ratio

^aResults for 28‐day mortality were inferred, because only one participant in the study died, at day 58.
^bWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small.
^cWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small; and once for indirectness because the result was only available at the 60‐day time point.
^dWe downgraded the certainty of evidence three times for imprecision because the number of participants was very small; and once for risk of bias in the selection of the reported result domain.

Critical outcomes

hIVIG from human plasma compared to saline placebo

These are critical outcomes, detailed in Table 1.

All‐cause mortality at day 28

One study reported all‐cause mortality at 28 days in 579 participants. We found an event rate of 77 per 1000 participants for all‐cause mortality up to 28 days, when treated with a saline placebo. hIVIG therapy may result in little to no difference in 28‐day mortality (RR 0.79, 95% CI 0.43 to 1.44; 61 per 1000; 1 study, 579 participants; low‐certainty evidence; Analysis 1.1). We downgraded the certainty of the evidence twice due to very serious imprecision, because of wide confidence intervals, and because the results were based on a single, small study.

1.1. Analysis.

Comparison 1: hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline), Outcome 1: All‐cause mortality at 28 days

Worsening of clinical status at day 28

One study reported clinical worsening at day 7. The evidence is very uncertain about the effect on clinical worsening at day 7 (RR 0.85, 95% CI 0.58 to 1.23; 149 per 1000; 1 study, 579 participants; very low‐certainty evidence; Analysis 1.2). We downgraded the certainty of the evidence twice for very serious imprecision because of wide confidence intervals, and because the result is based on a single, small study; and also downgraded once for indirectness because the outcome only included worsening that was ongoing on day 7.

1.2. Analysis.

Comparison 1: hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline), Outcome 2: Clinical worsening: clinical status worsened on day 7

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement at day 28, as the number of participants discharged from hospital, or reaching the most favourable category on a 7‐point ordinal scale. We are moderately certain that hIVIG therapy probably has little to impact on the number of people being discharged from hospital at 28 days, therefore little to no effect on clinical improvement at day 28 (RR 1.02, 95% CI 0.97 to 1.08; 908 per 1000; 1 study, 579 participants; moderate‐certainty evidence; Analysis 1.3). We downgraded the certainty of the evidence once for imprecision, because the result was based on a single, small study.

1.3. Analysis.

Comparison 1: hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline), Outcome 3: Clinical improvement: number of participants discharged, or reaching category 1 on the WHO scale on day 28

Quality of life

We did not identify any study reporting on quality of life.

Adverse events at any grade

One study reported adverse events of any grade. Data were only available for this outcome for day 1. hIVIG may have little to no effect on adverse events of any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study, 579 participants; low‐certainty evidence; Analysis 1.4). We downgraded the certainty of the evidence once for indirectness, because the outcome only included adverse events that occurred on day 1; and once for imprecision, because the result was based on a single, small study.

1.4. Analysis.

Comparison 1: hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline), Outcome 4: Adverse events at any grade on day 1

Adverse events at grades 3 to 4 severity

One study reported adverse events of grades 3 to 4 severity up to day 28. We are moderately certain that participants receiving hIVIG therapy probably experienced more grades 3 to 4 adverse events than those receiving placebo (RR 4.09, 95% CI 1.39 to 12.01; 58 per 1000; 1 study, 579 participants; moderate‐certainty evidence; Analysis 1.5). We downgraded the certainty of the evidence once for imprecision, because the result is based on a single, small study.

1.5. Analysis.

Comparison 1: hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline), Outcome 5: Adverse events at grades 3 to 4 severity

Serious adverse events

One study reported serious adverse events as a composite outcome of serious adverse events or death up to day 28. In the placebo group, we found an event rate of 133 per 1000. hIVIG therapy may have little to no effect on serious adverse events or death up to day 28 (RR 0.72, 95% CI 0.45 to 1.14; 96 per 1000; 1 study, 572 participants; low‐certainty evidence; Analysis 1.6). We downgraded the certainty of the evidence twice for imprecision, because of wide confidence intervals, and because the result is based on a single, small study.

1.6. Analysis.

Comparison 1: hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline), Outcome 6: Number of participants with serious adverse events or death up to day 28

RBD‐specific polyclonal F(ab')₂ fragments of equine antibodies (EpAbs) compared to saline placebo

These are critical outcomes, detailed in Table 2.

All‐cause mortality at 28 days

One study reported all‐cause mortality at 28 days. When treated with placebo, 114 participants per 1000 died by 28 days. EpAbs therapy may decrease mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; 68 per 1000; 1 study, 241 participants; low‐certainty evidence; Analysis 2.1; Table 2). We downgraded the certainty of evidence twice for very serious imprecision, because of wide confidence intervals, and because the result is based on a single, small study.

2.1. Analysis.

Comparison 2: Equine polyclonal antibodies (EpAbs) versus placebo, Outcome 1: All‐cause mortality at 28 days

Worsening of clinical status at day 28

Clinical worsening was reported as a new need for IMV, admission to ICU, or death, by day 28. EpAbs may reduce clinical worsening at day 28 (RR 0.67, 95% CI 0.38 to 1.18; 136 per 1000; 1 study, 241 participants; low‐certainty evidence; Analysis 2.2). We downgraded the certainty of evidence twice for imprecision, because of wide confidence intervals, and because the result is based on a single, small study.

2.2. Analysis.

Comparison 2: Equine polyclonal antibodies (EpAbs) versus placebo, Outcome 2: Worsening of clinical status: admission to ICU, need for mechanical ventilation, or death by day 28

Improvement of clinical status: number of participants discharged from hospital

Improvement of clinical status was reported as number of participants discharged from hospital on day 28. hIVIG therapy may have some effect on the number of patients discharged and thus, clinical improvement on day 28 (RR 1.06, 95% CI 0.96 to 1.17; 890 per 1000; 1 study, 241 participants; low‐certainty evidence; Analysis 2.3). We downgraded the certainty of the evidence twice for imprecision, because the result was based on a single, small study, and a wide confidence interval.

2.3. Analysis.

Comparison 2: Equine polyclonal antibodies (EpAbs) versus placebo, Outcome 3: Improvement of clinical status: number of patients discharged on day 28

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events of any grade up to day 28. EpAbs therapy may have little to no effect on adverse events of any grade on day 28 (RR 0.99, 95% CI 0.74 to 1.31; 437 per 1000; 1 study, 243 participants; low‐certainty evidence; Analysis 2.4). We downgraded the certainty of the evidence twice for imprecision, because the result was based on a single, small study, and a wide confidence interval.

2.4. Analysis.

Comparison 2: Equine polyclonal antibodies (EpAbs) versus placebo, Outcome 4: Adverse events at any grade

Adverse events at grades 3 to 4 severity

Grades 3 to 4 adverse events were not reported for this comparison.

Serious adverse events

One study reported serious adverse events up to day 28. EpAbs may reduce serious adverse events or death up to day 28 (RR 0.67, 95% CI 0.38 to 1.19; 134 per 1000; 1 study, 243 participants; low‐certainty evidence; Analysis 2.5). We downgraded the certainty of the evidence twice for imprecision, because of wide confidence intervals, and because the result was based on a single, small study.

2.5. Analysis.

Comparison 2: Equine polyclonal antibodies (EpAbs) versus placebo, Outcome 5: Serious adverse events

hIVIG 0.15 g/kg versus standard care

The following are important outcomes; details for all outcomes can be found in Table 7.

All‐cause mortality at 28 days

One study reported all‐cause mortality at 28 days. The evidence is very uncertain about the effect of hIVIG 0.15 g/kg on mortality at day 28 (RR 0.33, 95% CI 0.09 to 1.27; 1 study, 20 participants; very low‐certainty evidence; Analysis 3.1). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

3.1. Analysis.

Comparison 3: hIVIG 0.15 g/kg versus standard care, Outcome 1: All‐cause mortality at 28 days

Worsening of clinical status at day 28

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement as the number of participants discharged from hospital on day 28. The evidence is very uncertain about the effect of hIVIG 0.15 g/kg on clinical improvement at day 28 (RR 2.00, 95% CI 0.88 to 4.54; 1 study, 20 participants; very‐low certainty evidence; Analysis 3.2). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

3.2. Analysis.

Comparison 3: hIVIG 0.15 g/kg versus standard care, Outcome 2: Improvement of clinical status: number of participants discharged on day 28

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events at any grade. The evidence is very uncertain about the effect of hIVIG 0.15 g/kg on adverse event of any grade up to 28 days (RR 1.00, 95% CI 0.56 to 1.78; 1 study, 20 participants; very low‐certainty evidence; Analysis 3.3). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

3.3. Analysis.

Comparison 3: hIVIG 0.15 g/kg versus standard care, Outcome 3: Adverse events at any grade

Adverse events at grades 3 to 4 severity

Grades 3 to 4 adverse events were not reported for this comparison.

Serious adverse events

Serious adverse events were not reported for this comparison.

hIVIG from human plasma 0.2 g/kg versus standard care

The following are important outcomes; details for all outcomes can be found in Table 8.

All‐cause mortality at 28 days

One study reported all‐cause mortality. The evidence is very uncertain about the effect of hIVIG 0.2 g/kg on mortality at day 28 (RR 0.50, 95% CI 0.17 to 1.46; 1 study, 20 participants; very low‐certainty evidence; Analysis 4.1). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

4.1. Analysis.

Comparison 4: hIVIG 0.2 g/kg versus standard care, Outcome 1: All‐cause mortality at 28 days

Worsening of clinical status at day 28

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement as the number of participants discharged from hospital. The evidence is very uncertain about the effect of hIVIG 0.2 g/kg on clinical improvement at day 28 (RR 1.75, 95% CI 0.74 to 4.14; 1 study, 20 participants; very low‐certainty evidence; Analysis 4.2). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

4.2. Analysis.

Comparison 4: hIVIG 0.2 g/kg versus standard care, Outcome 2: Improvement of clinical status: number of participants discharged on day 28

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events at any grade. The evidence is very uncertain about the effect of hIVIG 0.2 g/kg on adverse events of any grade up to 28 days (RR 1.14, 95% CI 0.69 to 1.90; 1 study, 20 participants; very low‐certainty evidence; Analysis 4.3). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

4.3. Analysis.

Comparison 4: hIVIG 0.2 g/kg versus standard care, Outcome 3: Adverse events at any grade

Adverse events at grades 3 to 4 severity

Grades 3 to 4 adverse events were not reported for this comparison.

Serious adverse events

Serious adverse events were not reported for this comparison.

hIVIG 0.25 g/kg versus standard care

The following are important outcomes; details for all outcomes can be found in Table 9.

All‐cause mortality at 28 days

One study reported all‐cause mortality. The evidence is very uncertain about the effect of hIVIG 0.25 g/kg on mortality at day 28 (RR 0.17, 95% CI 0.02 to 1.14; 1 study, 20 participants; very low‐certainty evidence; Analysis 5.1). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

5.1. Analysis.

Comparison 5: hIVIG 0.25 g/kg versus standard care, Outcome 1: All‐cause mortality at 28 days

Worsening of clinical status at day 28

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement as the number of participants discharged from hospital. The evidence is very uncertain about the effect of hIVIG 0.25 g/kg on clinical improvement at day 28 (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants; very low‐certainty evidence; Analysis 5.2). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

5.2. Analysis.

Comparison 5: hIVIG 0.25 g/kg versus standard care, Outcome 2: Improvement of clinical status: number of participants discharged on day 28

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events at any grade. The evidence is very uncertain about the effect of hIVIG 0.25 g/kg on adverse events of any grade to 28 days (RR 0.71, 95% CI 0.34 to 1.50; 1 study, 20 participants; very low‐certainty evidence; Analysis 5.3). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

5.3. Analysis.

Comparison 5: hIVIG 0.25 g/kg versus standard care, Outcome 3: Adverse events at any grade

Adverse events at grades 3 to 4 severity

Adverse events at grades 3 to 4 were not reported for this comparison

Serious adverse events

Serious adverse events were not reported for this comparison.

hIVIG from human plasma 0.3 g/kg versus standard care

The following are important outcomes; details for all outcomes can be found in Table 10.

All‐cause mortality at 28 days

One study reported all‐cause mortality. The evidence is very uncertain about the effect of hIVIG 0.3 g/kg on mortality at day 28 (RR 0.67, 95% CI 0.27 to 1.66; 1 study, 20 participants; very low‐certainty evidence; Analysis 6.1). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

6.1. Analysis.

Comparison 6: hIVIG 0.3 g/kg versus standard care, Outcome 1: All‐cause mortality at 28 days

Worsening of clinical status at day 28

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement as the number of participants discharged from hospital. The evidence is very uncertain about the effect of hIVIG 0.3 g/kg on clinical improvement at day 28 (RR 1.50, 95% CI 0.60 to 3.74; 1 study, 20 participants; very low‐certainty evidence; Analysis 6.2). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

6.2. Analysis.

Comparison 6: hIVIG 0.3 g/kg versus standard care, Outcome 2: Improvement of clinical status: number of participants discharged on day 28

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events at any grade. The evidence is very uncertain about the effect of hIVIG 0.3 g/kg on adverse events of any grade up to 28 days (RR 1.14, 95% CI 0.69 to 1.90; 1 study, 20 participants; very low‐certainty evidence; Analysis 6.3). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

6.3. Analysis.

Comparison 6: hIVIG 0.3 g/kg versus standard care, Outcome 3: Adverse events at any grade

Adverse events at grades 3 to 4

Grades 3 to 4 adverse events were not reported for this comparison.

Serious adverse events

Serious adverse events were not reported for this comparison.

Swine glyco‐humanised polyclonal antibody 0.5 mg/kg on days 1 to 5 versus placebo

The following are important outcomes; details for all outcomes can be found in Table 12.

All‐cause mortality at 60 days

One study reported all‐cause mortality at 60 days. The evidence is very uncertain about the effect of polyclonal antibody 0.5 mg/kg on mortality at day 28 (RR not estimable 1 study, 11 participants; very low‐certainty evidence; Analysis 7.4). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

7.4. Analysis.

Comparison 7: Swine glyco‐humanised polyclonal antibody 0.5 mg/kg days 1 to 5 versus placebo, Outcome 4: All‐cause mortality at 60 days

Worsening of clinical status at day 29

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement as the number of participants discharged from hospital. The evidence is very uncertain about the effect of polyclonal antibody 0.5 mg/kg on clinical improvement at day 60 (RR 0.86, 95% CI 0.54 to 1.35; 1 study, 11 participants; very low‐certainty evidence; Analysis 7.1). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small. We also downgraded the evidence by one level for indirectness, because the result was only available at the 60‐day time point.

7.1. Analysis.

Comparison 7: Swine glyco‐humanised polyclonal antibody 0.5 mg/kg days 1 to 5 versus placebo, Outcome 1: Improvement of clinical status: number of participants discharged on day 60

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events at any grade. The evidence is very uncertain about the effect of polyclonal antibody 0.5 mg/kg on adverse events of any grade up to 29 days (RR 1.00, 95% CI 0.74 to 1.35; 1 study, 12 participants; very low‐certainty evidence; Analysis 7.2). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

7.2. Analysis.

Comparison 7: Swine glyco‐humanised polyclonal antibody 0.5 mg/kg days 1 to 5 versus placebo, Outcome 2: Adverse events at any grade

Adverse events at grades 3 to 4

One study reported adverse events of grades 3 to 4 severity. The evidence is very uncertain about the effect of polyclonal antibody 0.5 mg/kg on grades 3 to 4 adverse events up to 29 days (RR 0.48, 95% CI 0.12 to 1.88; 1 study, 12 participants; very low‐certainty evidence; Analysis 7.3). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

7.3. Analysis.

Comparison 7: Swine glyco‐humanised polyclonal antibody 0.5 mg/kg days 1 to 5 versus placebo, Outcome 3: Adverse events at grades 3 to 4 severity

Serious adverse events

Serious adverse events were not reported for this comparison.

Swine glyco‐humanised polyclonal antibody 2 mg/kg on days 1 to 5 versus placebo

The following are important outcomes; details for all outcomes can be found in Table 13.

All‐cause mortality at 60 days

One study reported all‐cause mortality at 60 days. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg days 1 to 5 on mortality at day 28 (RR not estimable; 1 study, 6 participants; very low‐certainty evidence; Analysis 8.4). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

8.4. Analysis.

Comparison 8: Swine glyco‐humanised polyclonal antibody 2 mg/kg days 1 to 5 versus placebo, Outcome 4: All‐cause mortality at 60 days

Worsening of clinical status at day 28

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement as the number of participants discharged from hospital at day 60. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg days 1 to 5 on clinical improvement at day 60 (RR 1.00, 95% CI 0.43 to 2.31; 1 study, 6 participants; very low‐certainty evidence; Analysis 8.1). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small. We also downgraded the evidence by one level for indirectness, because the result was only available at the 60‐day time point.

8.1. Analysis.

Comparison 8: Swine glyco‐humanised polyclonal antibody 2 mg/kg days 1 to 5 versus placebo, Outcome 1: Improvement of clinical status: number of participants discharged on day 28

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events of any grade. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg days 1 to 5 on adverse events of any grade up to day 29 (RR 1.00, 95% CI 0.43 to 2.31; 1 study, 6 participants; very low‐certainty evidence; Analysis 8.2). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

8.2. Analysis.

Comparison 8: Swine glyco‐humanised polyclonal antibody 2 mg/kg days 1 to 5 versus placebo, Outcome 2: Adverse events at any grade

Adverse events at grades 3 to 4

One study reported adverse events of grades 3 to 4 severity. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg days 1 to 5 on grades 3 to 4 adverse events up to 29 days (RR 0.43, 95% CI 0.04 to 5.19; 1 study, 6 participants; very low‐certainty evidence; Analysis 8.3). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

8.3. Analysis.

Comparison 8: Swine glyco‐humanised polyclonal antibody 2 mg/kg days 1 to 5 versus placebo, Outcome 3: Adverse events at grades 3 to 4 severity

Serious adverse events

Serious adverse events were not reported for this comparison.

Swine glyco‐humanised polyclonal antibody 2 mg/kg on day 1 only versus placebo

The following are important outcomes; details for all outcomes can be found in Table 14.

All‐cause mortality at 60 days

One study reported all‐cause mortality. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on day 1 only on mortality at day 60 (RR not estimable; 1 study, 10 participants; very low‐certainty evidence; Analysis 9.4). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

9.4. Analysis.

Comparison 9: Swine glyco‐humanised polyclonal antibody 2 mg/kg day 1 only versus placebo, Outcome 4: All‐cause mortality at 60 days

Worsening of clinical status at day 28

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

One study reported clinical improvement as the number of participants discharged from hospital. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on day 1 only on clinical improvement at day 60 (RR 1.00, 95% CI 0.71 to 1.41; 1 study, 10 participants; very low‐certainty evidence; Analysis 9.1). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small. We also downgraded the evidence by one level for indirectness, because the result was only available for the 60‐day time point.

9.1. Analysis.

Comparison 9: Swine glyco‐humanised polyclonal antibody 2 mg/kg day 1 only versus placebo, Outcome 1: Improvement of clinical status: number of participants discharged on day 60

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

One study reported adverse events at any grade. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on day 1 only on adverse events of any grade at day 29 (RR 0.82, 95% CI 0.49 to 1.38; 1 study, 10 participants; very low‐certainty evidence; Analysis 9.2). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

9.2. Analysis.

Comparison 9: Swine glyco‐humanised polyclonal antibody 2 mg/kg day 1 only versus placebo, Outcome 2: Adverse events at any grade

Adverse events at grades 3 to 4

One study reported adverse events of grades 3 to 4 severity. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on day 1 only on grades 3 to 4 adverse events up to 29 days (RR 0.67, 95% CI 0.18 to 2.42; 1 study, 10 participants; very low‐certainty evidence; Analysis 9.3). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

9.3. Analysis.

Comparison 9: Swine glyco‐humanised polyclonal antibody 2 mg/kg day 1 only versus placebo, Outcome 3: Adverse events at grades 3 to 4 severity

Serious adverse events

Serious adverse events were not reported for this comparison.

hIVIG 350 AU/mL from human plasma versus standard care

The following are important outcomes; details for all outcomes can be found in Table 11.

All‐cause mortality at 28 days

One study reported all‐cause mortality. The evidence is very uncertain about the effect of hIVIG 350 AU/mL on mortality at day 28 (RR 0.97, 95% CI 0.06 to 14.74; 1 study, 59 participants; very low‐certainty evidence; Analysis 10.1). We downgraded the certainty of the evidence once for risk of bias in the domains of randomisation and allocation to intervention, and twice for imprecision because of very wide confidence intervals.

Worsening of clinical status at day 28

We could not analyse data on clinical worsening, as the competing event of mortality was not considered in the analysis.

Improvement of clinical status: number of participants discharged from hospital

We could not analyse clinical improvement data because clinical status was reported as mean change in a clinical ordinal score; the number of participants showing improvement was not reported.

Quality of life

We did not identify any study reporting quality of life.

Adverse events at any grade

Adverse events of any grade were not reported for this comparison.

Adverse events at grades 3 to 4

Grades 3 to 4 adverse events were not reported for this outcome.

Serious adverse events

One study reported serious adverse events. The evidence is very uncertain about the effect of hIVIG 350 AU/mL on serious adverse events (RR 0.97, 95% CI 0.06 to 14.74; 33 per 1000; 1 study, 59 participants; very low‐certainty evidence; Analysis 10.2). We downgraded the certainty of the evidence once for risk of bias in the domain of allocation to the intervention, and twice for imprecision because of very wide confidence intervals.

Secondary outcomes

hIVIG from human plasma compared to saline placebo

Details for these outcomes can be found in Table 5.

All‐cause mortality at 60 days

All‐cause mortality at 60 days was not reported for this comparison.

All‐cause mortality at 90 days

All‐cause mortality at 90 days was not reported for this comparison.

Mortality: time to event

One study reported mortality as time to event. Hyperimmune immunoglobulin therapy may result in little to no difference in the length of time to mortality by 28 days (hazard ratio (HR) 0.80, 95% CI 0.42 to 1.51; 61 per 1000; 1 study, 579 participants; low‐certainty evidence; Analysis 1.7). We downgraded the certainty of evidence twice for very serious imprecision, because of very wide confidence intervals, and because the result is based on a single study.

1.7. Analysis.

Comparison 1: hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline), Outcome 7: Mortality (time to event)

Adverse events grades 1 or 2 severity

Grades 1 or 2 adverse events were not reported for this comparison.

Need for dialysis

We did not identify any study reporting the need for dialysis.

Admission to intensive care unit (ICU) on day 28

Admission to ICU on day 28 was not reported for this comparison.

Duration of hospitalisation

One study reported a recovery rate ratio (RRR) as participants discharged from hospital or reaching the ordinal category 1 (return to normal activities; reported RRR 1.07, 95% CI 0.92 to 1.26; 1 study, 579 participants).

Viral clearance

Viral clearance was not reported for this comparison.

RBD‐specific polyclonal F(ab´)₂ fragments of equine antibodies (EpAbs) compared to saline placebo

Details for these outcomes can be found in Table 6.

All‐cause mortality at 60 days

All‐cause mortality at 60 days was not reported for this comparison.

All‐cause mortality at 90 days

All‐cause mortality at 90 days was not reported for this comparison.

