Interleukin‐6 blocking agents for treating COVID‐19: a living systematic review

Lina Ghosn; Anna Chaimani; Theodoros Evrenoglou; Mauricia Davidson; Carolina Graña; Christine Schmucker; Claudia Bollig; Nicholas Henschke; Yanina Sguassero; Camilla Hansen Nejstgaard; Sonia Menon; Thu Van Nguyen; Gabriel Ferrand; Philipp Kapp; Carolina Riveros; Camila Ávila; Declan Devane; Joerg J Meerpohl; Gabriel Rada; Asbjørn Hróbjartsson; Giacomo Grasselli; David Tovey; Philippe Ravaud; Isabelle Boutron

doi:10.1002/14651858.CD013881

. 2021 Mar 18;2021(3):CD013881. doi: 10.1002/14651858.CD013881

Interleukin‐6 blocking agents for treating COVID‐19: a living systematic review

Lina Ghosn ^1,^2,³, Anna Chaimani ³, Theodoros Evrenoglou ³, Mauricia Davidson ^1,^2,³, Carolina Graña ^1,^2,³, Christine Schmucker ^4,⁵, Claudia Bollig ^4,⁵, Nicholas Henschke ⁶, Yanina Sguassero ⁶, Camilla Hansen Nejstgaard ^7,⁸, Sonia Menon ^1,^2,³, Thu Van Nguyen ³, Gabriel Ferrand ^1,^2,³, Philipp Kapp ^1,^2,³, Carolina Riveros ^1,^2,³, Camila Ávila ⁹, Declan Devane ^10,¹¹, Joerg J Meerpohl ^4,⁵, Gabriel Rada ^9,¹², Asbjørn Hróbjartsson ^7,⁸, Giacomo Grasselli ^13,^14,¹⁵, David Tovey ¹, Philippe Ravaud ^1,^2,³, Isabelle Boutron ^1,^2,^3,^✉

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC8406988 PMID: 33734435

Abstract

Background

Interleukin 6 (IL‐6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID‐19). Their immunosuppressive effect might be valuable in patients with COVID‐19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance.

Objectives

To assess the effect of IL‐6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID‐19.

We will update this assessment regularly.

Search methods

We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L‐OVE platform, and Cochrane COVID‐19 Study Register to identify trials up to 26 February 2021.

Selection criteria

We included randomised controlled trials (RCTs) evaluating IL‐6 blocking agents compared with standard care alone or with placebo for people with COVID‐19, regardless of disease severity.

Data collection and analysis

We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/‐ additional organ support OR death) (D28 / ≥ D60); all‐cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events.

Main results

We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer‐reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants).

All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi‐country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline.

We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple‐arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three‐arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison.

Tocilizumab versus standard care alone or with placebo

a. Effectiveness of tocilizumab for patients with COVID‐19

Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I² = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate‐certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer‐term follow‐up (≥ D60).

The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I² = 64.4%; 3 RCTs, 712 participants; low‐certainty evidence). We did not obtain data for longer‐term follow‐up (≥ D60).

Tocilizumab reduces all‐cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I² = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high‐certainty evidence). There is uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I² = 0.0%; 2 RCTs, 519 participants; low‐certainty evidence).

b. Safety of tocilizumab for patients with COVID‐19

The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I² = 86.4%; 7 RCTs, 1534 participants; very low‐certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I² = 0.0%; 8 RCTs, 2312 participants; moderate‐certainty evidence).

Sarilumab versus standard care alone or with placebo

The evidence is uncertain about the effect of sarilumab on all‐cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all‐cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded

No data were available for other critical outcomes.

Authors' conclusions

On average, tocilizumab reduces all‐cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist‐defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta‐analyses are needed to be able to identify which patients are more likely to benefit from this treatment.

Evidence for an effect of sarilumab is uncertain and evidence for other anti‐IL6 agents is unavailable.

Thirty‐nine RCTs of IL‐6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID‐NMA platform (covid-nma.com).

Plain language summary

Can medicines that block interleukin‐6 (a protein involved in immune responses) treat COVID‐19?

Key messages

Treating COVID‐19 with tocilizumab (a medicine that blocks interleukin‐6) reduces the numbers of people who die within 28 days of treatment, and probably results in fewer serious unwanted effects than placebo treatment.

Studies of other medicines that block interleukin‐6 to treat COVID‐19 are under way. We will update this review when results from them become available.