Mortality: time to event

One study reported mortality as time to event. EpAbs therapy may result in little to no difference in the length of time to mortality by 28 days (HR 0.58, 95% CI 0.24 to 1.37; 68 per 1000; 1 study, 241 participants; low‐certainty evidence; Analysis 2.6). We downgraded the certainty of evidence twice for very serious imprecision, because of very wide confidence intervals, and because the result is based on a single study.

2.6. Analysis.

Comparison 2: Equine polyclonal antibodies (EpAbs) versus placebo, Outcome 6: Mortality (time to event)

Adverse events grade 1 or 2 severity

Grade 1 or 2 adverse events were not reported for this comparison.

Need for dialysis

We did not identify any study reporting the need for dialysis.

Admission to ICU on day 28

One study reported admission to ICU. EpAbs may reduce admission to ICU by day 28 (RR 0.68, 95% CI 0.37 to 1.24; 127 per 1000; 1 study, 241 participants; low‐certainty evidence; Analysis 2.7). We downgraded the certainty of the evidence twice for imprecision, because of wide confidence intervals, and because the result is based on a single study.

2.7. Analysis.

Comparison 2: Equine polyclonal antibodies (EpAbs) versus placebo, Outcome 7: Admission to ICU at day 28

Duration of hospitalisation

Duration of hospitalisation could not be analysed for this outcome, because death was a competing event.

Viral clearance

One study reported viral clearance, but we were unable to extract the data in a format that we could analyse.

hIVIG from human plasma 0.15 g/kg versus standard care

Details for outcomes can be found in Table 7. This comparison did not report data for any of the secondary outcomes: all‐cause mortality at 60 days, or 90 days, or as time to mortality; adverse events of grade 1 or 2 severity; need for dialysis; admission to ICU at day 28; duration of hospitalisation (unable to analyse because death was a competing event); or viral clearance.

hIVIG from human plasma 0.2 g/kg versus standard care

Details for outcomes can be found in Table 8. This comparison did not report data for any of the secondary outcomes: all‐cause mortality at 60 days, or 90 days, or as time to mortality; adverse events of grade 1 or 2 severity; need for dialysis; admission to ICU at day 28; duration of hospitalisation (unable to analyse because death was a competing event); or viral clearance.

hIVIG from human plasma 0.25 g/kg versus standard care

Details for outcomes can be found in Table 9. This comparison did not report data for any of the secondary outcomes: all‐cause mortality at 60 days, or 90 days, or as time to mortality; adverse events of grade 1 or 2 severity; need for dialysis; admission to ICU at day 28; duration of hospitalisation (unable to analyse because death was a competing event); or viral clearance.

hIVIG from human plasma 0.3 g/kg versus standard care

Details for outcomes can be found in Table 10. This comparison did not report data for any of the secondary outcomes: all‐cause mortality at 60 days, or 90 days, or at time to mortality; adverse events of grade 1 or 2 severity; need for dialysis; admission to ICU at day 28; duration of hospitalisation (unable to analyse because death was a competing event); or viral clearance.

Swine glyco‐humanised polyclonal antibody 0.5 mg/kg on days 1 to 5 versus placebo

Details for outcomes can be found in Table 12.

All‐cause mortality at 60 days

All‐cause mortality at 60 days was reported in one study. The evidence is very uncertain about the effect of polyclonal antibody 0.5 mg/kg on days 1 to 5 on mortality to day 60(RR 2.57, 95% CI 0.13 to 52.12; 1 study, 11 participants; very low‐certainty evidence; Analysis 7.4). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

All‐cause mortality at 90 days

All‐cause mortality at 90 days was not reported for this comparison.

Mortality: time to event

A hazard ratio for the time to mortality was not available. One patient in the hIVIG group died on day 58 (1 study, 11 participants).

Adverse events grade 1 or 2 severity

One study reported adverse events of grade 1 or 2 severity. The evidence is very uncertain about the effect of polyclonal antibody 0.5 mg/kg on days 1 to 5 on grade 1 or 2 adverse events at day 28 (RR 1.00, 95% CI 0.74 to 1.35; 1 study, 12 participants; very low‐certainty evidence; Analysis 7.5). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

7.5. Analysis.

Comparison 7: Swine glyco‐humanised polyclonal antibody 0.5 mg/kg days 1 to 5 versus placebo, Outcome 5: Adverse events at grades 1 to 2 severity

Need for dialysis

We did not identify any study reporting the need for dialysis.

Admission to ICU on day 28

One study reported admission to ICU. The evidence is very uncertain about the effect of polyclonal antibody 0.5 mg/kg on days 1 to 5 on admission to ICU on day 28 (RR not estimable; 1 study, 11 participants; very low‐certainty evidence; Analysis 7.6). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

Duration of hospitalisation

Duration of hospitalisation could not be analysed for this outcome, because death was a competing event.

Viral clearance

Viral clearance was not reported for this comparison.

Swine glyco‐humanised polyclonal antibody 2 mg/kg on days 1 to 5 versus placebo

Details for outcomes can be found in Table 13.

All‐cause mortality at 60 days

One study reported all‐cause mortality at 60 days. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on days 1 to 5 on mortality at day 28 (RR not estimable; 1 study, 6 participants; very low‐certainty evidence; Analysis 8.4). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

All‐cause mortality at 90 days

All‐cause mortality at 90 days was not reported for this comparison.

Mortality: time to event

A hazard ratio for the time to mortality was not available; no participants died in either arm of this comparison.

Adverse events grade 1 or 2 severity

One study reported adverse events of grade 1 or 2 severity. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on days 1 to 5 on grade 1 or 2 adverse events up to day 28 (RR 1.00, 95% CI 0.43 to 2.31; 1 study, 6 participants; very low‐certainty evidence; Analysis 8.5). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

8.5. Analysis.

Comparison 8: Swine glyco‐humanised polyclonal antibody 2 mg/kg days 1 to 5 versus placebo, Outcome 5: Adverse events at grades 1 to 2 severity

Need for dialysis

We did not identify any study reporting the need for dialysis.

Admission to ICU on day 28

One study reported admission to ICU. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on days 1 to 5 on admission to ICU on day 28 (RR 1.00, 95% CI 0.06 to 15.99; 1 study, 6 participants; very low‐certainty evidence; Analysis 8.6). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small; and once for risk of bias in the selection of the reported result domain.

Duration of hospitalisation

Duration of hospitalisation could not be analysed for this outcome, because death was a competing event.

Viral clearance

Viral clearance was not reported for this comparison.

Swine glyco‐humanised polyclonal antibody 2 mg/kg on day 1 only versus placebo

Details for outcomes can be found in Table 14.

All‐cause mortality at 60 days

One study reported all‐cause mortality at 60 days The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on day 1 only on mortality at 60 days (RR not estimable; 1 study, 10 participants; very low‐certainty evidence; Analysis 9.4). We downgraded the certainty of evidence by three levels because of very serious imprecision, as the number of participants was very small.

All‐cause mortality at 90 days

All‐cause mortality at 90 days was not reported for this comparison.

Mortality: time to event

A hazard ratio for the time to mortality was not available; no participants died in either arm of this comparison.

Adverse events grade 1 or 2 severity

One study reported adverse events of grade 1 or 2 severity. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on day 1 only on grade 1 or 2 severity adverse events by day 28 (RR 0.82, 95% CI 0.49 to 1.38; 1 study, 10 participants; very low‐certainty evidence; Analysis 9.5). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small.

9.5. Analysis.

Comparison 9: Swine glyco‐humanised polyclonal antibody 2 mg/kg day 1 only versus placebo, Outcome 5: Adverse events at grades 1 to 2 severity

Need for dialysis

We did not identify any study reporting the need for dialysis.

Admission to ICU on day 28

One study reported on admission to ICU. The evidence is very uncertain about the effect of polyclonal antibody 2 mg/kg on day 1 only on admission to ICU on day 28 ( RR 2.00, 95% CI 0.26 to 15.62 participants; very low‐certainty evidence; Analysis 9.6). We downgraded the certainty of the evidence by three levels for very serious imprecision, because the number of participants was very small; and once for risk of bias in the selection of the reported result domain.

Duration of hospitalisation

Duration of hospitalisation could not be analysed for this outcome, because death was a competing event.

Viral clearance

Viral clearance was not reported for this comparison.

hIVIG 350 AU/mL from human plasma versus standard care

Details for outcomes can be found in Table 11.

All‐cause mortality at 60 days

All‐cause mortality at 60 days was not reported for this comparison.

All‐cause mortality at 90 days

All‐cause mortality at 90 days was not reported for this comparison.

Mortality: time to event

Time to mortality was not reported for this comparison.

Adverse events grade 1 or 2 severity

Grade 1 or 2 severity adverse events were not reported for this comparison.

Need for dialysis

We did not identify any study reporting the need for dialysis.

Admission to ICU on day 28

Admission to ICU on day 28 was not reported for this comparison.

Duration of hospitalisation

Duration of hospitalisation was not reported for this comparison.

Viral clearance

One study reported on the number of participants with a negative RT‐PCR test.

The evidence is very uncertain about the effect of hIVIG 350 AU/mL on the number of participants with a negative RT‐PCR test on day 3 (RR 1.23, 95% CI 0.67 to 2.25; 467 per 1000; 1 study, 59 participants; very‐low certain ty evidence Analysis 10.3).

The evidence is very uncertain about the effect of hIVIG 350 AU/mL on the number of participants with a negative RT‐PCR test on day 7 (RR 0.97, 95% CI 0.68 to 1.37; 667 per 1000; 1 study, 59 participants; very‐low certainty evidence Analysis 10.4).

The evidence is very uncertain about the effect of hIVIG 350 AU/mL on the number of participants with a negative RT‐PCR test on day 15 (RR 0.93, 95% CI 0.72 to 1.20, 767 per 1000; 1 study, 59 participants; low certainty evidence Analysis 10.4).

In each instance, we downgraded the certainty of the evidence once for risk of bias in the domains for randomisation and allocation to intervention, and twice for imprecision due to very wide confidence intervals for day 3 and day 7, and once for imprecision because of wide confidence intervals for day 15.

Subgroup and sensitivity analyses

Due to lack of available information, we were unable to undertake subgroup and sensitivity analyses for any of the comparisons.

Individuals with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild disease

We did not identify any completed studies that evaluated people with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild disease. 

Discussion

Summary of main results

We identified five studies that met our eligibility criteria, all in participants with moderate or severe COVID‐19. Three studies used human‐derived hIVIG, and two used animal‐derived polyclonal antibodies. All studies used different dosages, and we could not combine them for analysis. Therefore, we selected critical comparisons to present in summary of findings tables (Table 1; Table 2). We also identified additional results on the effectiveness of other dose ranges of hIVIG, not included in the summary of findings tables, but summarised in Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12; Table 13; and Table 14).

Hyperimmune immunoglobulin from humans

Benefits of hIVIG

We identified six comparisons with different dosages of hIVIG. hIVIG may have little to no impact on mortality at 28 days; the evidence is very uncertain about the effect on clinical worsening on day 7; and it may have little to no impact on clinical improvement by day 28. We did not identify any studies reporting on quality‐of‐life outcomes, so we do not know if hIVIG has any impact on quality of life. hIVIG therapy may result in little to no difference in 28‐day mortality (RR 0.79, 95% CI 0.43 to 1.44; 61 per 1000; 1 study, 579 participants; low‐certainty evidence. It probably has little to impact on the number of people being discharged from hospital at 28 days, therefore little to no effect on clinical improvement at day 28 (RR 1.02, 95% CI 0.97 to 1.08; 908 per 1000; 1 study, 579 participants; moderate‐certainty evidence).

Harms of hIVIG

Data on adverse events for this comparison were only available for day 1 after treatment. hIVIG may have little to no impact on adverse events of any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study, 579 participants; low‐certainty evidence). It may have little to no impact on serious adverse events or death up to day 28. People receiving hIVIG may experience more grade 3 or 4 adverse events than those who received placebo (RR 4.09, 95% CI 1.39 to 12.01; 58 per 1000; 1 study, 579 participants; moderate‐certainty evidence).

We also identified additional results on the harms of other dose ranges of hIVIG, summarised in Table 7; Table 8; Table 9; Table 10; and Table 11.

Animal‐derived polyclonal antibodies

Benefits of animal‐derived polyclonal antibodies

We identified four comparisons of different dosages and preparations of animal‐derived polyclonal antibodies. EpAbs may reduce mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; 1 study, 241 participants; low‐certainty evidence). It may reduce clinical worsening up to day 28 (RR 0.67, 95% CI 0.38 to 1.18; 1 study, 241 participants; low‐certainty evidence). It may have some impact on clinical improvement on day 28 (RR 1.06, 95% CI 0.96 to 1.17; 1 study, 241 participants; low‐certainty evidence). We did not identify any study reporting quality‐of‐life outcomes, so we do not know if EpAbs has any impact on quality of life.

Harms of animal‐derived polyclonal antibodies

We presented data on harms as the number of adverse events up to 28 days. We included data on one RCT (241 participants) to assess the harms of EpAbs compared to placebo. EpAbs may have little to no impact on the number of adverse events of any grade up to 28 days (RR 0.99, 95% CI 0.74 to 1.31; 1 study 241 participants; low‐certainty evidence). Patients receiving EpAbs may experience fewer serious adverse events than patients receiving placebo (RR 0.67, 95% CI 0.38 to 1.19; 1 study 241 participants; low‐certainty evidence).

We also identified results on the effectiveness of other animal‐derived polyclonal antibody doses, summarised in Table 6; Table 12; Table 13 and Table 14.

This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Overall completeness and applicability of evidence

All studies included hospitalised participants only, therefore there is a lack of evidence for non‐hospitalised participants, with asymptomatic infection or mild disease.

None of the studies assessed SARS‐CoV‐2 variants separately. We can only assume which variants the participants were exposed to based on the timing of the studies. Two studies were conducted entirely or mostly prior to the emergence of any variants of concern (ITAC 2022; Lopardo 2021). One study does not describe variants in circulation, but took place in Pakistan after the emergence of alpha and beta, but prior to the emergence of delta (Ali 2021). One study discusses the benefits of the intervention in relation to alpha and beta variants (Gaborit 2021), and one study does not discuss variants or report the timing of recruitment (Parikh 2021). Findings may not be transferable to the most recently occurring variants and subvariants. The polyclonal nature of hIVIG makes it less prone than monoclonal antibodies to lose efficacy against escape to SARS‐CoV‐2 mutants. Nevertheless, with the rapid development and dominance of new variants, hIVIG collected during previous waves may no longer be effective in subsequent new variants or subvariants.

Four studies included unvaccinated participants or were conducted prior to vaccine roll‐out in the country in which the study was conducted. One study included 12 vaccinated participants from 579 participants (ITAC 2022). This was the only study that used a higher dosage of 0.4 g/kg bodyweight, capped at 40 g. ITAC 2022 was also the only study that used international standards to quantify neutralising antibody levels. Information on standardisation of hIVIG products is limited, so it is not possible to compare the neutralising activity of products used between studies.

While we have some confidence that hIVIG is not effective in 957 patients with moderate to severe COVID‐19, we do not know about its benefit in people with ambulatory or mild disease as no studies were published in these populations. It has been suggested that hIVIG may be particularly relevant in certain patient subgroups, such as immunocompromised individuals who do not mount an effective immune response to SARS‐CoV‐2 vaccines. The benefit in this population remains unclear.

None of the included studies measured quality of life.

There are 10 ongoing studies.

Quality of the evidence

The main results of this review are based on two studies that evaluated hIVIG 0.4 g/kg (ITAC 2022), and EpAbs 4 mg/kg (Lopardo 2021).

For the intervention of hIVIG compared to saline placebo, we rated the certainty of the evidence as low or very low for the outcomes of all‐cause mortality at 28 days, clinical worsening at day 7, and adverse events. This was due to imprecision from wide confidence intervals and for the result being based on a single, small study; indirectness for the outcome of clinical worsening, as this included clinical worsening which was ongoing on day 7; and indirectness for the outcome of adverse events, as these only included the events that occurred on day 1. We rated the certainty of the evidence as moderate for the outcomes of clinical improvement (number of participants discharged from hospital or reaching category 1 on a 7‐point ordinal scale) and grade 3 to 4 adverse events, due to imprecision because the result was based on a single, small study.

For the intervention of EpAbs compared to saline placebo, we rated the certainty of the evidence as low for all outcomes (all‐cause mortality at 28 days, clinical worsening at day 28, clinical improvement at day 28, serious adverse events and adverse events) due to imprecision from wide confidence intervals and for the result being based on a single study.

We rated the certainty of the evidence as low or very low for each of the important outcomes in the other three interventions, which include other dose ranges of hIVIG and swine‐derived polyclonal antibodies (Ali 2021; Gaborit 2021; Parikh 2021).

Potential biases in the review process

This is the first publication of the living systematic review investigating hyperimmune immunoglobulin for people with COVID‐19, a spin‐off from the parent review investigating convalescent plasma and hyperimmune immunoglobulins for people with COVID‐19 (Piechotta 2021). We set out to include the best available evidence and adhered to the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022a) in all steps of the review.

To increase the informative value of our review, we are tracking all registered trials and plan to update this review as more evidence becomes available. There are currently still a number of trials awaiting publication, as can be seen from the 10 RCTs on the list of ongoing studies in this review. Before starting the update process, our interdisciplinary team of review authors will meet to review the methods and to discuss necessary amendments. We will follow the methods we agree upon, before starting with the update, and adhere to these decisions throughout each update process.

Two experienced information specialists developed a sensitive search strategy, to identify all ongoing and completed studies. We searched all relevant databases and trials registries, and two review authors conducted all review steps independently and in duplicate.

The adaptation of review methods after finalisation of the protocol, as described in Differences between protocol and review, is in general a potential source of bias in the review process. To be consistent with the parent review of this living systematic review (Piechotta 2021), we amended our primary and secondary outcomes. We do not expect bias to arise from this deviation, as the decision to amend our methods was made independent of the results of the included studies. We also amended the way evidence is presented, with a change in summary of findings tables from population‐based to study‐based. This change was made after recommendations from the Cochrane Editorial and Methods unit, and not influenced by study findings.

Agreements and disagreements with other studies or reviews

The main results of this review are based on two studies that investigated hIVIG 0.4g/kg (ITAC 2022), and EpAbs 4 mg/kg (Lopardo 2021). This review identified low‐certainty evidence about the effects of hIVIG or EpAbs for individuals with moderate to severe COVID‐19, when compared to placebo treatment. This level of certainty applies both to improvement in mortality up to day 28 and to harms. Evidence for improvement of clinical status was of moderate certainty, meaning hIVIG or EpAbs may have little to no impact on clinical worsening up to day 28. No studies included in this review reported on quality of life. We did not identify any studies that investigated individuals with asymptomatic or mild disease.

At the time of preparation of this review, one other systematic review included completed studies on hIVIG for people with COVID‐19 (Siemieniuk 2021). As only three studies with polyclonal antibody preparations were identified, of which one studied INM‐005, one studied XAV‐19 and one studied hyperimmune immunoglobulins, the authors concluded that more research is needed to make strong recommendations. One other review included ongoing trials and discussed potential advantages and disadvantages of hIVIG over convalescent plasma and monoclonal antibodies (Focosi 2021). Another review only included studies investigating convalescent plasma (Wang 2021).

Systematic reviews targeting multiple interventions for people with COVID‐19 have not consistently included hIVIG or polyclonal antibody preparations in their results, perhaps also because these studies have all been published only very recently. We expect future reviews will include hIVIGs or polyclonal antibody preparations, as there is still a need for better treatment options for people with COVID‐19. The continued emergence of new variants could further place a focus on these types of therapies, as they could be less sensitive to developing resistance due to mutations than other treatments (e.g. monoclonal antibodies).

Systematic reviews about hIVIG for other viral diseases have been published (Devasenapathy 2020; Mair‐Jenkins 2015; Xu 2020). Evidence from these reviews is likely to be less relevant for COVID‐19, as they only include small populations, and the diseases studied are not directly comparable to COVID‐19. Nevertheless, these reviews have carefully concluded that hIVIGs are a potential treatment option for viral diseases, especially when administration is early in the disease course, with a low risk of adverse events.

Several systematic reviews have investigated intravenous immunoglobulin (IVIG), not derived from people who have recovered from an infection with SARS‐CoV‐2, for COVID‐19 (Siemieniuk 2021; Wang 2021a; Xiang 2021). Although hIVIG can be considered a subgroup of IVIG, the evidence from these reviews about IVIG does not inform decision making on adoption of hIVIG for treating people with COVID‐19, as the process of hIVIG is separate and requires more resources and standardised antibody levels. Furthermore, with hIVIG the theoretical risk of antibody‐dependent enhancement poses a potential threat that should be investigated thoroughly (Morens 1994).

Authors' conclusions

Implications for practice.

We included data from five randomised controlled trials that evaluated hyperimmune immunoglobulin (hIVIG) compared to standard therapy. As studies evaluated different preparations (from humans, from various animals) and doses, we could not pool them. hIVIG prepared from humans may have little to no impact on mortality and clinical improvement and worsening but may increase grade 3 to 4 adverse events.

RBD‐specific polyclonal F(ab´)₂ fragments of equine antibodies may reduce mortality and clinical worsening and may improve clinical status. Moreover, it may decrease serious adverse events.

None of the included studies evaluated quality of life.

Implications for research.

As most studies were very small (dose‐finding studies), findings for these interventions are very uncertain. All studies evaluated hospitalised participants with moderate to severe disease, most of them unvaccinated.

As no study evaluated hIVIG for participants with asymptomatic infection or mild disease, further studies should evaluate potential benefits and harms of hIVIG for these individuals. Moreover, specific subgroups like immunosuppressed participants might be considered.

Variants should be considered, as variants might be important for the effectiveness of hIVIG.

History

Protocol first published: Issue 10, 2021

Date	Event	Description
30 August 2020	New citation required and conclusions have changed	Additional safety data included (more than 20,000 participants)
30 August 2020	New search has been performed	Two RCTs, eight controlled NRSIs and nine non‐controlled NRSIs included
3 June 2020	New citation required and conclusions have changed	We included results from one RCT and three controlled NRSIs and added further safety data from non‐controlled NRSIs.
31 May 2020	New search has been performed	We included eight new studies.

Risk of bias

Risk of bias for analysis 1.1 All‐cause mortality at 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

ITAC 2022

Low risk of bias

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or placebo plus SOC. Adequate information was provided on the randomization procedure.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. Twelve patients (2%) did not receive the intervention, but this will probably not have a substantial impact on the study results: "Twelve participants did not receive an infusion. Ten of these participants withdrew consent prior to being infused; for one participant, venous access could not be achieved; and one participant refused the infusion but continued in follow‐up."

Low risk of bias

Data for this outcome was available in nearly all participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration and statistical analysis plan.

Low risk of bias

For the outcome "all‐cause mortality at 28 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 1.2 Clinical worsening: clinical status worsened on day 7.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

ITAC 2022

Low risk of bias

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or placebo plus SOC. Adequate information was provided on the randomization procedure.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. Twelve patients (2%) did not receive the intervention, but this will probably not have a substantial impact on the study results: "Twelve participants did not receive an infusion. Ten of these participants withdrew consent prior to being infused; for one participant, venous access could not be achieved; and one participant refused the infusion but continued in follow‐up."

Low risk of bias

The primary ordinal outcome at day 7 was available for all but seven participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The primary objective is to compare the clinical status of patients in each group on day 7 of follow‐up using the primary ordinal outcome with 7 mutually exclusive categories. The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration and statistical analysis plan.

Low risk of bias

For the outcome "clinical worsening at day 7", there is a low risk of bias for all the domains.

Risk of bias for analysis 1.3 Clinical improvement: number of participants discharged, or reaching category 1 on the WHO scale on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

ITAC 2022

Low risk of bias

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or placebo plus SOC. Adequate information was provided on the randomization procedure.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. Twelve patients (2%) did not receive the intervention, but this will probably not have a substantial impact on the study results: "Twelve participants did not receive an infusion. Ten of these participants withdrew consent prior to being infused; for one participant, venous access could not be achieved; and one participant refused the infusion but continued in follow‐up."

Low risk of bias

Data for this outcome was available in nearly all participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration and statistical analysis plan.

Low risk of bias

For the outcome "clinical improvement: number of patients discharged, or reaching category 1 on the WHO scale on day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 1.4 Adverse events at any grade on day 1.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

ITAC 2022

Low risk of bias

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or placebo plus SOC. Adequate information was provided on the randomization procedure.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. Twelve patients (2%) did not receive the intervention, but this will probably not have a substantial impact on the study results: "Twelve participants did not receive an infusion. Ten of these participants withdrew consent prior to being infused; for one participant, venous access could not be achieved; and one participant refused the infusion but continued in follow‐up."

Low risk of bias

Data for this outcome was available in nearly all participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration and statistical analysis plan.

Low risk of bias

For the outcome "safety: any adverse event on day 1", there is a low risk of bias for all the domains.

Risk of bias for analysis 1.5 Adverse events at grades 3 to 4 severity.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

ITAC 2022

Low risk of bias

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or placebo plus SOC. Adequate information was provided on the randomization procedure.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. Twelve patients (2%) did not receive the intervention, but this will probably not have a substantial impact on the study results: "Twelve participants did not receive an infusion. Ten of these participants withdrew consent prior to being infused; for one participant, venous access could not be achieved; and one participant refused the infusion but continued in follow‐up."

Low risk of bias

Data for this outcome was available in nearly all participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration and statistical analysis plan.

Low risk of bias

For the outcome "safety: grade 3 and 4 adverse events", there is a low risk of bias for all the domains.

Risk of bias for analysis 1.6 Number of participants with serious adverse events or death up to day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

ITAC 2022

Low risk of bias

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or placebo plus SOC. Adequate information was provided on the randomization procedure.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. Twelve patients (2%) did not receive the intervention, but this will probably not have a substantial impact on the study results: "Twelve participants did not receive an infusion. Ten of these participants withdrew consent prior to being infused; for one participant, venous access could not be achieved; and one participant refused the infusion but continued in follow‐up."

Low risk of bias

Data for this outcome was available in nearly all participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration and statistical analysis plan.

Low risk of bias

For the outcome "Number of patients with serious adverse events or death up to day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 1.7 Mortality (time to event).

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

ITAC 2022

Low risk of bias

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or placebo plus SOC. Adequate information was provided on the randomization procedure.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. Twelve patients (2%) did not receive the intervention, but this will probably not have a substantial impact on the study results: "Twelve participants did not receive an infusion. Ten of these participants withdrew consent prior to being infused; for one participant, venous access could not be achieved; and one participant refused the infusion but continued in follow‐up."

Low risk of bias

Data for this outcome was available in nearly all participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration and statistical analysis plan.

Low risk of bias

For the outcome "mortality (time to event)", there is a low risk of bias for all the domains.

Risk of bias for analysis 2.1 All‐cause mortality at 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopardo 2021

Low risk of bias

Participants were randomized via R software block randomization method in a 1:1 ratio, to receive either INM005 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. A number of participants did not receive study medication: "One participant in each study group did not receive the protocol‐defined intervention" and "nine patients in the placebo group and one patient in the INM005 group had protocol deviations that precluded the completion of the study intervention"

Low risk of bias

Data for this outcome was available for 241 out of 245 participants. Authors state: "No patient was lost to follow up, neither discontinued study treatment due to a treatment emergent adverse event."

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Low risk of bias

For the outcome "all‐cause mortality at 28 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 2.2 Worsening of clinical status: admission to ICU, need for mechanical ventilation, or death by day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopardo 2021

Low risk of bias

Participants were randomized via R software block randomization method in a 1:1 ratio, to receive either INM005 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. A number of participants did not receive study medication: "One participant in each study group did not receive the protocol‐defined intervention" and "nine patients in the placebo group and one patient in the INM005 group had protocol deviations that precluded the completion of the study intervention"

Low risk of bias

Data for this outcome was available for 241 out of 245 participants. Authors state: "No patient was lost to follow up, neither discontinued study treatment due to a treatment emergent adverse event."

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Low risk of bias

For the outcome "clinical worsening: admission to ICU, need for mechanical ventilation or death by day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 2.3 Improvement of clinical status: number of patients discharged on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopardo 2021

Low risk of bias

Participants were randomized via R software block randomization method in a 1:1 ratio, to receive either INM005 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. A number of participants did not receive study medication: "One participant in each study group did not receive the protocol‐defined intervention" and "nine patients in the placebo group and one patient in the INM005 group had protocol deviations that precluded the completion of the study intervention"

Low risk of bias

Data for this outcome was available for 241 out of 245 participants. Authors state: "No patient was lost to follow up, neither discontinued study treatment due to a treatment emergent adverse event."

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Low risk of bias

For the outcome "clinical improvement: number of patients discharged on day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 2.4 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopardo 2021

Low risk of bias

Participants were randomized via R software block randomization method in a 1:1 ratio, to receive either INM005 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. A number of participants did not receive study medication: "One participant in each study group did not receive the protocol‐defined intervention" and "nine patients in the placebo group and one patient in the INM005 group had protocol deviations that precluded the completion of the study intervention"

Low risk of bias

Data for this outcome was available for 241 out of 245 participants. Authors state: "No patient was lost to follow up, neither discontinued study treatment due to a treatment emergent adverse event."

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the outcome stated in the protocol.

Low risk of bias

For the outcome "safety", there is a low risk of bias for all the domains.

Risk of bias for analysis 2.5 Serious adverse events.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopardo 2021

Low risk of bias

Participants were randomized via R software block randomization method in a 1:1 ratio, to receive either INM005 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. A number of participants did not receive study medication: "One participant in each study group did not receive the protocol‐defined intervention" and "nine patients in the placebo group and one patient in the INM005 group had protocol deviations that precluded the completion of the study intervention"

Low risk of bias

Data for this outcome was available for 241 out of 245 participants. Authors state: "No patient was lost to follow up, neither discontinued study treatment due to a treatment emergent adverse event."

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the outcome stated in the protocol.

Low risk of bias

For the outcome "safety", there is a low risk of bias for all the domains.

Risk of bias for analysis 2.6 Mortality (time to event).

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopardo 2021

Low risk of bias

Participants were randomized via R software block randomization method in a 1:1 ratio, to receive either INM005 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. A number of participants did not receive study medication: "One participant in each study group did not receive the protocol‐defined intervention" and "nine patients in the placebo group and one patient in the INM005 group had protocol deviations that precluded the completion of the study intervention"

Low risk of bias

Data for this outcome was available for 241 out of 245 participants. Authors state: "No patient was lost to follow up, neither discontinued study treatment due to a treatment emergent adverse event."

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Low risk of bias

For the outcome "mortality: time‐to‐event", there is a low risk of bias for all the domains.

Risk of bias for analysis 2.7 Admission to ICU at day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopardo 2021

Low risk of bias

Participants were randomized via R software block randomization method in a 1:1 ratio, to receive either INM005 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. A number of participants did not receive study medication: "One participant in each study group did not receive the protocol‐defined intervention" and "nine patients in the placebo group and one patient in the INM005 group had protocol deviations that precluded the completion of the study intervention"

Low risk of bias

Data for this outcome was available for 241 out of 245 participants. Authors state: "No patient was lost to follow up, neither discontinued study treatment due to a treatment emergent adverse event."

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Low risk of bias

For the outcome "admission to ICU at day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 3.1 All‐cause mortality at 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "all‐cause mortality at 28 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 3.2 Improvement of clinical status: number of participants discharged on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "number of patients discharged on day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 3.3 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety", there is a low risk of bias for all the domains.

Risk of bias for analysis 4.1 All‐cause mortality at 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "all‐cause mortality at 28 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 4.2 Improvement of clinical status: number of participants discharged on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "number of patients discharged on day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 4.3 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety", there is a low risk of bias for all the domains.

Risk of bias for analysis 5.1 All‐cause mortality at 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "all‐cause mortality at 28 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 5.2 Improvement of clinical status: number of participants discharged on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "number of patients discharged on day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 5.3 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety", there is a low risk of bias for all the domains.

Risk of bias for analysis 6.2 Improvement of clinical status: number of participants discharged on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "number of patients discharged on day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 6.3 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Ali 2021

Low risk of bias

Participants were randomized through sequentially numbered opaque sealed envelope simple randomization method in a 4:1 ratio to receive either hIVIG plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants were unaware of their assigned intervention and those delivering the intervention were aware of intervention assigned during the trial, but there were no deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all 50 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received would have affected outcome measurement.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety", there is a low risk of bias for all the domains.

Risk of bias for analysis 7.1 Improvement of clinical status: number of participants discharged on day 60.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "Clinical improvement: number of patients discharged on day 60", there is a low risk of bias for all the domains.

Risk of bias for analysis 7.2 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: any adverse event", there is a low risk of bias for all the domains.

Risk of bias for analysis 7.3 Adverse events at grades 3 to 4 severity.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: grade 3‐4 adverse events", there is a low risk of bias for all the domains.

Risk of bias for analysis 7.4 All‐cause mortality at 60 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion"

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "all‐cause mortality at 60 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 7.5 Adverse events at grades 1 to 2 severity.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: grade 1‐2 adverse events", there is a low risk of bias for all the domains.

Risk of bias for analysis 7.6 Admission to ICU on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Some concerns

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration, but it was unclear whether the timepoint was the same.

Some concerns

For the outcome "ICU admission", there are some concerns about the risk of bias due to multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain as the timepoint for this outcome was not specified in the paper.

Risk of bias for analysis 8.1 Improvement of clinical status: number of participants discharged on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "Clinical improvement: number of patients discharged on day 28", there is a low risk of bias for all the domains.

Risk of bias for analysis 8.2 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: any adverse event", there is a low risk of bias for all the domains.

Risk of bias for analysis 8.3 Adverse events at grades 3 to 4 severity.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: grade 3‐4 adverse events", there is a low risk of bias for all the domains.

Risk of bias for analysis 8.4 All‐cause mortality at 60 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "all‐cause mortality at 60 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 8.5 Adverse events at grades 1 to 2 severity.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: grade 1‐3 adverse events", there is a low risk of bias for all the domains.

Risk of bias for analysis 8.6 Admission to ICU on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Some concerns

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration, but it was unclear whether the timepoint was the same.

Some concerns

For the outcome "ICU admission", there are some concerns about the risk of bias due to multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain as the timepoint for this outcome was not specified in the paper.

Risk of bias for analysis 9.1 Improvement of clinical status: number of participants discharged on day 60.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "Clinical improvement: number of patients discharged on day 60", there is a low risk of bias for all the domains.

Risk of bias for analysis 9.2 Adverse events at any grade.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: any adverse event", there is a low risk of bias for all the domains.

Risk of bias for analysis 9.3 Adverse events at grades 3 to 4 severity.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: grade 3‐4 adverse events", there is a low risk of bias for all the domains.

Risk of bias for analysis 9.4 All‐cause mortality at 60 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "all‐cause mortality at 60 days", there is a low risk of bias for all the domains.

Risk of bias for analysis 9.5 Adverse events at grades 1 to 2 severity.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for all 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the protocol and trial registration.

Low risk of bias

For the outcome "safety: grade 1‐2 adverse events", there is a low risk of bias for all the domains.

Risk of bias for analysis 9.6 Admission to ICU on day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Gaborit 2021

Low risk of bias

Participants were randomized via EnnovClinical software block randomization method in a 1:1 ratio or 5:1 ratio, to receive either XAV‐19 plus SOC or only SOC. The allocation sequence was random and concealed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

Both participants and carers and people delivering the intervention were unaware of the assigned intervention received and the analysis was appropriate. One patient withdrew consent before the second infusion, but this will probably not have a substantial impact on the study results: "18 patients with COVID‐19‐related moderate pneumonia were randomized: 1 withdrew consent before the day 5 second infusion".

Low risk of bias

Data for this outcome was available for 17 out of 18 participants randomized.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups. The outcome assessors were not aware of the intervention received.

Some concerns

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration, but it was unclear whether the timepoint was the same.

Some concerns

For the outcome "ICU admission", there are some concerns about the risk of bias due to multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain as the timepoint for this outcome was not specified in the paper.

Risk of bias for analysis 10.1 All‐cause mortality at 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Parikh 2021

Some concerns

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or only SOC. The allocation sequence was random but there was no information provided on how the randomisation and concealment of treatment allocation were performed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants and those delivering the intervention were aware of intervention assigned during the trial, but there were only few deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for 59 out of 60 participants.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Some concerns

For the outcome "all‐cause mortality at 28 days", there are some concerns about the risk of bias due to no information provided on how the randomisation and concealment of treatment allocation were performed.

Risk of bias for analysis 10.2 Serious adverse events.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Parikh 2021

Some concerns

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or only SOC. The allocation sequence was random but there was no information provided on how the randomisation and concealment of treatment allocation were performed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants and those delivering the intervention were aware of intervention assigned during the trial, but there were only few deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for all study participants.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Some concerns

For the outcome "safety", there are some concerns about the risk of bias due to the randomization process due to no information provided on how the randomisation and concealment of treatment allocation were performed. There was a a low risk of bias for the other domains.

Risk of bias for analysis 10.3 Negative RT‐PCR test on day 3.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Parikh 2021

Some concerns

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or only SOC. The allocation sequence was random but there was no information provided on how the randomisation and concealment of treatment allocation were performed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants and those delivering the intervention were aware of intervention assigned during the trial, but there were only few deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for 59 out of 60 participants.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Some concerns

This outcome was not reported in the trial registry and likely not analysed according to a pre‐specified plan.

Some concerns

For the outcome "viral clearance", there are some concerns about the risk of bias due to no information provided on how the randomisation and concealment of treatment allocation were performed and selection of the reported result. There was a a low risk of bias for the other domains.

Risk of bias for analysis 10.4 Negative RT‐PCR test on day 7.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Parikh 2021

Some concerns

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or only SOC. The allocation sequence was random but there was no information provided on how the randomisation and concealment of treatment allocation were performed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants and those delivering the intervention were aware of intervention assigned during the trial, but there were only few deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for 59 out of 60 participants.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Some concerns

This outcome was not reported in the trial registry and likely not analysed according to a pre‐specified plan.

Some concerns

For the outcome "viral clearance", there are some concerns about the risk of bias due to no information provided on how the randomisation and concealment of treatment allocation were performed and selection of the reported result. There was a a low risk of bias for the other domains.

Risk of bias for analysis 10.5 Negative RT‐PCR on day 15.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Parikh 2021

Some concerns

Participants were randomized in a 1:1 ratio, to receive either hIVIG plus SOC or only SOC. The allocation sequence was random but there was no information provided on how the randomisation and concealment of treatment allocation were performed. There are no baseline differences that would suggest a problem with randomisation.

Low risk of bias

The participants and those delivering the intervention were aware of intervention assigned during the trial, but there were only few deviations from intended interventions and the analysis was appropriate.

Low risk of bias

Data for this outcome was available for 59 out of 60 participants.

Low risk of bias

The outcome assessors were aware of the intervention received, but it is unlikely that knowledge of intervention received could have affected outcome measurement or that the measurement differed between intervention groups.

Some concerns

This outcome was not reported in the trial registry and likely not analysed according to a pre‐specified plan.

Some concerns

For the outcome "viral clearance", there are some concerns about the risk of bias due to no information provided on how the randomisation and concealment of treatment allocation were performed and selection of the reported result. There was a a low risk of bias for the other domains.

Appendices

Appendix 1. Glossary of abbreviations and medical terms used in the review

Abbreviations

ACE2: angiotensin‐converting enzyme 2, a protein on the surface of many cells in the body

ARDS: acute respiratory distress syndrome, severe inflammation of the lungs following infection or injury

hIVIG: hyperimmune intravenous immunoglobulin, the intervention of interest in this review

IgE: immunoglobulin E, one of the five major classes of immunoglobulins with a role in allergic diseases

IgG: immunoglobulin G, one of the five major classes of immunoglobulins

MERS: Middle East respiratory syndrome, a coronavirus disease related to COVID‐19

NRSI: non‐randomised study of an intervention, a trial that compares two or more groups, but participants are not assigned to the groups randomly

pH: power of hydrogen, a standard scale for measuring acidity

REGN‐COV2: brand name of Regeneron Pharmaceuticals' antibody cocktail casirivimab/imdevimab, used to treat COVID‐19

SARS: severe acute respiratory syndrome, a coronavirus disease related to COVID‐19

SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2, the virus that causes COVID‐19

TACO: transfusion‐associated circulatory overload, a serious transfusion reaction, defined as acute or worsening swelling in the lungs during transfusion, or up to 12 hours afterwards. Alongside this, there can be cardiovascular changes which are caused by the transfusion and not by a patient’s underlying condition.

TAD: transfusion‐associated dyspnoea, difficulty in breathing caused by the body reacting to transfusion

TRALI: transfusion‐related acute lung injury, a serious transfusion reaction defined as a new and sudden lung injury, occurring within six hours of transfusion

WHO: World Health Organization, the United Nations agency dedicated to health promotion

WHOQOL‐100: a 100‐question standardised scale for assessing quality of life

Medical terms relating to hIVIG

Antibody‐dependent enhancement: a phenomenon where antibody treatment may cause the symptoms caused by the virus to be more severe

Antibody titre: the level of concentration of antibodies in blood or plasma

Antigen‐binding antibody fragments/fragment antibodies: antibodies that have been manipulated in a laboratory to make a smaller molecule

Anaphylactic reaction: a serious allergic reaction involving the IgE‐producing cells in the immune system

Anaphylactoid reaction: a serious allergic reaction not involving the IgE‐producing cells in the immune system

T cells: cells in the immune system produced in the thymus

Coagulation factors: proteins in the blood which control bleeding

Convalescent plasma: plasma from a person who has recovered from COVID‐19, containing the antibodies they made to the disease

Erythema: skin redness caused by inflammation of small blood vessels

Granulocytic cells: a type of immune cell that secretes enzymes during infection

Haemolytic reaction: a serious reaction to transfusion, where the recipient's body destroys the donated cells

Hyperimmune animal sera: a product containing antibodies extracted and produced from animals immunised with live virus

Macrophages: a type of white blood cell that removes dead cells

Microbodies: antibodies that have been manipulated in a laboratory to be smaller and more consistent

Monoclonal antibody therapy: a type of antibody originating from identical B‐cells, produced in a laboratory

Monocytes: the largest type of white blood cell

Nanobodies: antibodies that have been manipulated in a laboratory to be smaller and more consistent

Pathogen‐specific neutralising antibodies: antibodies to a specific illness, which prevent virus cells from entering healthy cells in the body

Pleural effusion: build up of fluid around the lungs

Polyclonal antibodies: a mixture of several antibodies, which originate from different B‐cells, and are prepared in a laboratory

Post‐exposure prophylaxis: a treatment given to someone who has come into contact with COVID‐19 but does not have the disease, to prevent them from becoming ill

Pre‐exposure prophylaxis: a treatment given to someone who does not have COVID‐19 but might come into contact with it in the future, to prevent them from becoming ill

Pulmonary embolism: a blood clot in the lungs

Pulmonary oedema: fluid in the lungs

Seronegative: the person does not have detectable antibodies to the virus in their blood

Seropositive: the person has detectable antibodies to the virus in their blood

Standard intravenous immunoglobulin: a product produced from donated plasma, containing antibodies

Transfusion‐transmitted infection: an infection caused by bacteria, virus, or parasite in a donated blood product

Appendix 2. Search strategies

MEDLINE OVID

# Searches

1. Coronavirus Infections/ or Coronavirus/ or SARS‐CoV‐2/ or COVID‐19/

2. ("2019 nCoV" or 2019nCoV or coronavir* or coronovir* or COVID or COVID19 or HCoV* or "nCov 2019" or "SARS CoV2" or "SARS CoV 2" or SARSCoV2 or "SARSCoV 2" or anti‐flu* or anti‐influenza* or antiflu* or antinfluenza*).tw,kf.

3. ((corona* or corono*) adj1 (virus* or viral* or virinae*)).tw,kf.

4. "severe acute respiratory syndrome coronavirus 2".tw,kf,nm.

5. or/1‐4

6. Plasma/ or Immunoglobulins/ or Immunoglobulins, Intravenous/ or Immune Sera/

7. ((convalesc* or recovered or cured or rehabilitat* or survivor* or survived or virus‐positive or virus neutrali* or virus inactivated or antibod* or high‐titre* or high‐titer*) adj6 (plasma or blood or serum or sera)).tw,kf.

8. (high‐dos* adj3 (plasma or immunoglobulin* or IVIG* or immune globulin* or globulin* or IgG)).tw,kf.

9. ((plasma adj1 therap*) or gamma‐globulin or gammaglobulin or "y‐Globulin" or hyper‐lg or "C19‐IG").tw,kf.

10. (plasma adj5 (immun* or antibod* or exchange* or donor* or donat* or transfus* or infus*)).tw,kf.

11. ((convalesc* or recovered or cured or rehabilitat* or survivor* or survived or virus‐positive or virus inactivated or antibody‐positive) adj5 (donor* or donat*)).tw,kf.

12. (hyperimmune* or hyper‐immune* or serotherap* or sero‐therap*).tw,kf.

13. exp Immunization, Passive/

14. (passiv* adj3 (antibod* transfer* or immunization* or immunotherap* or immuno‐therap* or vaccin*)).tw,kf.

15. (passiv* adj3 (therap* or treatment* or neutrali?ing or prevent* or protect* or prophylax*)).tw,kf.

16. ((immunoglobulin* or immune globulin*) adj2 (therap* or treatment* or prevent* or protect* or prophylax*)).tw,kf.

17. (passive immunit* or hIVIG or CSL760 or INM005 or XAV‐19 or SAB‐185 or equine or IgY‐110 or IgY110 or GIGA‐2050 or GIGA2050 or GC5131 or 5131A).tw,kf.

18. (((anti‐coronavirus or anticoronavirus) adj1 immunoglobulin*) or ITAC or "Hyperimmune anti‐COVID‐19 IVIG" or C‐IVIG or CIVIG or equine polyclonal antibod* or EpAbs or BSVEQAb or EqAb‐COV‐19 or flebogamma or "F(ab)2").tw,kf.

19. ((bovine adj2 (colostrum* or milk*)) or bioblock*).tw,kf.

20. or/6‐19

21. 5 and 20

22. "Covid‐19 Serotherapy".px.

23. or/21‐22

24. randomized controlled trial.pt.

25. controlled clinical trial.pt.

26. randomi?ed.ab.

27. placebo.ab.

28. drug therapy.fs.

29. randomly.ab.

30. trial.ab.

31. groups.ab.

32. or/24‐31

33. exp animals/ not humans/

34. 32 not 33

35. clinical trial, phase iii/

36. ("Phase 3" or "phase3" or "phase III" or P3 or "PIII").ti,ab,kw.

37. (35 or 36) not 33

38. 34 or 37

39. 23 and 38

40. limit 39 to yr="2020 ‐Current"

41. remove duplicates from 40

Embase OVID

# Searches

1. coronavirinae/ or coronaviridae/ or coronaviridae infection/ or coronavirus disease 2019/ or Coronavirus infection/

2. sars‐related coronavirus/ or "Severe acute respiratory syndrome coronavirus 2"/

3. ((corona* or corono*) adj1 (virus* or viral* or virinae*)).tw,kw.

4. ("2019 nCoV" or 2019nCoV or coronavir* or coronovir* or COVID or COVID19 or HCoV* or "nCov 2019" or "SARS CoV2" or "SARS CoV 2" or SARSCoV2 or "SARSCoV 2").tw,kw.

5. "Severe acute respiratory syndrome coronavirus 2".mp.

6. or/1‐5

7. Plasma Transfusion/ or exp Immunoglobulin/

8. ((convalesc* or recovered or cured or survivor* or survived or rehabilitat* or virus‐positive or virus‐neutrali* or virus inactived or antibody‐rich or high‐tire* or high‐titer*) adj6 (plasma or blood or serum or sera)).mp.

9. ((plasma adj1 therap*) or gamma‐globulin or gammaglobulin or "y‐Globulin" or hyper‐lg or "C19‐IG").tw,kw.

10. (plasma adj5 (immun* or antibod* or exchange* or donor* or donat* or transfus* or infus*)).tw,kw.

11. (high‐dos* adj3 (plasma or immunoglobulin* or IVIG* or immune globulin* or globulin* or IgG)).tw,kw.

12. ((convalesc* or recovered or cured or rehabilitat* or survivor* or survived or virus‐positive or virus inactivated or antibody‐positive) adj5 (donor* or donat*)).tw,kw.

13. (serotherap* or sero‐therap* or hyperimmune* or hyper‐immune*).tw,kw.

14. passive immunization/

15. (passiv* adj3 (therap* or treatment* or neutrali?ing or prevent* or protect* or prophylax*)).tw,kw.

16. (passive immunit* or hIVIG or CSL760 or INM005 or XAV‐19 or SAB‐185 or equine or IgY‐110 or IgY110 or GIGA‐2050 or GIGA2050 or GC5131 or 5131A).tw,kw.

17. (passiv* adj3 (antibod* transfer* or immunization* or immunotherap* or immuno‐therap* or vaccin*)).tw,kw.

18. ((immunoglobulin* or immune globulin*) adj2 (therap* or treatment* or prevent* or protect* or prophylax*)).tw,kw.

19. (((anti‐coronavirus or anticoronavirus) adj1 immunoglobulin*) or ITAC or "Hyperimmune anti‐COVID‐19 IVIG" or C‐IVIG or CIVIG or equine polyclonal antibod* or EpAbs or BSVEQAb or EqAb‐COV‐19 or flebogamma or "F(ab)2").tw,kw.

20. ((bovine adj2 (colostrum* or milk*)) or bioblock*).tw,kw.

21. or/7‐20

22. Randomized controlled trial/

23. Controlled clinical trial/

24. random*.ti,ab.

25. randomization/

26. intermethod comparison/

27. placebo.ti,ab.

28. (compare or compared or comparison).ti.

29. ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab.

30. (open adj label).ti,ab.

31. ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.

32. double blind procedure/

33. parallel group*1.ti,ab.

34. (crossover or cross over).ti,ab.

35. ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.

36. (assigned or allocated).ti,ab.

37. (controlled adj7 (study or design or trial)).ti,ab.

38. (volunteer or volunteers).ti,ab.

39. human experiment/

40. trial.ti.

41. or/22‐40

42. (random$ adj sampl$ adj7 (cross section$ or questionnaire$1 or survey$ or database$1)).ti,ab. not (comparative study/ or controlled study/ or randomi?ed controlled.ti,ab. or randomly assigned.ti,ab.)

43. Cross‐sectional study/ not (randomized controlled trial/ or controlled clinical study/ or controlled study/ or randomi?ed controlled.ti,ab. or control group$1.ti,ab.)

44. (((case adj control$) and random$) not randomi?ed controlled).ti,ab.

45. (Systematic review not (trial or study)).ti.

46. (nonrandom$ not random$).ti,ab.

47. Random field$.ti,ab.

48. (random cluster adj3 sampl$).ti,ab.

49. (review.ab. and review.pt.) not trial.ti.

50. we searched.ab. and (review.ti. or review.pt.)

51. update review.ab.

52. (databases adj4 searched).ab.

53. (rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti. and animal experiment/

54. Animal experiment/ not (human experiment/ or human/)

55. or/42‐54

56. 41 not 55

57. phase 3 clinical trial/

58. ("Phase 3" or "phase3" or "phase III" or P3 or "PIII").tw,kw.

59. (animal experiment/ or Animal experiment/) not (human experiment/ or human/)

60. (57 or 58) not 59

61. 57 or 58

62. 61 not 59

63. 6 and 21 and (56 or 60)

64. limit 63 to yr="2020 ‐Current"

65. limit 64 to medline

66. 64 not 65

67. remove duplicates from 66

Cochrane COVID‐19 Study Register

plasma or convalesc* or serum or sera or donor* or donation* or serotherapy or "sero‐therapy" or "flu‐IVIG" or "passive immunity" or hyperimmune* or "hyper‐immune" or IVIG or immunoglobulin* or "immune‐globulin" or "immune‐globuline" or globulin* or "gamma‐globulin" or "γ‐Globulin" or "hyper‐Ig" or immunization or immunisation or immunotherap* or "immuno‐therapy" or CSL760 or INM005* or equine* or "XAV‐19" or "SAB‐185" or hIVIG* or INOSARS* or "GIGA‐2050" or GIGA2050 or "IGY‐110" or IGY1109 or "GC5131" or "5131A" or ITAC* or "C‐IVIG" or CIVIG or flebogamma* or EpAbs* or BSVEQAb* or "EqAb‐COV‐19" or "F(ab)2" or "bovine colostrum" or "bovine milk" or "SARS‐CoV‐2‐IG" or "hyper‐Ig" or bioblock*

Study characteristics:

1) Intervention assignment: randomised, unclear

2) Study design: parallel/crossover, unclear"

PubMed

#1 "2019 ncov"[Title/Abstract] OR "2019nCoV"[Title/Abstract] OR "corona virus"[Title/Abstract] OR "corona viruses"[Title/Abstract] OR "Coronavirus"[Title/Abstract] OR "coronaviruses"[Title/Abstract] OR "COVID"[Title/Abstract] OR "COVID19"[Title/Abstract] OR "ncov 2019"[Title/Abstract] OR "SARS‐CoV2"[Title/Abstract] OR "SARS‐CoV‐2"[Title/Abstract] OR "SARSCoV2"[Title/Abstract] OR "SARSCoV‐2"[Title/Abstract] OR "COVID‐19"[MeSH Terms] OR "Coronavirus"[MeSH Terms:noexp] OR "SARS‐CoV‐2"[MeSH Terms] OR "COVID‐19"[Supplementary Concept] OR "severe acute respiratory syndrome coronavirus 2"[Supplementary Concept]

#2 ("convalesc*"[Title/Abstract] OR "recovered"[Title/Abstract] OR "cured"[Title/Abstract] OR "rehabilitat*"[Title/Abstract] OR "survivor*"[Title/Abstract] OR "survived"[Title/Abstract] OR "virus‐positive"[Title/Abstract] OR "virus neutrali*"[Title/Abstract] OR "virus inactivated"[Title/Abstract] OR "antibod*"[Title/Abstract] OR "high titre*"[Title/Abstract] OR "high titer*"[Title/Abstract]) AND ("plasma"[Title/Abstract] OR "blood"[Title/Abstract] OR "donor*"[Title/Abstract] OR "donat*"[Title/Abstract])

#3 ("plasma"[Title] AND ("immun*"[Title/Abstract] OR "transfus*"[Title/Abstract] OR "infus*"[Title/Abstract] OR "exchange*"[Title/Abstract]))

#4 "high dos*"[Title/Abstract] AND ("plasma"[Title/Abstract] OR "immunoglobulin*"[Title/Abstract] OR "ivig*"[Title/Abstract] OR "immune globulin*"[Title/Abstract] OR "globulin*"[Title/Abstract] OR "IgG"[Title/Abstract])

#5 "immunization, passive"[MeSH Terms] OR "passive immunit*"[Title/Abstract] OR "hyperimmune"[Title/Abstract] OR "hyperimmunity"[Title/Abstract] OR "serotherap*"[Title/Abstract] OR "sero therap*"[Title/Abstract] OR "therapeutic plasma"[Title/Abstract] OR "plasma therapy"[Title/Abstract] OR "immune plasma"[Title/Abstract] OR "plasma exchange"[Title/Abstract] OR "serum"[Title] OR "sera"[ Title]

#6 "passiv*"[Title/Abstract] AND (("antibod*"[Title/Abstract] AND "transfer*"[Title/Abstract]) OR "immunisation*"[Title/Abstract] OR "vaccin*"[Title/Abstract] OR "immunization*"[Title/Abstract] OR "immunotherap*"[Title/Abstract] OR "immuno therap*"[Title/Abstract])

#7 ("immunoglobulin*"[Title] OR "immune globulin*"[Title]) AND ("therap*"[Title/Abstract] OR "treat*"[Title/Abstract] OR "prevent*"[Title/Abstract] OR "protect*"[Title/Abstract] OR "prophylax*"[Title/Abstract])

#8 "bovine colostrum"[Title/Abstract] OR "bovine milk"[Title/Abstract] OR "F(ab)2"[Title/Abstract] OR "equine*"[Title/Abstract] OR "Hyperimmune anti‐COVID‐19 IVIG"[Title/Abstract] OR "c ivig*"[Title/Abstract] OR "XAV‐19"[Title/Abstract] OR "5131A"[Title/Abstract] OR "equine polyclonal antibod*"[Title/Abstract] OR "EpAbs"[Title/Abstract] OR "flebogamma*"[Title/Abstract] OR "BSVEQAb"[Title/Abstract] OR "EqAb‐COV‐19"[Title/Abstract] OR "γ‐Globulin"[Title/Abstract] OR "hyper‐Ig"[Title/Abstract] OR Title/Abstract] OR INM005*[Title/Abstract] OR "SAB‐185"[Title/Abstract] OR hIVIG*[Title/Abstract] OR INOSARS*[Title/Abstract] OR "GIGA‐2050"[Title/Abstract] OR GIGA2050[Title/Abstract] OR "IGY‐110"[Title/Abstract] OR "GC5131"[Title/Abstract] OR "5131A"[Title/Abstract] OR ITAC*[Title/Abstract] OR "C‐IVIG"[Title/Abstract] OR CIVIG[Title/Abstract] OR XVR011* [Title/Abstract] OR bioblock*[Title/Abstract] OR "gammaglobulin*"[Title/Abstract] OR "gamma‐globulin"[Title/Abstract] OR "hyper‐Ig"[Title/Abstract]

#9 (("anti‐coronavirus"[Title/Abstract] OR "anticoronavirus"[Title/Abstract]) AND "immunoglobulin*"[Title/Abstract]))

#10 #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9

#11 #1 AND #10

#12 ((randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab] NOT (animals [mh] NOT humans [mh]))

#13 (publisher[sb] OR inprocess[sb] OR pubmednotmedline[sb])

#14 #11 AND #12 AND #13

Filters: from 2020/1/1 ‐ 3000/12/12

World Health Organization COVID‐19 Global literature on coronavirus disease

Advanced search: search fileds: title, abstract subject

Search I:

random* or placebo or trial or groups or "phase 3" or "phase3" or p3 or "pIII"

and

convalesc*~6plasma or convalesc*~6blood or convalesc*~6serum or convalesc*~6sera or cured~6plasma or cc‐ured~6blood or cured~6serum or cured~6sera or survivor*~6plasma or survivor*~6blood or survivor*~6serum or survivor*~6sera or survived*~6plasma or survived*~6blood or survived*~6serum or survived*~6sera or rehabilitat*~6plasma or rehabilitat*~6blood or rehabilitat*~6serum or rehabilitat*~6sera or virus‐positive~6plasma or virus‐positive~6blood or virus‐positive~6serum or virus‐positive~6sera or virus‐neutrali*~6plasma or virus‐neutrali*~6blood or virus‐neutrali*~6serum or virus‐neutrali*~6sera or virus inactived~6plasma or virus inactived~6blood or virus inactived~6serum or virus inactived~6sera or antibody‐rich~6plasma or antibody‐rich~6blood or antibody‐rich~6serum or antibody‐rich~6sera or high‐tire*~6plasma or high‐tire*~6blood or high‐tire*~6serum or high‐tire*~6sera or high‐titer*~6plasma or high‐titer*~6blood or high‐titer*~6serum or high‐titer*~6sera or plasma~1therap*

Search II:

random* or placebo or trial or groups or "phase 3" or "phase3" or p3 or "pIII"

and

gamma‐globulin or "y‐Globulin" or hyper‐lg or plasma~5immun* or plasma~5antibod* or plasma~5exchange* or plasma~5donor* or plasma~5 donat* or plasma~5transfus* or plasma~5infus* or high‐dos*~3plasma or high‐dos*~3immunoglobulin* or high‐dos*~3IVIG* or high‐dos*~3immune globulin* or high‐dos*~3globulin* or high‐dos*~3IgG or convalesc*~5donor* or recovered~5donor* or cured~5donor* or rehabilitat*~5donor* or survivor*~5donor* or survived~5donor* or virus‐positive~5donor* or virus inactivated~5donor* or antibody‐positive~5donor* or convalesc*~5donat or recovered~5donat or cured~5donat or rehabilitat*~5donat or survivor*~5donat or survived~5donat or virus‐positive~5donat or virus inactivated~5donat or antibody‐positive~5donat or serotherap* or sero‐therap* or hyperimmune*

Search III:

random* or placebo or trial or groups or "phase 3" or "phase3" or p3 or "pIII"

and

hyper‐immune* or passiv*~3therap* or passiv*~3treatment* or passiv*~3neutralising or passiv*~3neutralizing or passiv*~3prevent* or passiv*~3protect* or passiv*~3prophylax* or immunoglobulin*~2therap* or immunoglobulin*~2treat* or immunoglobulin*~2prevent* or immunoglobulin*~2protect* or immunoglobulin*~2prophylax* or immune globulin*~2therap* or immune globulin*~2treat* or immune globulin*~2prevent* or immune globulin*~2protect* or immune globulin*~2 or passive immunit*

Search IV:

random* or placebo or trial or groups or "phase 3" or "phase3" or p3 or "pIII"

and

hIVIG or CSL760 or INM005 or "XAV‐19" or "SAB‐185" or equine or "IgY‐110" or IgY110 or "GIGA‐2050" or GIGA2050 or GC5131 or 5131A or ITAC or "Hyperimmune anti‐COVID‐19 IVIG" or C‐IVIG or CIVIG or EpAbs or BSVEQAb or "EqAb‐COV‐19" or flebogamma or bovine~2colostrum* or bovine~2milk*

Search V:

random* or placebo or trial or groups or "phase 3" or "phase3" or p3 or "pIII"

and

passiv*~3antibod* or passiv*~3transfer* or passiv*~3immunization* or passiv*~3immunotherap* or passiv*~3immuno‐therap* or passiv*~3vaccin* or anti‐coronavirus~1immunoglobulin* or anticoronavirus~1immunoglobulin*

Epistemonikos, L*OVE List Coronavirus disease (COVID‐19)

Covid‐19 by PICO

Prevention or treatment: passive immunization: antibody therapies: convalescent plasma

Filtered by primary studies and results by RCT

Prevention or treatment: passive immunization: antibody therapies: immunoglobulin therapy

Filtered by primary studies and results by RCT

Prevention or treatment: passive immunization: Heterologous antibodies

Filtered by primary studies and results by RCT

Data and analyses

Comparison 1. hIVIG 0.4 g/kg (capped at 40 g) versus placebo (saline).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality at 28 days	1	579	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.43, 1.44]
1.2 Clinical worsening: clinical status worsened on day 7	1	579	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.58, 1.23]
1.3 Clinical improvement: number of participants discharged, or reaching category 1 on the WHO scale on day 28	1	579	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.97, 1.08]
1.4 Adverse events at any grade on day 1	1	579	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.81, 1.18]
1.5 Adverse events at grades 3 to 4 severity	1	579	Risk Ratio (M‐H, Random, 95% CI)	4.09 [1.39, 12.01]
1.6 Number of participants with serious adverse events or death up to day 28	1	572	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.45, 1.14]
1.7 Mortality (time to event)	1		Hazard Ratio (IV, Random, 95% CI)	0.80 [0.42, 1.52]

Comparison 2. Equine polyclonal antibodies (EpAbs) versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality at 28 days	1	241	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.26, 1.37]
2.2 Worsening of clinical status: admission to ICU, need for mechanical ventilation, or death by day 28	1	241	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.38, 1.18]
2.3 Improvement of clinical status: number of patients discharged on day 28	1	241	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.96, 1.17]
2.4 Adverse events at any grade	1	243	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.74, 1.31]
2.5 Serious adverse events	1	243	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.38, 1.19]
2.6 Mortality (time to event)	1		Hazard Ratio (IV, Random, 95% CI)	0.58 [0.24, 1.37]
2.7 Admission to ICU at day 28	1	241	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.37, 1.24]

Comparison 3. hIVIG 0.15 g/kg versus standard care.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 All‐cause mortality at 28 days	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.09, 1.27]
3.2 Improvement of clinical status: number of participants discharged on day 28	1	20	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.88, 4.54]
3.3 Adverse events at any grade	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.56, 1.78]

Comparison 4. hIVIG 0.2 g/kg versus standard care.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 All‐cause mortality at 28 days	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.17, 1.46]
4.2 Improvement of clinical status: number of participants discharged on day 28	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.74, 4.14]
4.3 Adverse events at any grade	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.69, 1.90]

Comparison 5. hIVIG 0.25 g/kg versus standard care.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 All‐cause mortality at 28 days	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.02, 1.14]
5.2 Improvement of clinical status: number of participants discharged on day 28	1	20	Risk Ratio (M‐H, Random, 95% CI)	2.25 [1.02, 4.94]
5.3 Adverse events at any grade	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.34, 1.50]

Comparison 6. hIVIG 0.3 g/kg versus standard care.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 All‐cause mortality at 28 days	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.27, 1.66]
6.2 Improvement of clinical status: number of participants discharged on day 28	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.50 [0.60, 3.74]
6.3 Adverse events at any grade	1	20	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.69, 1.90]

Comparison 7. Swine glyco‐humanised polyclonal antibody 0.5 mg/kg days 1 to 5 versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Improvement of clinical status: number of participants discharged on day 60	1	11	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.54, 1.35]
7.2 Adverse events at any grade	1	12	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.74, 1.35]
7.3 Adverse events at grades 3 to 4 severity	1	12	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.12, 1.88]
7.4 All‐cause mortality at 60 days	1	11	Risk Ratio (M‐H, Random, 95% CI)	2.57 [0.13, 52.12]
7.5 Adverse events at grades 1 to 2 severity	1	12	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.74, 1.35]
7.6 Admission to ICU on day 28	1	11	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Comparison 8. Swine glyco‐humanised polyclonal antibody 2 mg/kg days 1 to 5 versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Improvement of clinical status: number of participants discharged on day 28	1	6	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.43, 2.31]
8.2 Adverse events at any grade	1	6	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.43, 2.31]
8.3 Adverse events at grades 3 to 4 severity	1	6	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.04, 5.19]
8.4 All‐cause mortality at 60 days	1	6	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
8.5 Adverse events at grades 1 to 2 severity	1	6	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.43, 2.31]
8.6 Admission to ICU on day 28	1	6	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.06, 15.99]

Comparison 9. Swine glyco‐humanised polyclonal antibody 2 mg/kg day 1 only versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Improvement of clinical status: number of participants discharged on day 60	1	10	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.71, 1.41]
9.2 Adverse events at any grade	1	10	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.49, 1.38]
9.3 Adverse events at grades 3 to 4 severity	1	10	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.18, 2.42]
9.4 All‐cause mortality at 60 days	1	10	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
9.5 Adverse events at grades 1 to 2 severity	1	10	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.49, 1.38]
9.6 Admission to ICU on day 28	1	10	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.26, 15.62]

Comparison 10. hIVIG 350 AU/mL versus standard care.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 All‐cause mortality at 28 days	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.06, 14.74]
10.2 Serious adverse events	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.06, 14.74]
10.3 Negative RT‐PCR test on day 3	1	59	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.67, 2.25]
10.4 Negative RT‐PCR test on day 7	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.68, 1.37]
10.5 Negative RT‐PCR on day 15	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.72, 1.20]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ali 2021.

Study characteristics
Methods	Trial design: RCT Type of publication: full‐text journal article (peer‐reviewed) Setting: inpatient, tertiary care Recruitment dates: 19 June 2020‐3 February 2021 Country: Pakistan Language: English Number of centres: 1 Trial registration number: NCT04521309 Date of trial registration: 20 August 2020
Participants	Age hIVIG: 55.9 +/‐ 1.34 (mean SD) Control: 59.1 +/‐ 12.06 (mean SD) Sex: male 35 (70%) Ethnicity: NR Number of participants recruited, allocated, evaluated 50 recruited, allocated and evaluated 1 participant in hIVIG group lost to follow‐up and excluded from analysis for secondary outcomes. Severity of condition According to study definition: severely or critically ill with ARDS According to WHO score: hIVIG: 4, 17 (42.5%); 5, 22 (55%); 6, 1 (2.5%) control: 4, 5 (50%); 5, 5 (50%) Comorbidities hIVIG: diabetes: 14 (35%) hypertension: 22 (55%) chronic lung disease: 5 (12.5%) cardiac disease: 3 (7.5%) Control: diabetes: 4 (40%) hypertension 4(40%) cardiac disease 1 (10%) Inclusion criteria Adults Confirmed COVID‐19 infection Admitted to the clinical trial site approved tertiary care hospital (Sindh Infectious Diseases Hospital & Research Center, Dow University Hospital) in Karachi, Pakistan. Classified as either severely (hospitalised, requiring any supplemental oxygen) or critically (hospitalised, requiring non‐invasive ventilation, high‐flow oxygen or invasive ventilation) ill Presence of ARDS i.e. dyspnoea, respiratory rate ≥ 30/min, blood oxygen saturation ≤ 90%, PaO2/FiO2 < 300, and lung infiltrates > 50% on chest X‐ray Exclusion criteria History of IgA deficiency History of autoimmune disorder History of thromboembolic disorder History of allergic reaction to immunoglobulin treatment Pregnancy Requiring ≥ 2 inotropic agents to maintain blood pressure Acute or chronic kidney injury/failure Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation) hIVIG MV 1 (2.5%) Non‐invasive ventilation or high‐flow oxygen: 22 (55%) Other supplemental oxygen n =1 7 (42.5%) Control Non‐invasive ventilation or high‐flow oxygen: 5 (50%) Any supplemental oxygen 5 (50%) Baseline serostatus: positive 100%
Interventions	hIVIG therapy: hyperimmune polyclonal immunoglobulin Concomitant therapy hIVIG group only: saline rehydration and injected 40 mg methylprednisolone prior to infusion Intervention and control groups both received: remdesivir (200 mg loading then 100 mg once daily for 5 days) enoxaparin and corticosteroids, dexamethasone (6 mg once daily) or methylprednisolone (0.5‐1 mg/kg twice daily) initiated at the time of hospitalisation until resolution of ARDS Duration of follow‐up: 28 days Donors' disease severity: NR Methods of hIVIG preparation Source: animal or human? Human, recovered from COVID‐19 and asymptomatic > 15 d. Pooled plasma had variable anti‐SARS‐CoV‐2 antibody level of up to 104 ± 30 COI measured through ECLIA Dose: 5% C‐IVIG doses with standard care: Arm 1: 0.15 g/kg Arm 2: 0.2 g/kg Arm 3: 0.25 g/kg Arm 4: 0.3 g/kg Route: infusion Timing of administration from onset of symptoms: timing of enrolment from onset of symptoms: 8.0 +/‐3.08 (control), and 8.37+/‐3.14 days (intervention arms) Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: plasma tested, with a lower limit of 10 COI, measurement through ECLIA
Outcomes	Primary study outcomes 28‐day mortality Participant's clinical status during study duration (7‐point ordinal scale) Horowitz index at outcome day (assessment of ARDS severity using PaO2/FiO2 ratio) Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time‐to‐event, and at hospital discharge: reported for 28 days, time to event up to 28 days Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death; reported improvement of clinical status: participants discharged. Participants should be discharged without clinical deterioration; reported Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100, a standardised scale for assessing QoL) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, transfusion‐associated circulatory overload (TACO), transfusion‐associated dyspnoea (TAD), acute transfusion reactions, headache, thromboembolic events); reported SAEs, defined as the number of participants with any event; reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: reported improvement of clinical status: reported Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: reported Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported
Notes	Sponsor/funding: Higher Education Commission (HEC), Pakistan (Ref no. 20‐RRG‐134/RGM/R&D/HEC/2020)

Gaborit 2021.

Study characteristics
Methods	Trial design: RCT (Phase 2a of ongoing trial) Type of publication: journal article Setting: hospitalised patients with moderate disease Recruitment dates: 1 September 2020‐7 December 2020 Country: France Language: English Number of centres: 4 Trial registration number:NCT04453384 Date of trial registration: July 1, 2020
Participants	Age: 71 (51; 75) Sex: male 11 (64.7%) Ethnicity: NR Number of participants recruited, allocated, evaluated 18 patients group 1: 7 group 2: 1 group 3: 5 placebo: 5 Severity of condition According to study definition: moderate/severe According to WHO score: 5‐6 Comorbidities Asthma 3/17 (17.6%) Cardiovascular disease 5/17 (29.4%) Chronic kidney disease 1/17 (5.9%) Diabetes 2/17 (11.8%) Hypertension 8/17 (47.1%) Obesity 3/17 (17.6%) Solid organ transplant 1/17 (5.9%) Solid tumour 2/17 (11.8%) HIV infection 1/17 (5.9%) Inclusion criteria Willing and able to provide written informed consent prior to performing study procedures Male or female ≥ 18 years and ≤ 85 years Hospitalised for COVID‐19 Positive SARS‐CoV‐2 RT‐PCR in any body specimen (nasopharynx, saliva, sputum) ≤ 10 d before enrolment Evidence of pulmonary involvement on lung examination (rales/crackles) and/or chest‐imaging (chest X‐ray or CT) Requiring O2 supplement ≤ 6L/min at screening Requiring O2 supplementation with SpO2 ≥ 94% on O2 therapy at screening First onset of COVID‐19 symptoms ≤ 10 days, among fever and/or chills, headache, myalgias, cough, shortness of breath, whichever as occurred fist Women of childbearing potential must have a negative urinary pregnancy test the day of inclusion All sexually active male participants must agree to use an adequate method of contraception throughout the study period and for 90 d after the last dose of study drug and agree to no sperm donation until the end of the study, or for 90 d after the last dose of XAV‐19, whichever is longer Patients with French social security Exclusion criteria Evidence of multiorgan failure (severe COVID‐19) Mechanically ventilated (including ECMO) Receipt of immunoglobulins or any blood products in the past 30 days Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the investigator, would affect participant safety and/or compliance End‐stage renal disease (eGFR < 15 ml/min/1,73 m2) Child‐Pugh C stage liver cirrhosis Decompensated cardiac insufficiency History of active drug abuse Known allergy, hypersensitivity, or intolerance to the study drug, or to any of its components Women of childbearing potential without contraceptive method, or with positive pregnancy test, breastfeeding, or planning to become pregnant during the study period Current documented and uncontrolled bacterial infection Prior severe (grade 3) allergic reactions to plasma transfusion Patient participating in another interventional clinical trial Life expectancy estimated to be < 6 months Patient under guardianship or trusteeship Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): antibiotics, steroids, remdesivir, anticoagulant, O2 therapy Baseline serostatus: NR
Interventions	hIVIG therapy Concomitant therapy: antibiotics, steroids, remdesivir, anticoagulant, oxygen therapy Duration of follow‐up: 60 days Donors' disease severity: NR Methods of hIVIG preparation Source: animal (swine glyco‐humanised polyclonal antibody) Dose: 0.5 mg/kg of body weight at day 1 and day 5 (group 1) 2 mg/kg at day 1 and day 5 (group 2) 2 mg/kg at day 1 (group 3) or placebo Route: infusion Timing of administration from onset of symptoms: 8 (6; 9) Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: neutralising antibody levels target serum concentration was established at 10 μg/mL Whether the donors were tested by nasal swabs or whether the plasma was tested: N/A
Outcomes	Primary study outcome Phase 2a: XAV‐19 antibody titres (time frame: day 8) Phase 2a: AEs of XAV‐19 (time frame: day 29) Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported for day 28, 60 Clinical status, at day 28, day 60, and up to the longest follow‐up: reported for day 28, 60 QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4): Reported SAEs: reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: reported improvement of clinical status: reported Need for dialysis at up to 28 days: NR Admission to ICU on day 28: reported Duration of hospitalisation: reported Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: NR
Notes	Sponsor/funding: Nantes University Hospital

ITAC 2022.

Study characteristics
Methods	Trial design: international double‐blind, placebo‐RCT Type of publication: full‐text journal article (peer‐reviewed) Setting: inpatient Recruitment dates: 8 October 2020‐10 February 2021 Countries: Argentina, Denmark, Germany, Greece, Indonesia, Israel, Japan, Nigeria, Spain, UK, USA Language: English Number of centres: 63 Trial registration number: NCT04546581; JRCT2031200174 Date of trial registration: 14 September 2020
Participants	Age Median (IQR) total: 59 (49–70) hIVIG: 58 (48–70) Placebo: 60 (50–70) Sex Total: male 329 (57%) hIVIG: male 149 (51%) Placebo: male 149 (51%) Ethnicity White 56% Hispanic 15% Black 15% Asian 12% Other 2% Number of participants: 579 Severity of condition According to study definition: moderate/severe According to WHO score: 4‐6 Comorbidities Hypertension requiring medication Diabetes requiring medication Renal impairment Asthma COPD Heart failure Compromised immune function Inclusion criteria SARS‐CoV‐2 infection documented by PCR or other NAT within 3 d prior to randomisation OR documented by NAT > 3 d prior to randomisation AND progressive disease suggestive of ongoing SARS‐CoV‐2 infection Symptomatic COVID‐19 disease Duration of symptoms attributable to COVID‐19 ≤ 12 d Requiring inpatient hospital medical care for clinical manifestations of COVID‐19 (admission for public health or quarantine only is not included) Willingness to abstain from participation in other COVID‐19 treatment trials until after study day 7 Provision of informed consent by participant or LAR Exclusion criteria Prior receipt of SARS‐CoV‐2 hIVIG or CP from a person who recovered from COVID‐19 at any time Prior receipt of standard IVIG (not hyperimmune to SARS‐CoV‐2) within 45 days Current or predicted imminent (within 24 hours) requirement for any of the following: Invasive ventilation Non‐invasive ventilation Extracorporeal membrane oxygenation Mechanical circulatory support Continuous vasopressor therapy History of allergy to IVIG or plasma products History of selective IgA deficiency with documented presence of anti‐IgA antibodies Any medical conditions for which receipt of the required volume of intravenous fluid may be dangerous to the patient (includes New York Association Class III or IV stage heart failure) Any of the following thrombotic or procoagulant disorders: Acute coronary syndromes, cerebrovascular syndromes and pulmonary or deep venous thrombosis within 28 days of randomisation History of prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antithrombin III deficiency, protein C deficiency, protein S deficiency or antiphospholipid syndrome Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the protocol‐specified assessments Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): hIVIG: corticosteroids (58%), antibacterial (42%), heparin (61%), antiplatelets/anticoagulants (13%), ACE inhibitor/ARB (19%), NSAID (8%), Control: corticosteroids (55%), antibacterial (42%), heparin (61%), antiplatelets/anticoagulants (14%), ACE inhibitor/ARB (24%), NSAID (7%) Baseline serostatus: 48% have detectable neutralising antibodies
Interventions	hIVIG therapy drug name: HIVIG to SARS‐CoV‐2 dose: 100 mg/ml number of doses: 1 route: intravenous use source: human Concomitant therapy hIVIG group High‐flow oxygen: 25 (8%) Supplementary oxygen ≥ 4 L/min 84 (28%) Supplementary oxygen < 4 L/min 107 (36%) Corticosteroids 172 (58%) Antibacterial 124 (42%) Heparin 179 (61%) Other antiplatelets or anticoagulants 38 (13%) ACE inhibitor or ARB 56 (19%) NSAID 24 (8%) Control High‐flow oxygen: 33 (12%) Supplementary oxygen ≥ 4 L/min 78 (27%) Supplementary oxygen < 4 L/min 92 (32%) Corticosteroids 155 (55%) Antibacterial 118 (42%) Heparin 173 (61%) Other antiplatelets or anticoagulants 39 (14%) ACE inhibitor or ARB 67 (24%) NSAID 20 (7%) Duration of follow‐up: 28 days Donors' disease severity: NR Methods of hIVIG preparation Source: animal or human? Human Dose: 400 mg/kg bodyweight, capped at 40 g Route: intravenous Timing of administration: 0.5 mg/kg/min for approximately 30 min. If tolerated, the rate of infusion could be doubled after intervals of not less than 30 min up to a maximum of 4 mg/kg/min Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: hIVIG lots underwent central testing and were required to meet a prespecified range of neutralising activity Whether the donors were tested by nasal swabs or whether the plasma was tested: plasma was tested for potency
Outcomes	Primary study outcomes Clinical status on ordinal scale (day 7) Death End‐organ failure Life‐threatening end‐organ dysfunction Serious end‐organ dysfunction Moderate end‐organ dysfunction Limiting symptoms due to COVID‐19 No limiting symptoms due to COVID‐19 All‐cause mortality at day 28, day 60, time to event, and at hospital discharge All‐cause mortality at hospital discharge: NR All‐cause mortality at day 28, day 60, time to event, and at hospital discharge 30‐day mortality: yes (day 28) Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported improvement of clinical status: participants discharged from hospital. Participants should be discharged without clinical deterioration: reported QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): yes SAEs, defined as the number of participants with any event: yes Secondary review outcomes Clinical status at day 28, day 60, and up to the longest follow‐up: partially (see primary study outcomes) Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: NR Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: NR Additional study outcomes Clinical status on ordinal scale (see: primary study outcome), days 3, 5, 14, 28 Change in NEWS day 0 to day 7 Time to worsening of at least 3 favourable categories on the primary ordinal scale (see: primary study outcome) days 7, 14, 28 Percentage of discharged participants, days 7, 14, 28 Days alive outside the hospital (up to 28 days) Pulmonary‐only components of the primary ordinal outcome, days 3, 5, 7, 14, 28 Thrombotic components of the primary ordinal outcome, days 3, 5, 7, 14, 28 Time to recovery, defined as the 2 most favourable categories on the primary ordinal scale, days 7, 14, 28 Clinical organ dysfunction, defined as new onset of any one or more of the following (up to day 28) respiratory dysfunction cardiac and vascular dysfunction renal dysfunction hepatic dysfunction neurological dysfunction haematological dysfunction serious infection Infusion reactions, interruptions, or cessation, days 1, 3, 7, 28 Change in neutralising antibody level, days 1, 3, 7, 28
Notes	Sponsor/funding: University of Minnesota, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), The International Network for Strategic Initiatives in Global HIV Trials

Lopardo 2021.

Study characteristics
Methods	Trial design: RCT Type of publication: journal article (peer‐reviewed) Setting: inpatient Recruitment dates: 1 August‐26 October 2020 Country: Argentina Language: English Number of centres: 19 Trial registration number: NCT04494984 Date of trial registration: 31 July 2020
Participants	Age: 54 (44‐63) median (IQR): hIVIG group 54 (43‐63); Control: 54 (45‐65) Sex: 157 male: hIVIG group: 80; control: 77 Ethnicity: total: white: 196; Hispanic/Latino: 27; Native American: 15; Asian: 3. hIVIG group: white: 93; Hispanic/Latino: 18; Native American: 6; Asian: 1. Control group: Caucasian: 103; Hispanic/Latino: 9; Native American: 9; Asian: 2 Number of participants (recruited/allocated/evaluated): 247 screened; 245 randomised; 241 included in modified ITT analysis Severity of condition according to study definition: moderate: 147 (74 hIVIG group,73 control); severe: 94 (44 hIVIG group, 5 control) Severity of condition according to WHO score: 4 (3‐4) median (IQR) [8‐point ordinal scale] Comorbidities: no comorbidities: 49 (24 hIVIG, 25 control); 1 comorbidity: 78 (39 hIVIG, 39 control); ≥ 2 comorbidities: 114 (55 hIVIG, 59 control) Inclusion criteria 18‐79 years of age SARS‐CoV‐2 infection confirmed by PCR Informed consent by patient or representative < 10 days since onset of symptoms at screening visit Negative pregnancy test for women of childbearing potential Exclusion criteria Receipt of CP Participation in other clinical trials ICU admission or need for mechanical ventilation History of anaphylaxis, to equine serum, or allergic reaction to contact or exposure to horses Pregnancy or lactation Life expectancy of < 30 days due to a concomitant disease other than COVID‐19 Likely to be referred to another institution within 72 h Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): Dexamethasone: 138 (hIVIG: 65; control: 73) Baseline serostatus NR
Interventions	hIVIG therapy: polyclonal antibody, equine‐derived F(ab’)2 fragments Concomitant therapy: dexamethasone (57%) Duration of follow‐up: 28 Donors' disease severity: N/A Methods of hIVIG preparation Source: animal or human? Animal (hyperimmunised horses, injected x 4 over 28 d with 3.5 mg receptor‐binding domain of SARS‐CoV‐2 Dose: 4 mg/kg x 2 Route: intravenous Timing of administration from onset of symptoms: study day 0 and day 2 (participants were < 10 d from symptom onset at baseline) Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels; "The protein content in the final product was adjusted to 30 mg/ml." Whether the donors were tested by nasal swabs or whether the plasma was tested: N/A
Outcomes	Primary study outcome: clinical improvement of at least 2 points on WHO 8‐point ordinal scale at 28 days Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported for 28 days Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported improvement of clinical status: participants discharged from hospital. Participants should be discharged without clinical deterioration: reported QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported SAEs, defined as the number of participants with any event: reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: reported improvement of clinical status: reported Need for dialysis at up to 28 days: NR Admission to ICU on day 28: reported Duration of hospitalisation: reported Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: NR
Notes	Sponsor/funding: the funder of the study (Inmunova S.A.) participated in study design, data collection, data analysis, data interpretation and writing of the report. Inmunova S.A. was also responsible for sites and principal investigator selection and contracts, project management and supervision of sites monitoring through a Contract Research Organization.

Parikh 2021.

Study characteristics
Methods	Trial design: RCT Type of publication: preprint article (not peer‐reviewed) Setting: inpatient Recruitment dates: NR (trial protocol is wrongly referenced in publication) Country: India Language: English Number of centres: 7 Trial registration number: CTRI/2020/09/027903 (trial number wrong in the paper) Date of trial registration: 22 May 2020
Participants	Age Total: 52 ± 10.1 hIVIG: 53 ± 9.1 Standard care: 52 ± 11.2 Sex Total: 44 male (73.3%) hIVIG: 24 (80.0%) Standard care: 20 (66.7%) Ethnicity: NR Number of participants recruited, allocated, evaluated: 60 allocated; 59 evaluated Severity of condition According to study definition: moderate‐severe According to WHO score: Comorbidities: diabetes: 24: hIVIG: 17; SOC 7 Inclusion criteria Participant and/or LAR must sign consent to participate in the study indicating that the participant understands the purpose of, and procedures required for the study as described in this protocol and is willing to and will be able to adhere to requirement of the protocol Participant must be 18‐65 years of age (both inclusive), at the time of signing the informed consent Participants must have documented laboratory‐confirmed SARS‐CoV‐2 infection as determined by RT‐PCR in any specimen, within < 72 h prior to randomisation Participants with moderate or severe active COVID‐19 (Clinical Management of COVID‐19 Guidelines of MOHFW) at screening and baseline defined as, radiological evidence of pulmonary infiltrates or clinical features such as dyspnoea and/or hypoxia, fever, cough SpO2 of < 94 % on room air respiratory rate of ≥ 24/min A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: is not a woman of childbearing potential (WOCBP) Is a WOCBP and using an acceptable contraceptive method Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study intervention: must agree not to donate sperm for the purpose of reproduction must agree to use contraception /barrier Exclusion criteria Participant requiring IMV or having haemodynamic instability (MOHFW guideline) or multiple organ dysfunction/failure or evidence of bacterial superinfection (as defined by procalcitonin level ≥ 0.5 μg/L or other applicable diagnostic parameters as per standard medical care) as per the independent clinical judgement of the Investigator at screening and/or baseline Documented medical history of known allergies, hypersensitivity, or intolerance to intravenous immunoglobulin or other injectable form of IgG or blood products. Documented medical history of known IgA deficiency Participants with a lifetime history of at least 1 thrombotic event including deep vein thrombosis, cerebrovascular accident, pulmonary embolism, transient ischaemic attacks, or myocardial infarction Participants who have received any blood products within 30 days prior to randomisation Participants with > 5 d of COVID‐19 specific hospitalisation prior to the first administration of treatment at baseline. Participants who have > 10 d between the onset of symptoms and the day of first administration of treatment at baseline Pregnant or breastfeeding female participants Currently receiving renal replacement therapy/dialysis OR creatinine clearance < 50 mL/min using the Cockcroft‐Gault formula Documented medical history of hepatitis B surface antigen (HbsAg) or hepatitis C antibody (anti‐HCV) positive, or other clinically active liver disease, or tests positive for HbsAg or anti‐HCV at screening. Documented medical history of HIV antibody‐positive, or tests positive for HIV at screening. Currently receiving or has received in the last 14 days, experimental immune modulators, and/or monoclonal antibody therapies Confirmed diagnosis of bacterial pneumonia or other active/uncontrolled fungal or viral infections at screening/baseline Participants who have received organ transplantation or major surgery in the past 6 months Participants whose ALT/AST levels are 5 times higher than the normal upper limit and total bilirubin is 3 times higher than the upper limit of normal Co‐morbid systemic illnesses (uncontrolled diabetes, uncontrolled hypertension, cardiac disease, chronic lung disease, chronic kidney disease, immune‐suppression and cancer or other severe concurrent disease) which, in the judgement of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed treatment Current participation in another interventional clinical trial (with an investigational drug) that is not an observational registry and have received an investigational intervention 30 days or 5 half‐lives (whichever is longer) before the signing the consent Participation in any other clinical trial of an experimental treatment for COVID‐19 Any other clinical/social/ psychiatric condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g. compromise the well‐being) or that could prevent, limit, or confound the protocol‐specified assessments Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation) Baseline serostatus: positive, all participants at baseline
Interventions	hIVIG therapy: a purified SARS‐CoV‐2 hyper‐IgG preparation rich in neutralising antibodies against COVID‐19 Concomitant therapy: anti‐virals, antimalarials, antibiotics, remdesivir, corticosteroids, at investigators' discretion Duration of follow‐up: 14 days Donors' disease severity: NR Methods of hIVIG preparation Source: animal or human? Human Dose: 350 AU/mL as a 30 mL infusion Route: infusion Timing of administration from onset of symptoms: < 10 d from symptom onset, < 5 d from hospitalisation, on study days 1 and 2 Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels, tested using serum microneutralisation assay and plaque reduction neutralisation test (PRNT) Whether the donors were tested by nasal swabs or whether the plasma was tested: NR
Outcomes	Primary study outcome Mean change in clinical status from day 1‐day 8 Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported day 28 Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: NR improvement of clinical status: participants discharged from hospital. Participants should be discharged without clinical deterioration: NR QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported SAEs, defined as the number of participants with any event: reported Secondary review outcomes Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: NR improvement of clinical status: NR Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: NR Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: Reported
Notes	Sponsor/funding: Intas Pharmaceuticals Ltd., India

ACE: angiotensin‐converting enzyme; AE: adverse event; ALT: alanine transaminase; ARB: angiotensin receptor blocker; ARDS: acute respiratory distress syndrome; AST: aspartate transaminase; C‐IVIG: anti‐COVID intravenous immunoglobulin; COI: cut‐off index; COPD: chronic obstructive pulmonary disease; CP: convalescent plasma; CT: computed tomography; ECLIA: electrochemiluminescence immunoassay analyser;ECMO: extracorporeal membrane oxygenation; eGFR: estimated glomerular filtration rate; FiO₂: fractional inspired oxygen; hIVIG: hyperimmune immunoglobulin; ICU: intensive care unit; IgA (B/G/M): immunoglobulin A (B/G/M); IL‐6: interleukin‐6;IMV: invasive mechanical ventilation; IQR: interquartile range; IV: intravenous; IVIG: intravenous immunoglobulin; LAR: legal authorised representative; LDH: lactate dehydrogenase; MV: mechanical ventilation; N/A: not applicable; NAT: nucleic acid test; NEWS: National Early Warning Score; NR: not reported; NSAID: non‐steroidal anti‐inflammatory drug; NYHA: New York Heart Association; PaO₂: arterial blood oxygen partial pressure; PCR: polymerase chain reaction; QoL: quality of life; RCT: randomised controlled trial; RT‐PCR: reverse transcription polymerase chain reaction; SAE: serious adverse event; SARS: severe acute respiratory syndrome; SD: standard deviation; SpO₂: peripheral capillary oxygen saturation; TACO: transfusion‐associated circulatory overload; TAD: transfusion‐associated dyspnoea; TRALI: transfusion‐related acute lung injury; WHO: World Health Organization; WHOQOL‐100: World Health Organization Quality of Life Scale

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
ACTRN12620001249943	Study is prophylaxis only; patients with current or prior COVID‐19 infection are excluded
EudraCT 2020‐002345‐42	Ineligible intervention: normal IVIG
IRCT20201004048922N1	Ineligible intervention: CP
Kangro 2021	Ineligible intervention: bovine colostrum‐derived IVIG; ineligible population: healthy volunteers
Mazeraud 2021	Ineligible intervention ‐ non‐immune IVIG
NCT04264858	Non‐randomised study
NCT04468958	Healthy participants only
NCT04884295	Ineligible intervention; XVR011 is a nanobody

CP: convalescent plasma; IVIG: intravenous immunoglobulin;

Characteristics of studies awaiting classification [ordered by study ID]

Gaborit 2020.

Methods	Trial design: double‐blind, placebo‐controlled RCT (clinical trial) Sample size: 414 Setting: hospital Country: France Language: English Number of centres: NR
Participants	Inclusion criteria: Phase 2a Willing and able to provide written informed consent prior to performing study procedures Male or female ≥ 18 years and ≤ 85 years Hospitalised for COVID‐19 Positive SARS‐CoV‐2 RT‐PCR in any body specimen (nasopharynx, saliva, sputum) ≤ 10 d before enrolment Evidence of pulmonary involvement (on lung examination (rales/crackles) and/or chest‐imaging (chest X‐ray or CT) Requiring O2 supplement ≤ 6L/min at screening Requiring O2 supplementation with SpO2 ≥ 94% on O2 therapy at screening First onset of COVID‐19 symptoms ≤ 10 d, among fever and/or chills, headache, myalgias, cough, shortness of breath, whichever occurred fist Women of childbearing potential must have a negative urinary pregnancy test the day of inclusion All sexually active men must agree to use an adequate method of contraception throughout the study period and for 90 d after the last dose of study drug and agree to no sperm donation until the end of the study, or for 90 d after the last dose of XAV‐19, whichever is longer Patients with French social security Exclusion criteria: phase 2a Evidence of multiorgan failure (severe COVID‐19) Mechanically ventilated (including ECMO) Receipt of immunoglobulins or any blood products in the past 30 days Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the investigator, would affect participant safety and/or compliance End‐stage renal disease (eGFR < 15 ml/min/1,73 m2) Child‐Pugh C stage liver cirrhosis Decompensated cardiac insufficiency History of active drug abuse Known allergy, hypersensitivity, or intolerance to the study drug, or to any of its components Women of childbearing potential without contraceptive method, or with positive pregnancy test, breastfeeding, or planning to become pregnant during the study period Current documented and uncontrolled bacterial infection Prior severe (grade 3) allergic reactions to plasma transfusion Patient participating in another interventional clinical trial Life expectancy estimated to be < 6 months Patient under guardianship or trusteeship Inclusion criteria: phase 2b Willing and able to provide written informed consent prior to performing study procedures Male or female ≥ 18 years and ≤ 85 years Hospitalised for COVID‐19 Positive SARS‐CoV‐2 RT‐PCR in any body specimen (nasopharynx, saliva, sputum) ≤ 10 days before enrolment Evidence of pulmonary involvement (on lung examination (rales/crackles) and/or chest‐imaging (chest X‐ray or CT) Requiring O2 supplement ≤ 6L/min at screening Requiring O2 supplementation with SpO2 ≥ 92% on O2 therapy at screening (or ≥ 90 % if COPD) First onset of COVID‐19 symptoms ≤ 10 days, among fever and/or chills, headache, myalgias, cough, shortness of breath, whichever as occurred fist (other symptoms such as asthenia not to be considered in this list) WOCBP must have a negative urinary pregnancy test on the day of inclusion All sexually active men must agree to use an adequate method of contraception throughout the study period and for 90 d after the last dose of study drug and agree to no sperm donation until the end of the study, or for 90 d after the last dose of XAV‐19, whichever is longer Patients with French social security Exclusion criteria: phase 2b Evidence of multiorgan failure (severe COVID‐19) Mechanically ventilated (including ECMO) Receipt of immunoglobulins or any blood products in the past 30 days Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the investigator, would affect participant safety and/or compliance End‐stage renal disease (eGFR < 15 ml/min/1,73 m2) Child‐Pugh C stage liver cirrhosis Decompensated cardiac insufficiency History of active drug abuse Known allergy, hypersensitivity, or intolerance to the study drug, or to any of its components Women of childbearing potential without contraceptive method, or with positive pregnancy test, breastfeeding, or planning to become pregnant during the study period Current documented and uncontrolled bacterial infection Prior severe (grade 3) allergic reactions to plasma transfusion Patient participating in another interventional clinical trial Life expectancy estimated to be < 6 months Patient under guardianship or trusteeship
Interventions	CP therapy or hIVIG therapy: hIVIG therapy Details: type: XAV‐19 volume: XAV‐19 at 0.5 mg/kg (Group 1) or at 2 mg/kg (Group 2) number of doses: 2 antibody titre: NR pathogen inactivated or not: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: comparator (type): Placebo Concomitant therapy: NR Treatment cross‐overs: none
Outcomes	Primary study outcomes Phase 2a: XAV‐19 antibody titres (time frame: day 8) Phase 2a: AEs of XAV‐19 (time frame: day 29) Phase 2b: time to weaning of supplemental oxygen (time frame: day 15) Primary review outcomes All‐cause mortality at hospital discharge: NR 30‐day mortality: yes, all cause mortality day 29 Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): AEs of XAV‐19 between the 2 groups of treated patients and vs placebo over 29 days Number of participants with SAEs: reported as occurrence of all suspected XAV‐19 related adverse effects or Incidence of SAEs Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020d), WHO Ordinal Scale for Clinical Improvement (WHO 2020e) at up to 7 d, 8‐15 d, 16‐30 d: reported as clinical status using the 8‐point ordinal scale assessed and difference between baseline and D3, D5, D8, D15, and D29 Mortality (time to event): NR 90‐day mortality: NR Time to discharge from hospital: yes Admission to ICU: reported as evaluation of transfer to intensive care Length of stay on the ICU: NR Viral clearance, assessed with RT‐PCR test at baseline, up to 3, 7, and 15 days: QoL: NR Additional study outcomes Phase 2a: pharmacokinetic analysis (time frame: day 1 (pre‐dose, post‐dose), at day 5 (pre‐dose, post‐dose), day 8, day 15, and day 29) Phase 2a: antibody titre between the 2 groups (time frame: day 15) Phase 2a: duration supplemental oxygen (time frame: day 1‐day 29) Phase 2a: normalisation of fever (time frame: day 1 to day 29) Biomarkers: CRP, ferritin Phase 2b: NEWS (time frame: day 8, day 15 and day 29) Proportion of participants who die, develop respiratory failure (requiring noninvasive ventilation, high‐flow oxygen or IMV) between baseline and day 8, then between baseline and day 29 Time to improvement of 1 category from admission using the 8‐point ordinal scale. This scale is rated 0‐8 with score 0 being the better score (no clinical impact) and 8 being the worst score (death) Phase 2b: fever normalisation (time frame: 29 days) Phase 2b: duration of oxygen therapy Phase 2b: oxygen requirement Phase 2b: time to weaning Phase 2b: ventilation
Notes	Recruitment status: recruiting Prospective completion date: Estimated Primary Completion Date: December 2020 Estimated Study Completion Date: December 2021 Sponsor/funding: Nantes University Hospital BPIfrance Xenothera SAS

NCT04366245.

Methods	Trial design: phase 1/2 RCT, open‐label, parallel assignment Sample size: 36 in each arm (72) Setting: inpatient Country: Spain Language: English Number of centres: NR
Participants	Inclusion criteria Both sexes ≥ 18 years Informed consent prior to performing procedures. Oral consent accepted to prevent paper handling SARS‐CoV‐2 infection determined by PCR in a sample of naso‐oropharyngeal exudate or other respiratory specimen or determination of specific positive IgM antibodies, in < 72 h before randomisation Patients requiring hospitalisation for pneumonia COVID‐19 without need of IMV or non‐IMV until randomisation and at least 1 of the following: O2 saturation ≤ 94% in ambient air, or PaO2/FiO2 ≤ 300 mm Hg Age > 65 years Presence of: high blood pressure, chronic heart failure, COPD, liver cirrhosis, or other chronic pulmonary and cardiovascular diseases, diabetes, or obesity Exclusion criteria Requirement before randomisation of IMV or non‐IMV Any of the following analytical data before randomisation: IL‐6 > 80 pg/mL, D‐dimer > 10 times upper limit of normal, ferritin > 1000 ng/mL Participation in another clinical trial or experimental treatment for COVID‐19 In the opinion of the clinical team, progression to death or mechanical ventilation is highly probable within 24 h, regardless of treatment provision Incompatibility or allergy to the administration of human plasma Severe chronic kidney disease grade 4 or requiring dialysis (i.e. eGFR < 30) Pregnant, lactating, or fertile women who are not using an effective method of contraception. (Women of childbearing age considered to be all women from 18 years and up to a year after the last menstrual period in the case of menopausal women)
Interventions	Intervention(s): COVID‐19 hyperimmune CP Details of CP Type of plasma: NR Volume: NR Number of doses: NR Antibody titre: NR Pathogen inactivated: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): before mechanical ventilation is required Comparator: standard care Concomitant therapy: hydroxychloroquine + azithromycin or lopinavir/ritonavir + interferon β‐1b + hydroxychloroquine Treatment cross‐overs: no
Outcomes	Primary study outcome(s) Safety: incidence of AEs and SAEs grade 3 and 4, related to the product under investigation or the administration procedure, graduated according to the common toxicity criteria scale (CTCAE). (Time frame: 30 days after enrolment). Efficacy: death from any cause (time frame: day +21 after randomisation) Efficacy: need for mechanical ventilation (time frame: day +21 after randomisation) Efficacy: any of the following analytical data after 72 h of randomisation. (time frame: day +21 after randomisation). IL‐6 > 40 pg/mL, D‐dimer > 1500, ferritin > 1000 ng/mL Efficacy: SOFA scale ≥ 3 after 72 h of randomisation. (time frame: day +21 after randomisation) Primary review outcomes reported All‐cause mortality at hospital discharge: yes Death from any cause (time frame: day +21 after randomisation) Mortality on days 14 and 28 (time frame: days 14 and 28) Time to death: NR Secondary review outcomes reported Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): yes Incidence of AEs and SAEs grade 3 and 4, related to the product under investigation or the administration procedure, graduated according to the common toxicity criteria scale (CTCAE). (time frame: 30 days after enrolment) Number of participants with SAEs: yes Incidence of AEs and SAEs grade 3 and 4, related to the product under investigation or the administration procedure, graduated according to the common toxicity criteria scale (CTCAE) Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: yes Need for mechanical ventilation (time frame: day +21 after randomisation) 30‐day and 90‐day mortality: no Admission on ICU: yes Proportion of participants who required mechanical ventilation (time frame: until day 28) Length of stay on the ICU: no Time to discharge from hospital: yes Duration of hospitalisation (days) (time frame: until day 21) Additional outcomes Proportion of participants who develop analytical alterations. (time frame: day +21 after randomisation.). IL‐6 > 40 pg/mL, D‐dimer > 1500, ferritin > 1000 ng/mL until the cure test Cure/clinical improvement (disappearance or improvement of signs and symptoms of COVID‐19) in the cure test. (time frame: day +21 after randomisation) PCR‐negative for SARS‐CoV‐2 (time frame: on days 7, 14 and 21) Proportion of participants who required treatment with tocilizumab (time frame: until day 21) Virology and immunological variables: qualitative PCR for SARS‐CoV‐2 in naso‐oropharyngeal exudate sample (time frame: at baseline and on day 14) Virology and immunological variables: total antibody quantification (time frame: at baseline and on days 3, 7, 10 (while hospitalisation lasts), and on days 14 and 28 (if able to return to the clinic or are still hospitalised) Virology and immunological variables: quantification of total antibodies in PC donors recovered from COVID‐19 (time frame: before infusion)
Notes	Recruitment status: recruiting Prospective completion date: December 2021 Sponsor/funding: Andalusian Network for Design and Translation of Advanced Therapies

NCT04395170.

Methods	Trial design: open‐label RCT Sample size: 75 Setting: inpatient Country: Colombia Language: English Number of centres: 1
Participants	Inclusion criteria Obtaining patients' informed written consent before carrying out the study procedures Adult patients ≥ 18 years at the time of recruitment for the study Patients with laboratory‐confirmed SARS‐CoV‐2 infection as determined by PCR on nasal/oropharyngeal swabs or any other relevant specimen < 72 h before randomisation Patients requiring hospitalisation for COVID‐19 without IMV or non‐IMV including an oxygen mask with reserve bag) and at least 1 of the following: radiographic evidence of pulmonary infiltrates by images (chest radiography, CT, etc.) clinical evaluation (evidence of rales/crackles on examination) and oxygen saturation ≤ 94% in ambient air requiring supplemental oxygen Patient with no more than 72 h (3 d) of hospitalisation prior to the administration of CP treatment (except the days after initial hospital admission for other reasons and prior to COVID‐19 infection) Patients with no more than 10 d between the onset of symptoms (fever or cough) and the day of administration of treatment or the demonstration of the absence of anti‐SARS‐CoV‐2 antibodies (patients with > 10 d of symptoms they can only be included if a negative antibody result has been confirmed) Exclusion criteria Pregnant women Require IMV or non‐IMV, including oxygen mask with reserve bag) on examination Participation in any other clinical trial of an experimental treatment for COVID‐19 At the discretion of the clinical team, progression to death is imminent and inevitable within the next 24 h, regardless of the provision of treatments Any incompatibility or allergy to the administration of plasma of human origin Severe chronic kidney disease in stage 4 or requiring dialysis (that is, GFR < 30) Any condition that in the investigator's opinion limits participation in the study.
Interventions	Intervention(s): CP therapy and hIVIG therapy Details of intervention CP Type of plasma: NR Volume: 200‐250 mL Number of doses: 2, at days 1 and 3 of treatment Antibody titre: NR Pathogen inactivated: yes hIVIG Anti‐COVID‐19 human immunoglobulin produced by Lifefactors Zona Franca S.A.S, IV at a dose of immunoglobulin 10% IgG solution (10% mL vial) for: participant ≥ 50 kg, 50 mL, administered on days 1 and 3 of treatment participant < 50 kg, 1 mL/kg, administered on days 1 and 3 of treatment the supply of anti‐COVID‐19 human immunoglobulin produced by Lifefactors Zona Franca S.A.S included once it has been authorised by INVIMA and/or the regulatory requirements in force for the production of drugs are met. Treatment details, including time of plasma therapy (e.g. early stage of disease): hospitalised patients not requiring mechanical ventilation Comparator: standard therapy for COVID‐19 according to the recommended pharmacological recommendations of the Colombian Association of Infectious Diseases ‐ ACIN. This therapy is subject to changes that are defined by the Colombian Health Regulatory Authorities. To date, these therapies may include remdesivir, chloroquine, hydroxychloroquine, azithromycin Concomitant therapy: non‐specific supportive treatment for COVID‐19 such as oxygen, IV liquid or corticosteroids Treatment cross‐overs: not applicable
Outcomes	Primary study outcome Admission to ICU and/or mechanical ventilation within 1 year Primary review outcomes reported All‐cause mortality at hospital discharge: mortality (up to 1 year) Time to death: NR Secondary review outcomes reported Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): yes Number of participants with SAEs: yes Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: yes 30‐day and 90‐day mortality: yes (28‐day mortality) Admission on the ICU: yes Length of stay on the ICU: NR Time to discharge from hospital: NR QoL: NR Additional study outcomes: neutralising antibody (IgG) titres against COVID‐19 (up to 1 year)
Notes	Recruitment status: not yet recruiting Prospective completion date: December 2020 Sponsor/funding: Lifefactors Zona Franca, SAS

NCT04469179.

Methods	Trial design: phase 1B, double‐blind, placebo‐controlled, single ascending dose RCT Sample size: 21 Setting: outpatient Country: USA Language: English Number of centres: 3
Participants	Inclusion criteria 18‐60 years of age Positive for presence of SARS‐CoV‐2 on naso‐ or oropharyngeal swab by FDA‐authorised RT‐PCR test within 7 d prior to infusion At least 1 current symptom of COVID‐19, onset within 7 d prior to infusion: fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhoea Able to understand the study and comply with all study procedures Agrees not to participate in any other trial of an investigational product during the study period Willing and able to provide written informed consent prior to the start of any study‐related activities If female, meets at least 1 of the following reproductive risk criteria post‐menopausal for at least 12 months use of ≥ 1 of the following highly effective contraceptive methods for at least 90 d following the last dose of study product: combined oestrogen and progestogen containing or progestogen‐only hormonal contraception, intrauterine device, intrauterine hormone‐releasing system, surgical bilateral tubal occlusion vasectomised sole sexual partner who has received medical assessment of the surgical success Male and female participants agree to sexual abstinence (refraining from heterosexual intercourse for at least 90 d following the last dose of study product) if not using birth control or condoms for men Exclusion criteria Dyspnoea at rest Respiratory rate > 30 breaths per min SpO2 ≤ 93% on room air Heart rate ≥ 125 beats per min Respiratory distress or respiratory failure Evidence of critical illness Female participants with positive pregnancy test, breastfeeding, or planning to become pregnant/breastfeed during the study period Hospitalisation or need for hospitalisation for any cause Treatment or participation in another clinical trial of any other investigational agent within 30 d prior to enrolment Use of other drugs that, in the opinion of the investigator, could complicate analysis of SAB‐185 Participants with the following risk factors Compromised immune system including confirmed diagnosis of current cancer under treatment, inherited deficiencies of the immune system, immune suppressing medication, or other conditions causing leukopenia or neutropenia Known autoimmune condition requiring therapy more intensive than intermittent non‐steroidal anti‐inflammatories in the prior 6 months (for example: rheumatoid arthritis, lupus, inflammatory bowel disease) Chronic respiratory disease including COPD, emphysema, cystic fibrosis, pulmonary hypertension, or other chronic condition that requires the routine use of supplemental oxygen Chronic asthma requiring the use of oral steroids or hospitalisation in the last 6 months Renal failure or renal insufficiency requiring dialysis Congestive heart failure or significant atherosclerotic disease (coronary artery disease or peripheral vascular disease) Receipt of pooled immunoglobulin or plasma in past 30 days Any other underlying medical (cardiac, liver, renal, neurological, respiratory) or psychiatric condition that in the view of the investigator would preclude use of SAB‐185 Known IgA deficiency or previous allergic reaction to IVIG/subcutaneous immunoglobulin Positive for hepatitis B virus surface antigen, hepatitis C virus antibody, or HIV antibody by medical history History of allergy, anaphylaxis, or severe reaction to beef products (including milk and gelatin)
Interventions	Details of hIVIG therapy Drug name: SAB‐185 Dose: Group 1: 10 mg/kg SAB‐185 in normal (0.9%) saline; concentration 4 mg/mL (0.4%) Group 2: 25 mg/kg SAB‐185 in normal (0.9%) saline; concentration 20 mg/mL (2%) Group 3: 50 mg/kg SAB‐185 in normal (0.9%) saline; concentration 20 mg/mL (2%) Number of doses: NR Route: administered intravenously Source: human Treatment details, including time of plasma therapy (e.g. early stage of disease): early stage For studies including a control group: comparator (type): placebo ((0.9%) saline in approximately the same volume as each cohort in the experimental drug arm) Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome Incidence and severity of other AEs and SAEs (up to day 29) Number of participants having transfusion‐related AEs (up to day 29) Primary review outcomes All‐cause mortality: NR Admission to hospital: NR Secondary review outcomes Development of severe clinical COVID‐19 symptoms, defined as WHO Clinical Progression Scale ≥ 6 (WHO 2020d): NR Time to symptom onset: NR Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020d), WHO Ordinal Scale for Clinical Improvement (WHO 2020e) at up to 7 days, 8 to 15 days, 16 to 30 days: NR Mortality (time to event): NR 90‐day mortality: NR Length of hospital stay, for hospitalised patients: NR Admission to ICU: NR Viral clearance, assessed with RT‐PCR test: yes (day 29) QoL: NR Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, TACO, TAD, acute transfusion reactions): NR Number of participants with SAEs: yes Additional study outcomes Incidence and severity of other AEs and severe AEs (SAE)(up to day 90) Measurement of SARS CoV‐2 neutralising (PRNT80) antibody titres (up to day 90) Immune response elicited by SAB‐185 (up to day 90) Concentration of participant anti‐SAB‐185 antibodies elicited by SAB‐185 (up to day 90) Level of SARS‐CoV‐2 in swab specimens as measured by quantitative RT‐PCR through study (day 29)
Notes	Recruitment status: active, not recruiting Prospective completion date: March 2021 Sponsor/funding: SAb Biotherapeutics, Inc., Biomedical Advanced Research and Development Authority, Joint Program Executive Office (JPEO) Chemical, Biological, Radiological, and Nuclear Defense (CBRND) Enabling Biotechnologies (EB)

NCT04555148.

Methods	Trial design: RCT Sample size: 60 Setting: inpatient Country: Republic of Korea Language: English Number of centres: 1 Trial registration number: NCT04555148 Date of registration: 18 September 2020
Participants	Inclusion criteria Adults > 19 years with diagnosis of COVID‐19 Hospitalised, with COVID‐19 symptoms within 7 d Positive PCR test ≤ 3 d prior to randomisation Exclusion criteria Asymptomatic Requiring ventilation or ECMO Requiring oxygen therapy before onset of COVID‐19 illness Receipt of antiviral drugs for another illness within previous 4 weeks History of allergy to IVIG or plasma Prior receipt of IVIG or CP therapy IgA deficiency Creatinine > 2 X upper limit of normal History of thrombosis or high risk of thromboembolism Reduced heart function (NYHA Functional Class 3 or 4; or cerebral cardiovascular disorder, or history of ischaemic disease, cardiovascular disease, cerebrovascular disorder, blood vessel disorder, etc.) Donor eligibility criteria: NR Donor exclusion criteria: NR
Interventions	Intervention(s): hIVIG Details of therapy Type of therapy: GC5131 hIVIG Volume: NR. 3 dose regimens: low, medium and high Number of doses: NR Antibody titre: 3 dose regimens, low, medium and high Pathogen inactivated: n/a Treatment details, including time of plasma therapy (e.g. early stage of disease): within 7 d of symptom onset Comparator: placebo (saline) Concomitant therapy: standard care Treatment cross‐overs: NR
Outcomes	Primary study outcome Reduction of ≥ 2 points on ordinal scale (days 7, 14, 21 and 28) Primary review outcomes reported All‐cause mortality at hospital discharge: yes Time to death: NR Secondary review outcomes reported Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): NR Number of participants with SAEs: NR Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: yes 30‐day and 90‐day mortality: Up to 28 days Admission to ICU: NR Length of stay on the ICU: NR Time to discharge from hospital: NR QoL: NR Virological response: yes Additional outcomes: change in NEWS from baseline (Days 7, 14, 21 and 28 days)
Notes	Recruitment status: recruiting Prospective completion date: 30 December 2020 Sponsor/funding: Green Cross Corporation

NCT04573855.

Methods	Trial design: RCT Sample size: 41 Setting: inpatient Country: Brazil Language: NR Number of centres: NR Trial registration number: NCT04573855 Date of registration: 5 October 2020
Participants	Inclusion criteria Adults > 18 and < 75 years with diagnosis of COVID‐19 by PCR Time between symptom onset and inclusion ≤ 10 d No indication of invasive ventilatory support at the time of randomisation Exclusion criteria Pregnancy or lactation Severe comorbidity: severe heart disease, severe COPD or O2‐dependent COPD, terminal cancer Any confirmed or suspected immunosuppressive or immunodeficiency state, including HIV (regardless of treatment, CD4 count or viral load status); asplenia; severe recurrent infections and chronic use (> 14 d) of immunosuppressive medication in the last 6 months, except for topical steroids or short‐term oral steroids (cycle lasting ≤ 14 d) History of anaphylaxis or severe allergic reaction Previous use of any heterologous serum Participation in trials of prophylactic drugs or vaccines for COVID‐19 Administration of immunoglobulins and/or any blood products in the previous 3 months Donor eligibility criteria: NR Donor exclusion criteria: NR
Interventions	Intervention(s): hIVIG Details of therapy Type of plasma: anti‐SARS‐CoV‐2 immunoglobulin Volume: NR Number of doses: NR Antibody titre: n/a Pathogen inactivated: n/a Treatment details, including time of plasma therapy (e.g. early stage of disease): Within 10 days of symptom onset Comparator: standard care Concomitant therapy: standard care Treatment cross‐overs: NR
Outcomes	Primary study outcome Rate of infusion‐related AEs (28 days) Clearance of viral RNA (72 hours) Primary review outcomes reported All‐cause mortality at hospital discharge: yes Time to death: NR Secondary review outcomes reported Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions: yes Number of participants with SAEs: yes Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: yes 30‐day and 90‐day mortality: NR Admission to ICU: NR Length of stay in the ICU: NR Time to discharge from hospital: yes QoL: NR Virological response: yes Additional outcomes Infusion reaction rate (28 days) Modulation of serum and cellular inflammatory marker (days 0, 3, and 7)
Notes	Recruitment status: not yet recruiting Prospective completion date: 28 February 2021 Sponsor/funding: D'Or Institute for Research and Education

NCT04610502.

Methods	Trial design: RCT Sample size: 26 Setting: inpatient Country: Mexico Language: English Number of centres: 1
Participants	Inclusion criteria Agreement to participate in the study by signing the prior informed consent Age > 18 years Inpatient with RT‐PCR confirmation of SARS‐CoV‐2 Period of onset of symptoms related to COVID‐19 < 10 d Presence of at least 2 documented risk factors Moderate and severe clinical presentation of the disease Exclusion criteria Patients who did not sign the Informed Consent Critical patient Patient previously bitten by a snake that was treated with equine hyperimmune serum Patients with COVID‐19 on an outpatient basis Pregnant women Patients in haemodialysis programme Patients who have already received plasma from a convalescent COVID‐19 patient Patients who were classified prior to the diagnosis of COVID‐19 by the treating physician as having a reserved prognosis with a short lifespan
Interventions	hIVIG therapy: equine immunoglobulin anti‐SARS‐CoV‐2 Concomitant therapy: premedication with acetaminophen (paracetamol) 500 mg oral, cimetidine 300 mg IV and chlortrimeton 10 mg IV Duration of follow‐up: 3 months Donors' disease severity: NR Methods of hyperimmune immunoglobulin preparation Source: animal or human: equine Dose: 10 mL Route: IV Timing of administration from onset of symptoms: < 10 d Whether hyperimmune immunoglobulin dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: N
Outcomes	Primary study outcome Change in clinical status (days requiring supplemental oxygen) between the 2 treatment groups To identify the adverse effects of anti‐SARS‐CoV‐2 type "S" or type "M" equine immunoglobulins Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported to 24 days Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): NR QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 d, up to 28 d, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported SAEs, defined as the number of participants with any event: reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: new need for IMV: reported new need for non‐IMV or high‐flow oxygen: NR new need for oxygen by mask or nasal prongs: NR improvement of clinical status: weaning or liberation from IMV in surviving participants: reported as change in ventilatory support ventilator‐free days: reported as change in ventilatory support duration to liberation from IMV: liberation from supplemental oxygen in surviving patients: NR duration to liberation from supplemental oxygen: NR Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: reported Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported
Notes	Recruitment status: completed Prospective completion date: 6 December 2020 Sponsor/funding: Caja Costarricense de Seguro Social

AE: adverse event; COPD: chronic obstructive pulmonary disease; CP: convalescent plasma; CRP: C‐reactive protein; CT: computed tomography; ECMO: extracorporeal membrane oxygenation; eGFR: estimated glomerular filtration rate; FDA: (US) Food and Drug Administration; FiO₂: fractional inspired oxygen; ICU: intensive care unit; IgA (B/G/M): immunoglobulin A (B/G/M); IL‐6: interleukin‐6; IMV: invasive mechanical ventilation; IV: intravenous; IVIG: intravenous immunoglobulin; NEWS: National Early Warning Score; NR: not reported; NYHA: New York Heart Association; PaO₂: arterial blood oxygen partial pressure; PCR: polymerase chain reaction; QoL: quality of life; RCT: randomised controlled trial; RT‐PCR: reverse transcription polymerase chain reaction; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; SOFA: sequential organ failure assessment; TACO: transfusion‐associated circulatory overload; TAD: transfusion‐associated dyspnoea; TRALI: transfusion‐related acute lung injury: WHOQOL‐100: World Health Organization Quality of Life scale

Characteristics of ongoing studies [ordered by study ID]

CTRI/2020/11/028779.

Study name	Effect of SARS‐CoV‐2 equine antiserum immunoglobulin (purified F(ab)2 fragment) in hospitalised COVID‐19 patients with moderate disease
Methods	Trial design: RCT (parallel‐group) Sample size: 72 Setting: inpatient Country: India Language: English Number of centres: 2
Participants	Inclusion criteria Both male and female patients aged between 18‐55 years who signed the informed consent Patients screened for Covid‐19 by RT‐PCR method?72 hours from the date of RT‐PCR confirmation and/or 7 days from the start of symptoms. Respiratory rate > 24 breaths/min and SpO2?93% on room air Patients screened for intradermal sensitivity testing prior to initiation of infusion Exclusion criteria Pregnant women Breastfeeding women Known hypersensitivity to blood products and reactive to intradermal sensitivity test prior to infusion Receipt of pooled immunoglobulin in last 30 days Critically ill patients: severe ARDS cases shock (requiring vasopressor to maintain a mean arterial pressure of 65 mmHg or mean arterial pressure < 65) Participating in any other clinical trial Clinical status precluding infusion of blood products Patients are not suitable for transfusion therapy Patients with severe pneumonia defined as: respiratory rate 30 times/min or oxygen saturation 90% in resting state or PaO2/FiO2 100 mmHg or respiratory failure and mechanical ventilation are required or shock occurs or ICU monitoring with presence of other organ failure Acute life‐threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection. (Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia) Patients on any other immunoglobulin or immunomodulatory treatment Patients with known history of allergy to horse proteins or severe allergic reactions to any component of the equine antiserum
Interventions	hIVIG therapy: SARS‐CoV‐2 (COVID‐19) antiserum immunoglobulins (purified F(ab)2 fragment along with standard care Concomitant therapy: standard care Duration of follow‐up: Donors' disease severity: NR Methods of hyperimmune immunoglobulin preparation Source: animal or human: equine Dose: 2 x 4 mL doses at day 0 and Day 1 Route: IV Timing of administration from onset of symptoms: study day 0 (inclusion criteria within 7 days of symptom onset or < 72 h from positive PCR test) Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: n/a equine
Outcomes	Primary study outcome: proportion of patients with treatment‐emergent AEs including infusion‐related reactions (to study day 28) Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported up to day 28 Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV or death: reported up to day 28 Improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): NR QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 d, up to 28 d, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported SAEs, defined as the number of participants with any event: reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: new need for IMV: reported as disease progression new need for non‐IMV or high‐flow oxygen: reported as disease progression new need for oxygen by mask or nasal prongs: reported as disease progression improvement of clinical status: weaning or liberation from IMV in surviving patients: reported as duration of respiratory support ventilator‐free days: NR duration to liberation from IMV: liberation from supplemental oxygen in surviving patients: reported as duration of respiratory support duration to liberation from supplemental oxygen: Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: NR Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported day 14 and day 28
Starting date	5 November 2020
Contact information	Dr Subhash Thuluva, Vice President ‐ Clinical Development, Biological E.Limited, Clinical affairs & Pharmacovigilance Dept, 2nd floor, Road No.35, Jubilee Hills Hyderabad TELANGANA 500033 India, 04071216248; subhash.thuluva@biologicale.com
Notes	Recruitment status: NR Prospective completion date: Feburary 2022 Sponsor/funding: Biological ELimited, 18/1&3, Azamabad, Hyderabad ‐ 500020, Telangana, India. (Pharmaceutical industry‐Indian)

CTRI/2021/02/031566.

Study name	Evaluation of Equine antibody treatment in patient with COVID 19 infection
Methods	Trial design: RCT, parallel‐group Sample size: 160 Setting: inpatient Country: India Language: English Number of centres: 10
Participants	Inclusion criteria Age: phase 1: ≥ 18 years to ≤ 55 years phase 2: ≥ 18 years to ≤ 65 years Men or non‐pregnant women who agree to contraceptive requirements Patients with RT‐PCR confirmed COVID‐19 in ≤ 72 h prior to randomisation (Ct ≥ 24) Have SpO2 < 94% (range 90%‐93%) on room air Have ≥ 1 of the following‐ dyspnoea, fever, cough, respiratory rate ≥ 24/min and heart rate up to 120/min Patients who agree to participate in the study and follow all study‐related procedures Exclusion criteria Require mechanical ventilation Have oxygen saturation ≤ 89% Patients re‐infected with SARS‐CoV‐2 Suspected or proven serious active bacterial fungal viral or other infection Patients with positive skin test with IP Patients with known equine allergies or past medical history of serum sickness Patients who are HIV, HCV, Hepatitis B positive or immunocompromised Patients with significant co‐morbidities at screening Moribund state Pregnant or nursing women Participating in other clinical trial
Interventions	hIVIG therapy: equine COVID‐19 antiserum (F(ab)2 (BSVEQAb) Concomitant therapy: standard care Duration of follow‐up: 28 days Donors' disease severity: n/a Methods of hyperimmune immunoglobulin preparation Source: animal or human: equine Dose: 5 mg/kg or 10 mg/kg body weight Route: IV in 100‐150 mL saline over 1‐2 h Timing of administration from onset of symptoms: NR Whether hyperimmune immunoglobulin dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: n/a
Outcomes	Primary study outcome Phase 1: number of patients with ≥ 1 unexpected SAEs considered by the investigator to be related to study drug administration Phase 2: proportion (percent) of patients turning COVID‐19‐negative day 5 and day 7 Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: NR Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: NR worsening of clinical status: participants with clinical deterioration (new need forIMV) or death: reported as mean reduction in WHO clinical progression scale improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): NR QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 d up to 28 d, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported SAEs, defined as the number of participants with any event: reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: new need for IMV: NR new need for non‐IMV or high‐ flow oxygen: new need for oxygen by mask or nasal prongs improvement of clinical status: reported as mean reduction in WHO clinical progression scale weaning or liberation from IMV in surviving patients: ventilator‐free days: NR duration to liberation from IMV: liberation from supplemental oxygen in surviving patients: NR duration to liberation from supplemental oxygen: NR Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: NR Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported up to 7 days
Starting date	15 March 2021
Contact information	Dr Ramesh Jagannathan, Vice President ‐ Medical Affairs, Bharat serums and Vaccines LTd, rd floor, Liberty tower, Behind Reliable Plaza, Airoli, Navi mumbai, Thane, MAHARASHTRA, 400708, India 022‐45043456 Ramesh.Jagannathan@bharatserums.com
Notes	Recruitment status: NR Prospective completion date: September 2022 Sponsor/funding: Bharat Serums and Vaccines ltd. 3rd floor, Liberty tower, Behind Reliable Plaza, Airoli, Navi mumbai MAHARASHTRA 400708 India

IRCT20200508047346N1.

Study name	(WHO 2020d)Evaluation of the effectiveness of rabbit antibody against coronavirus in patients
Methods	Trial design: open‐label, parallel‐arm, phase III, RCT Sample size: 124 Setting: inpatient Country: Iran Language: English Number of centres: 1
Participants	Inclusion criteria Clinical symptoms of COVID‐19 Signed conscious consent Age > 18 years Hospitalised at beginning and end of study 1 of the moderate to severe clinical symptoms of COVID‐19 shortness of breath respiratory rate more than 30 times/min Oxygen saturation of blood < 93% (at rest) Ratio of arterial oxygen pressure to inhaled oxygen < 300 Pulmonary infiltration > 50% over 24‐48 h Exclusion criteria History of allergies to blood products such as IVIG or albumin Critical conditions such as multiple organ failure Pregnant women Breastfeeding mothers Receiving treatment and medication outside the standard COVID‐19 treatment protocol Physician believes that the patient is not suitable to participate in this trial Known sensitivity to rabbit proteins
Interventions	Details of hIVIG therapy Drug name: CoviGlobulin (rabbit polyclonal antibody) Dose: 1‐3 mg per kg body weight Body (1‐3 mg / kg / d) for 2‐4 days Number of doses: 2‐4 Route: NR Source: rabbit Treatment details, including time of plasma therapy (e.g. early stage of disease): hospitalised patients For studies including a control group: comparator (type): standard care Concomitant therapy: none Treatment cross‐overs: NR
Outcomes	Primary study outcomes Clinical improvement (14 days), 6‐point scale includes: score 6: death score 5: hospitalisation for ECMO and (or) mechanical ventilation score 4: non‐invasive ventilation or high‐current oxygen therapy score 3: hospitalisation for oxygen therapy (not high‐current and mechanical ventilation) not required) score 2: hospitalisation score 1: clearance Mortality (14 days) Primary review outcomes All‐cause mortality at hospital discharge: NR 30‐day mortality: NR Secondary review outcomes Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020d), WHO Ordinal Scale for Clinical Improvement (WHO 2020e) at up to 7 days, 8 to 15 days, 16 to 30 days: partially (see primary study outcomes) Mortality (time to event): NR 90‐day mortality: NR Time to discharge from hospital: hospitalisation, duration Admission to ICU: NR Length of stay on the ICU: yes Viral clearance, assessed with RT‐PCR test at baseline, up to 3, 7, and 15 days: yes (proportion of PCR‐negative (3 and 7 days after transfusion)) QoL: NR Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): NR Number of participants with SAEs: NR Additional study outcomes Invasive mechanical ventilation ECMO duration Clinical characteristics including, fever, respiratory frequency(RF) and PaO2/FiO2
Starting date	21 May 2020
Contact information	Corresponding Author Name: Prof. Mostafa Ghanei Affiliation: Bagheiat‐allah University of Medical Sciences Full Address: Mulla Sadra, Sheikh Baha'i, Baqiyatallah Al‐Azam Hospital, Teheran, 1435915371 Email: mghaneister@gmail.com
Notes	Recruitment status: recruiting Prospective completion date: NR Sponsor/funding: Kowsar Biotechnology Co., Sirous Zeinali, No. 41, Kosar Complex, 3rd Floor, Majlesi St., Valiasr St., Above Fatemi St., Tehran, Tehran

NCT04514302.

Study name	Safety and efficacy of anti‐SARS‐CoV‐2 equine antibody fragments (INOSARS) for hospitalized patients with COVID‐19
Methods	Trial design: RCT: parallel‐assignment Sample size: 51 Setting: inpatient (level 4‐6) Country: Mexico Language: English Number of centres: 2
Participants	Inclusion criteria Patients of both sexes aged ≥ 18 years Patients with a confirmed infection with SARS‐CoV‐2 by PCR Patients admitted for hospitalisation for COVID‐19 disease that fulfils any of the following: clinical or imaging evidence of pneumonia defined as: SpO2 < 94% or PaO2/FiO2 (SpO2/FiO2) < 300 or chest imaging consistent with pneumonia or clinical evidence of pneumonia (fever, cough, dyspnoea and respiratory frequency > 24 respirations/min) OR score of 4 (hospitalised no oxygen requirement, requires medical care), 5 (hospitalised, low‐flow oxygen requirement) or 6 (hospitalised, high‐flow oxygen or non‐IMV requirement) in the National Institute of Allergy and Infectious Diseases (NIAID) 8‐point ordinal scale (DMID/NIAID/NIH 2020) of clinical status for COVID‐19 high‐risk markers of disease progression (at least on serum inflammatory marker elevated: CRP, D‐dimer, lactate dehydrogenase, ferritin) Agrees to participate in the study and signs written informed consent (signed by relative if applicable) Exclusion criteria Patients with known equine allergies Patients with past medical history of serum sickness Patients with > 4 d of hospitalisation before being randomised in study Patients who have received CP or IVIG for COVID‐19 Pregnant or breastfeeding women Patients with chronic kidney disease under dialysis Patients under IMV and/or ECMO at the beginning of study Patients participating in another intervention clinical trial Patients who are immunocompromised or with another chronic condition, that is judged by medical staff, to be at higher risk of infection or complications from participating in study Patients who are judged by medical staff unlikely to survive at 48 h
Interventions	CP therapy or hIVIG therapy: equine immunoglobulin Details of hyperimmune immunoglobulin therapy: Drug name: fragments INOSARS Dose: Number of doses 1 dose of 2 vials of INOSARS in 150 mL of saline solution 1 dose of 6 vials of INOSARS in 150 mL of saline solution Route: IV Source (eg human/equine/other): equine Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: comparator (type): placebo (saline) Concomitant therapy: NR Treatment cross‐overs: none
Outcomes	Primary study outcome: proportion of patients with improvement in clinical status (time frame: 28 days) Clinical improvement is defined as (whichever is first): a) hospital discharge or reduction of 1 point in the NIAID 8‐point ordinal scale Primary review outcomes All‐cause mortality at hospital discharge: NR 30‐day mortality: NR Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): yes, immediate AEs and late AEs Number of participants with SAEs: NR Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020d), WHO Ordinal Scale for Clinical Improvement (WHO 2020e) at up to 7 days, 8 to 15 days, 16 to 30 days: yes but with NIAID 8‐point ordinal scale Mortality (time to event): NR 90‐day mortality:NR Time to discharge from hospital: yes, duration of hospitalisation Admission to the intensive care unit (ICU): NR Length of stay on the ICU: NR Viral clearance, assessed with RT‐PCR test at baseline, up to 3, 7, and 15 days: yes, at day 3 QoL: NR Additional study outcomes Time to clinical improvement (time frame: 28 days)
Starting date	20 October 2020 (estimated start date)
Contact information	Contact: Servando Cardona‐Huerta, MD, Ph. D.+5218112121946, servandocardona@tec.mx Contact: Alejandro Torres‐Quintanilla, MD, MSc+528180205853, atorresq@tec.mx
Notes	Recruitment status: not yet recruiting Planned completion date: February 20, 2021 Sponsors: Hospital San Jose Tec de Monterrey

NCT04838821.

Study name	Efficacy and safety of three different doses of an anti SARS‐CoV‐2 hyperimmune equine serum in COVID‐19 patients (SECR‐02)
Methods	Trial design: RCT Sample size: 156 Setting: inpatient Country: Costa Rica and Mexico Language: English Number of centres: 4
Participants	Inclusion criteria Male or female patients, aged ≥ 18 Participant or relative (if applicable) signed informed consent SARS‐CoV‐2 infection confirmed by RT‐PCR SARS‐CoV‐2 pneumonia confirmed by chest X‐ray Patients with moderate or severe disease clinical presentation of the disease that require hospitalisation Being within 10 d of the initial COVID‐19‐related symptoms onset Admission in the participating centre within a 24‐h period Female patients of child‐bearing age with a negative pregnancy test Exclusion criteria COVID‐19 patients who do not require hospitalisation (outpatient setting) Patients who are participating in other therapeutic clinical trials COVID‐19 patients who have received CP treatment Critical disease COVID‐ 19 patients (respiratory failure, septic shock, and/or multiple organ dysfunction, admission PaO2/FIO2 ratio < 100) Previously snake‐bitten individuals that received any type of equine hyperimmune serum treatment History of an allergic reaction due to contact or exposure to horse Pregnant or breastfeeding women. Patients who, at the investigator's discretion, are not likely to comply with study indications and procedures Patients currently undergoing haemodialysis in a renal support programme Individuals who were previously classified by their treating physicians (prior to the COVID‐19 diagnosis), of having an unfavourable prognosis with a short lifespan due to a concomitant disease other than the study disease.
Interventions	hIVIG therapy: Anti‐SARS‐CoV‐2 equine hyperimmune serum Concomitant therapy: NR Duration of follow‐up: 28 days Donors' disease severity: NR Methods of hyperimmune immunoglobulin preparation Source:animal or human: equine Dose: 12 mg/kg, 30 mg/kg or 56 mg/kg Route: IV Timing of administration from onset of symptoms: study day 1 Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: NR
Outcomes	Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Crude mortality at 28 days All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported up to day 28 Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: Reported at day 28 Improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): reported up to day 28 QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported to day 28 SAEs, defined as the number of participants with any event: reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: new need for IMV: reported as change in mechanical ventilation requirement at day 28 new need for non‐IMV or high‐flow oxygen: NR new need for oxygen by mask or nasal prongs: NR improvement of clinical status: weaning or liberation from IMV in surviving patients: NR ventilator‐free days: NR duration to liberation from IMV: liberation from supplemental oxygen in surviving patients: NR duration to liberation from supplemental oxygen: NR Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: reported to day 28 Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported as change in viral load up to day 28
Starting date	29 March 2021
Contact information	Contact: Rodrigo Aguilar, MD; 22328233; raguilart@ccss.sa.cr Taciano Lemos, MD; 21014837; tlemosp@ccss.sa.cr Douglas Montero, MD; 21047555; dmontero@ccss.sa.cr Ileana Balmaceda, MD; 25478000; ibalmace@ccss.sa.cr
Notes	Recruitment status: recruiting Prospective completion date: 29 September 2021 Sponsor/funding: Caja Costarricense de Seguro Social

NCT04891172.

Study name	Anti COVID 19 hyperimmune intravenous immunoglobulin (C‐IVIG) therapy for severe COVID‐19 patients
Methods	Trial design: RCT (parallel‐assignment) Sample size: 310 Setting: inpatient Country: Pakistan Language: English Number of centres: 3
Participants	Inclusion criteria > 18 years of age Have positive COVID PCR on nasopharyngeal and/or oropharyngeal swabs Classified as severe COVID‐19 according to WHO guideline Consent given by the patient or first‐degree relative Exclusion criteria Critical COVID‐19 patients Pregnant women Previous allergic reaction to immunoglobulin treatment Patient given immunomodulatory drug (e.g. tociluzumab) Patient requiring 2 inotropic agents to maintain blood pressure Known case of any autoimmune disorder Chronic kidney disease Known case of thromboembolic disorder Aseptic meningitis
Interventions	hIVIG therapy: anti‐COVID‐19 IVIG Concomitant therapy: Standard care: airway support, anti‐viral medication, antibiotics, fluid resuscitation, haemodynamic support, steroids, painkillers, anti‐pyretics, anti‐coagulant Duration of follow‐up: 28 days Donors' disease severity: NR Methods of hIVIG preparation Source: animal or human: human Dose: 0.15 g/kg Route: IV Timing of administration from onset of symptoms: NR Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: NR
Outcomes	Primary study outcome: 28‐day mortality Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported as clinical status at day 28 improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): reported as clinical status at day 28 QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): NR SAEs, defined as the number of participants with any event: reported Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: reported as clinical status at day 28 new need for IMV: reported as clinical status at day 28 new need for non‐IMV or high‐flow oxygen: reported as clinical status at day 28 new need for oxygen by mask or nasal prongs. reported as clinical status at day 28 Improvement of clinical status: reported as clinical status at day 28 weaning or liberation from IMV in surviving patients: reported as clinical status at day 28 ventilator‐free days: NR duration to liberation from IMV: liberation from supplemental oxygen in surviving patients: NR duration to liberation from supplemental oxygen: NR Need for dialysis at up to 28 days: NR Admission to the ICU on day 28: Duration of hospitalisation: Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days:
Starting date	1 August 2021
Contact information	Shaukat Ali, PhD +92‐3363010185 ali.shaukat@duhs.edu.pk
Notes	Recruitment status: recruiting Prospective completion date: 2 August 2022 Sponsor/funding: Dow University of Health Sciences

NCT04910269.

Study name	Outpatient treatment with anti‐coronavirus immunoglobulin (OTAC)
Methods	Trial design: RCT (parallel‐assignment) Sample size: 820 Setting: outpatient Country: USA and Denmark Language: English Number of centres: 14
Participants	Inclusion criteria Clinical risk based on age ≥ 55 years or an adult (age ≥ 18 years) with an immunosuppressed condition Positive test for SARS‐CoV‐2 within ≤ 5 days (if > 1 test, the first positive is within ≤ 5 days) Tests may include an institutional‐based nucleic acid amplification test (NAAT), or any protocol‐approved rapid test Within ≤ 5 days from symptom onset, if symptomatic from current SARS‐CoV‐2 infection Agrees to not participate in another clinical trial for the treatment or management of SARS‐CoV‐2 infection through day 7, or until hospitalised or significant disease progression if prior to day 7 (defined by ordinal category 4 or 5) Participant provides written informed consent prior to study procedures, and understands and agrees to adhere to planned study procedures through day 28 Ongoing immunosuppressive condition or immunosuppressive treatment, includes: steroids equivalent to prednisone > 10 mg/d for at least the last 28 days rheumatologic or autoimmune disorder treated with a biologic or non‐biologic immunosuppressive therapy anti‐rejection medicine after solid organ or stem cell transplantation cancer treatment with systemic chemotherapy, biologic and/or cell‐based therapy in the last 12 months primary or acquired severe B‐ or T‐lymphocyte immune dysfunction HIV infection splenectomy or functional asplenia Exclusion criteria Asymptomatic and had prior symptoms from the current infection that have now resolved (for > 24 h) Asymptomatic and has received a vaccination for COVID‐19 (≥ 1 dose) Undergoing evaluation for possible admission to hospital for medical management (this does not include evaluation of possible hospitalisation for public health purposes) Evidence of pneumonia and/or hypoxia due to COVID‐19 (NOTE: chest imaging is not required, but if available it should not show new infiltrates suggestive of pneumonia; hypoxia is defined by new oxygen supplementation or increase above pre‐illness level) Prior receipt of immunoglobulin product or passive immune therapy for SARS‐CoV‐2 in the past 90 days (i.e. CP, SARS‐CoV‐2 monoclonal antibodies, or any IVIG) Any of the following thrombotic or procoagulant conditions or disorders: acute coronary syndrome, cerebrovascular syndrome, pulmonary embolism, or deep venous thrombosis within 28 days of randomisation prothrombin gene mutation 20210, homozygous Factor V Leiden mutations, antiphospholipid syndrome, or a deficiency in antithrombin III, protein C, or protein S History of hypersensitivity to blood, plasma or IVIG excipients Known IgA deficiency or anti‐IgA antibodies. Medical conditions for which receipt of 300 mL volume of IV fluid from study treatment may pose specific risk to the patient (e.g. decompensated congestive heart failure) In the opinion of the investigator, any condition for which participation would not be in the best interest of the participant or that could prevent or confound protocol assessments.
Interventions	hIVIG therapy: hIVIG Concomitant therapy Steroids equivalent to prednisone > 10 mg/d for at least the last 28 days Rheumatologic or autoimmune disorder treated with a biologic or non‐biologic immunosuppressive therapy Anti‐rejection medicine after solid organ or stem cell transplantation Cancer treatment with systemic chemotherapy, biologic and/or cell‐based therapy in the last 12 months Primary or acquired severe B‐ or T‐lymphocyte immune dysfunction HIV infection Splenectomy or functional asplenia Duration of follow‐up: up to 28 days Donors' disease severity: NR Methods of hIVIG preparation: NR Source: NR Dose: 300 mL at a concentration of 0.1 g/mL Route: IV Timing of administration from onset of symptoms: within 5 d of symptom onset if symptomatic, positive test for SARS‐CoV‐2 within ≤ 5 days Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: NR
Outcomes	Primary study outcome: clinical status at 7 days Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported up to day 28 Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported up to day 28 improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): reported up to day 28 QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: reported AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): NR SAEs, defined as the number of participants with any event: NR Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: new need for IMV: reported up to day 28 new need for non‐IMV or high‐flow oxygen: reported up to day 28 new need for oxygen by mask or nasal prongs: reported up to day 28 improvement of clinical status: weaning or liberation from IMV in surviving patients: reported up to day 28 ventilator‐free days: NR duration to liberation from IMV: reported up to day 28 liberation from supplemental oxygen in surviving patients: reported up to day 28 duration to liberation from supplemental oxygen: reported up to day 28 Need for dialysis at up to 28 days: NR Admission to ICU on day 28: NR Duration of hospitalisation: NR Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported
Starting date	2 June 2021
Contact information	Gary Collins 612‐626‐9006 gary‐c@ccbr.umn.edu
Notes	Recruitment status: recruiting Prospective completion date: August 2023 Sponsor/funding: University of Minnesota

NCT04928430.

Study name	Efficacy and safety of XAV‐19 for the rreatment of moderate‐to‐severe COVID‐19
Methods	Trial design: RCT (parallel‐assignment) Sample size: 722 Setting: inpatient Country: Bulgaria, Greece, Romania, Spain, Turkey Language: English Number of centres: 18
Participants	Inclusion criteria Male or female patient aged ≥ 18 years, weighing > 50 kg and < 120 kg, at the time of signing the informed consent Patient presenting in a specialised or an emergency unit Patient presenting signs of pneumonia evidenced by at least 1 of the following: auscultation, chest X‐Ray, CT scan OR presenting COVID‐19 related symptoms having started < 10 d prior to screening visit, including at least 2 of the following: fever, cough, sore throat or nasal discharge, dyspnoea (shortness of breath), thoracic pain, headache or fatigue, myalgia, anosmia, dysgeusia, diarrhoea, nausea Patient with SpO2 > 90% (at ambient air) Patient with a first positive SARS‐CoV‐2 test (RT‐PCR, RT‐qPCR or antigen test) in the last 10 days or at screening Women of childbearing potential (WOCBP) must have a negative urine pregnancy test at screening and use a highly effective birth control until 90 days after the administration of study drug Non‐vasectomised male patients having a female partner of childbearing potential must agree to use a highly effective method of contraception until 90 days after the administration of study drug Patient capable of giving signed informed consent Exclusion criteria Patient with a positive SARS CoV‐2 test (RT‐PCR, RT‐qPCR or antigen test) of > 10 days before the screening visit Patient with multi‐organ failure Patient requiring immediate ICU hospitalisation Patient participating in another clinical trial with an investigative agent Pregnancy or breastfeeding
Interventions	hIVIG therapy: XAV‐19, heterologous swine glyco‐humanised polyclonal antibody (GH‐pAb) Concomitant therapy: NR Duration of follow‐up: at least 15 days Donors' disease severity: NR Methods of hyperimmune immunoglobulin preparation Source: animal or human Dose: 150 mg Route: IV infusion Timing of administration from onset of symptoms: < 10 days since positive test Whether hIVIG dosage was adjusted based on batch‐dependent neutralising antibody levels: NR Whether the donors were tested by nasal swabs or whether the plasma was tested: NR
Outcomes	Primary study outcome: number of participants with clinical worsening of at least 1 point on the WHO 7‐point ordinal scale Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: NR (reported up to 15 days) Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported up to 15 days improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): reported up to 15 days QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported up to 15 days SAEs, defined as the number of participants with any event: reported up to 15 days Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Clinical status at day 28, day 60, and up to the longest follow‐up, including: worsening of clinical status: new need for IMV: reported up to 15 days new need for non‐IMV or high‐flow oxygen: NR new need for oxygen by mask or nasal prongs: NR Improvement of clinical status: weaning or liberation from IMV in surviving patients: NR ventilator‐free days: NR duration to liberation from IMV: liberation from supplemental oxygen in surviving patients: NR duration to liberation from supplemental oxygen: NR Need for dialysis at up to 28 days: NR Admission to the ICU on day 28: reported up to 15 days Duration of hospitalisation: reported up to 15 days Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported up to 8 days
Starting date	28 April 2021
Contact information	Bernard Vanhove, Dr +33(0)255 10 11 73 bernard.vanhove@xenothera.com
Notes	Recruitment status: recruiting Prospective completion date: 1 April 2022 Sponsor/funding: Xenothera SAS

NCT05173441.

Study name	Human COVID‐19 immunoglobulin (COVID‐HIG) therapy for COVID‐19 patients
Methods	Trial design: RCT Sample size: 180 Setting: inpatient Country: United Arab Emirates Language: English Number of centres: 1
Participants	Inclusion criteria ≥ 18 and < 65 years of age when signing the informed consent form, male or female. Positive testing by virologic test (SARS‐CoV‐2 virus nucleic acid test, result of RT‐PCR within 3 days are acceptable) before randomisation COVID‐19‐related clinical symptoms (fever or respiratory symptoms, etc.) progresses before randomisation Inpatients with moderate or severe COVID‐19 (severity is graded by FDA standard). With early warning signs for severe/critical cases, meet any of the following indicators Progressive exacerbation of hypoxaemia or respiratory distress Deterioration of tissue oxygenation or progressive hyperlactataemia Rapid decrease in lymphocyte count or steady increase in inflammatory markers such as IL‐6, CRP, and ferritin Significant increase of D‐dimer and other related indexes of coagulation function Chest imaging showing rapid progression of lung lesions Randomisation should be within 10 days of COVID‐19 symptoms onset Participants (including their partners) have no pregnancy plan and voluntarily take effective contraceptive measures from signing consent to 3 months after he/she finished the trial Willing to comply with the requirements, and co‐operate when collecting of nasopharyngeal swabs and venous blood for testing according to the protocol; and willing to complete the study Able to consent, and willing to sign the consent form Exclusion criteria Asymptomatic infection, mild or critical COVID‐19 SP02 < 93% under high‐flow oxygen inhalation, or receiving IMV or ECMO Reinfected patients with historical confirmed COVID‐19, detectable by SARS‐CoV‐2 serological test (nasopharyngeal SARS‐CoV‐2 RNA levels or serum antibody) May be transferred to another hospital, that is not one of the trial sites, within 72 h Meets 1 of the following high‐risk factors Pre‐existing cardiovascular condition (including uncontrolled hypertension: SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg) and cerebrovascular diseases, chronic lung diseases (COPD, moderate to severe asthma), diabetes (HbA1c > 9.0%), chronic liver diseases, chronic kidney diseases, malignancies or other complicated diseases Pre‐existing Immunosuppression (such as AIDS, long‐term use of corticosteroids or other immunosuppressive drugs that lead to a weakened immune function) Obesity: BMI ≥ 35 Heavy smokers: ≥ 20 cigarettes per day on average History of allergy to IVIG, other plasma proteins or blood products, history of selective IgA deficiency with presence of anti‐IgA antibodies Vaccinated in last 8 weeks, such as influenza, poliomyelitis, measles, rubella, mumps and varicella virus vaccines May worsen and progress to critical COVID‐19 rapidly Usage of other antiviral drugs to treat SARS‐CoV‐2 (except the basic treatment specified in the protocol) before randomisation History of major surgery (defined as life‐threatening surgery, requiring general anaesthesia and causing severe bleeding, including bone and joint surgery on elbow, shoulder, hip, knee, ankle and spine) within 8 weeks before screening (including 8 weeks), or plan to have surgery during the trial, which may bring unacceptable risks to the participants, evaluation by investigators ALT or AST > 2 times the normal range upper limit, or Ccr < 60 mL/min D‐dimer increased significantly (> 1 mg/L); history of thromboembolism or coagulation diseases in last year, such as acute coronary syndrome, cerebrovascular syndrome, pulmonary or deep vein thrombosis, etc Positive virus makers (positive HBsAg, HCV‐Ab, or Treponema pallidum‐specific antibody) History of organ transplantation (such as heart, lung, liver, kidney, etc Pregnant or lactating Other participants who are not suitable to participate in the trial considered by the investigator, such as potential compliance problems, can not complete all the examinations and evaluations according to the protocol, mental illness, obvious mental disorders; Incapacity or cognitive ability caused by other reasons Participated in other clinical trials to investigate drugs or medical devices in last 1 month before signing consent form
Interventions	CP therapy or hIVIG therapy: hIVIG therapy Type of plasma: human COVID‐19 immunoglobulin Volume: NR Number of doses: up to 5 Antibody titre: NR Pathogen inactivated or not: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): within 10 days of symptom onset For studies including a control group: comparator (type): placebo (0.9% sodium chloride) Concomitant therapy: standard care Treatment cross‐overs: none
Outcomes	Primary study outcome: time to clinical improvement (up to 28 days) Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time to event, and at hospital discharge: reported up to 28 days Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported up to 28 days Improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): reported up to 28 days QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): NR SAEs, defined as the number of participants with any event: NR Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Need for dialysis at up to 28 days: NR Admission to ICU on day 28: reported Duration of hospitalisation: reported Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported
Starting date	Not yet recruiting
Contact information	YunKai Yang, Prof; +86‐13601126881; yangyunkai@sinopharm.com
Notes	Recruitment status: not yet recruiting Prospective completion date: 30 November 2023 Sponsor/funding: Sinopharm Wuhan Plasma‐derived Biotherapies Co., Ltd.; China National Biotec Group Company Limited; Beijing Tiantan Biological Products Co., Ltd.

RPCEC00000379.

Study name	Exploratory, controlled, randomized, open and monocentric clinical trial to evaluate the safety and explore the antiviral effect of anti‐SARSCoV‐2 gamma globulin in SARS‐Cov‐2 adult serious with COVID‐19
Methods	Trial design: RCT Sample size: NR Setting: inpatient Country: Cuba Language: English and Spanish Number of centres: NR
Participants	Inclusion criteria Severe patients > 19 years of age, with a confirmed diagnosis by RT‐PCR of infection by the SARS‐CoV‐2 virus Patients with < 10 d of evolution since the onset of symptoms Patients who gives informed consent Exclusion criteria Ventilated With acute and chronic kidney disease Previous thromboembolic events History of previous anaphylaxis Previous history of adverse reaction to intravenous gamma globulin Pregnant or lactating woman Severe comorbidity: terminal cancer and severe heart disease BMI ≥ 30 9 With a diagnosis of selective IgA immunodeficiency With autoimmune diseases Being treated with the anti‐CD 6 monoclonal antibody Itolizumab History of having received treatment with blood products 1 month before inclusion in the study
Interventions	CP therapy or hIVIG therapy: hIVIG therapy Type of plasma: human COVID‐19 immunoglobulin Volume: 150 mg/kg (1100 IU/Kg) diluted in 300 mL of 0.9 % saline solution (total volume) Number of doses: 1 Antibody titre: NR Pathogen inactivated or not: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: comparator (type): Cuban national action protocol for COVID‐19. Version 1.6. (except itolizumab) Concomitant therapy: Cuban national action protocol for COVID‐19. Version 1.6. (except itolizumab) Treatment cross‐overs: none
Outcomes	Primary study outcomes SAEs Causation relationship (1. Possible, 2. Probable, 3. Definitive) Measurement time: 7 days after treatment Exploring the Effect: Antiviral and anti‐inflammatory favourable response on the 7th day after the treatment The favourable response is measured if there is an increase in the Ct value, in the RT PCR and a decrease in the neutrophil/lymphocyte ratio; of CRP and D‐Dimer). Measurement time: days 0, 3, 5 and 7 after treatment. Primary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease All‐cause mortality at day 28, day 60, time‐to‐event, and at hospital discharge: reported up to 7 days Clinical status, at day 28, day 60, and up to the longest follow‐up, including the following: worsening of clinical status: participants with clinical deterioration (new need for IMV) or death: reported up to 7 days improvement of clinical status: participants discharged from hospital (participants should be discharged without clinical deterioration): reported up to 7 days QoL, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 28 days, and longest follow‐up available: NR AEs (any grade, grade 1‐2, grade 3‐4), defined as the number of participants with any event and including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions, headache, thromboembolic events): reported up to 7 days SAEs, defined as the number of participants with any event: reported up to 7 days Secondary review outcomes Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Need for dialysis at up to 28 days: NR Admission to the ICU on day 28: reported Duration of hospitalisation: reported Viral clearance, assessed with RT‐PCR test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days: reported up to day 7
Starting date	7 July 20221
Contact information	Beatriz Amat Valdes, Military Hospital Dr. Luis Diaz Soto, Havana 10900, Cuba, bsuatv@infomed.sld.cu
Notes	Recruitment status: recruiting Prospective completion date: 31 January 2022 Sponsor/funding: AICA Laboratorories Company

AE: adverse event; ALT: alanine transaminase; ANC: absolute neutrophil count; ARDS: acute respiratory distress syndrome; AST: aspartate transaminase; BMI: body mass index; COI: conflict of interest;Ccr: creatinine clearance rate COPD: chronic obstructive pulmonary disease; CP: convalescent plasma; CRP: C‐reactive protein; DBP: diastolic blood pressure; ECMO: extracorporeal membrane oxygenation; F(ab)2: fragment antibodiesFDA: US Food and Drug Administration; FiO₂: fractional inspired oxygen; HBV/HCV: hepatitis B/C; ICU: intensive care unit; IgA (B/G/M): immunoglobulin A (B/G/M); IL‐6: interleukin‐6;IMV: invasive mechanical ventilation; IP: Incontinentia Pigmenti IV: intravenous; IVIG: intravenous immunoglobulin; NIAID: National Institute of Allergy and Infectious Diseases; NR: not reported; NYHA: New York Heart Association;PaO₂: arterial blood oxygen partial pressure; PCR: polymerase chain reaction; QoL: quality of life; RCT: randomised controlled trial; RF: respiratory failure; RNA: ribonucleic acid; RT‐PCR: reverse transcription polymerase chain reaction; SAE: serious adverse event; SARS: severe acute respiratory syndrome; SBP: systolic blood pressure; SpO₂: peripheral capillary oxygen saturation; TACO: transfusion‐associated circulatory overload; TAD: transfusion‐associated dyspnoea; TRALI: transfusion‐related acute lung injury; WHO: World Health Organization; WHOQOL‐100: World Health Organization Quality of Life scale

Differences between protocol and review

Types of outcome measures

Primary outcomes

We had planned to present one summary of findings table per population. As we were unable to combine doses and interventions, we presented each dose of each intervention as a separate comparison, so there were too many to present in the summary of findings table. We selected the most important comparisons to present in the summary of findings table, and summarised all data from the other comparisons in additional tables.

Secondary outcomes

In line with other reviews on COVID‐19, we removed some secondary outcomes, because they did not consider competing events, whereas the primary outcomes of clinical worsening and clinical improvement did take into account competing events. The following outcomes specified in the protocol were removed from the final review:

Secondary outcomes relating to worsening of clinical status

• New need for invasive mechanical ventilation

• New need for non‐invasive mechanical ventilation or high flow oxygen

• New need for oxygen by mask or nasal prongs

Secondary outcomes relating to improvement of clinical status

• Weaning or liberation from invasive mechanical ventilation in surviving patients

• Ventilator free days

• Duration to liberation from invasive mechanical ventilation

• Liberation from supplemental oxygen in surviving patients

• Duration to liberation from supplemental oxygen

Electronic searches

We decided to exclude individual study registries from the search strategy because they are already included in the Cochrane COVID‐19 Study Register. From April 2021 onwards, the searches were restricted to RCTs with the use of RCT study filters. Newly identified search terms are constantly being included in the search strategies.

Contributions of authors

CK: clinical expertise, study selection, data extraction and assessment, and conception and writing of the manuscript

SJV: clinical expertise, study selection, data extraction and assessment, and conception and writing of the manuscript

KLC: clinical expertise, study selection, data extraction and assessment, and conception and writing of the manuscript

VP: methodological expertise, study selection, data extraction and assessment, and conception and writing of the manuscript

CI: methodological expertise, study selection, data extraction and assessment, and writing of the manuscript

IM: development of the search strategy

EMW: clinical expertise and advice

AL: clinical expertise and advice

DJR: clinical expertise and advice

ZM: clinical expertise and advice

CS‐O: clinical expertise and advice

LJE: clinical expertise, and conception and writing of the manuscript

NS: methodological expertise, study selection, data extraction and assessment, and conception and writing of the manuscript

Sources of support

Internal sources

• Sanquin Blood Supply, Netherlands

  Center for Clinical Transfusion Research

• University Hospital of Cologne, Germany

  Cochrane Cancer, Department I of Internal Medicine

• Monash University, Australia

  Transfusion Research Unit, Department of Epidemiology and Preventive Medicine

• NHS Blood and Transplant, UK

  NHS Blood and Transplant

• Leukaemia Foundation and HSANZ, Australia

  Haematology Society of Australia and New Zealand (HSANZ)

External sources

• European Union's Horizon 2020 research and innovation programme, Belgium

  SUPPORTing high‐quality evaluation of covid‐19 convalescent plasma throughout EUROPE (Support‐E)

Declarations of interest

CK: none known

SJV: is receiving a PhD scholarship from the not‐for‐profit Sanquin blood bank and was co‐author on a Comment for the Lancet: doi.org/10.1016/S0140‐6736(22)00112‐X.

KLC: HSANZ Leukaemia Foundation PhD scholarship to support studies at Monash University. This is not related to the work in this review.

VP: none known

CI: none known, Managing Editor of Cochrane Haematology, but not involved in the editorial process for this review

IM: none known; Information Specialist of Cochrane Haematology, but not involved in the editorial process for the this review.

EMW: I have received funding support from the Australian Medical Research Future Fund for a trial of convalescent plasma. I was not involved in bias assessment, data extraction or interpretation, but served as a content expert.

AL: none known

DJR: I am principal Investigator on a grant relating to the study of patients in the Convalescent Plasma trial, National Institute for Health (UKRIDHSC COVID‐19 Rapid Response Rolling Call, The use of convalescent plasma to treat hospitalised and critically ill patients with COVID‐19 disease, Grant Reference Number COV19‐RECPLAS). I am Editor‐in‐Chief, Transfusion Medicine by Wiley.

ZM: I have received funding support from the Australian Medical Research Future Fund for a trial of convalescent plasma. I was not involved in bias assessment, data extraction or interpretation, but served as a content expert.

CS‐O: is a member of the BEST Collaborative Clinical Study Group and Associate Editor, Transfusion Medicine. I was not involved in bias assessment, data extraction or interpretation, but served as a content expert.

LJE: co‐lead of the COVID‐19 immunoglobulin domain of the REMAP‐CAP trial and investigator on the RECOVERY trial. I was not involved in bias assessment, data extraction or interpretation, but served as a content expert. LJE is Co‐ordinating Editor of Cochrane Haematology, but was not involved in the editorial process for this review.

NS: none known; she is Co‐ordinating Editor of Cochrane Haematology, but was not involved in the editorial process for this review.

contributed equally

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