COVID‐19

COVID‐19 is an infectious respiratory disease caused by a type of virus called a coronavirus. If the infection becomes severe, people may need intensive care and support in hospital, including machines to help them breathe (mechanical ventilation). Medicines that are currently used to treat other diseases are being tested in the search to find effective treatments for COVID‐19.

Blocking interleukin‐6

An immune response is how the body recognises and defends itself against harmful substances, such as viruses. COVID‐19 can disrupt the immune system, causing it to over‐react and produce dangerously high levels of inflammation. Interleukin‐6 (IL‐6) is a protein involved in triggering inflammation. Blocking the production of interleukin‐6 could reduce inflammation and help the immune system to fight COVID‐19.

Why we did this Cochrane Review

Tocilizumab and sarilumab are two medicines that block interleukin‐6. They are used to treat other conditions that involve an "over‐reactive" immune system, such as rheumatoid arthritis. We wanted to find out if medicines that block interleukin‐6 can be used to treat COVID‐19, and whether they might cause any unwanted effects.

What did we do?

We searched for studies that tested if medicines that block interleukin‐6 could treat COVID‐19.

We looked for randomised controlled studies, in which the treatments people received were decided by chance. This type of study usually gives the most reliable evidence about the effects of a treatment.

Search date: we searched for trials up to 26 February 2021.

What we found

We found 10 studies in 6896 people with COVID‐19. The average age of people in the studies was 56 to 65 years, and 66% of the people enrolled were men. The studies took place in Brazil, China, France, Italy, the UK and the USA; four studies took place in more than one country. Three studies were funded by pharmaceutical companies.

The medicines tested were tocilizumab and sarilumab. Both medicines were compared against a placebo (a dummy treatment that appears identical to the medicine being tested but without any active medicine) or standard care. The results were measured 28 days after treatment and after 60 days or more.

We also found 41 more studies of medicines blocking interleukin‐6 to treat COVID‐19 that had not yet published any results. These included 20 studies of tocilizumab, 11 studies of sarilumab and 10 studies of other medicines. Some of those studies are still ongoing and we will update this review to include their results when published.

What are the main results of our review?

Compared with placebo treatment or standard treatment, treatment with tocilizumab:

· reduces the number of people who died, of any cause, after 28 days (evidence from 6363 people in 8 studies); on average, 32 fewer people per 1000 died when treated with tocilizumab plus standard care, compared with standard care alone or placebo.

· probably makes little or no difference to clinical improvement (which is defined as leaving hospital or improvement in COVID‐19 symptoms) at 28 days (evidence from 5585 people in 7 studies).

· probably reduces slightly the number of serious unwanted effects, such as life‐threatening conditions or death (evidence from 2312 people in 8 studies).

We are uncertain about the effects of tocilizumab treatment on:

‐ severity of COVID‐19; that is, how many patients died of COVID‐19 or needed a ventilator or additional organ support at 28 days (evidence from 712 people in 3 studies); or

‐ how many patients died, of any cause, after 60 days or more (evidence from 519 people in 2 studies).

No results were reported for tocilizumab after 60 days or more for improvement, or severity at 28 days of COVID‐19.

We are uncertain about how sarilumab treatment affected the:

‐ numbers of people who died (of any cause) at 28 days (evidence from 880 people in 2 studies) and after 60 days (evidence from 420 people in 1 study); or

‐ the numbers of serious unwanted effects, such as life‐threatening conditions or death (evidence from 880 people in 2 studies).

‐ Sarilumab probably does not cause more unwanted effects (of any type) than placebo treatment (evidence from 420 people in 1 study). No other results for sarilumab treatment were reported.

We were not able to explore which COVID‐19 patients are more likely to benefit from this treatment.

Our confidence in our results

We are confident that tocilizumab reduced the number of deaths (from any cause) at 28 days. Our confidence in the other results for tocilizumab is moderate to low; further evidence may change our results. Our confidence in the results for sarilumab is low; further evidence is likely to change these results. Our confidence was lowered because some of the studies did not report all their results.

Summary of findings

Background

Description of the condition

In December 2019, a novel coronavirus outbreak began in Wuhan, Hubei Province, China. Infection with this severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spread rapidly. The World Health Organization (WHO) declared the coronavirus 19 (COVID‐19) disease a pandemic on 11 March 2020 (WHO 2020a). The COVID‐19 prevalence has increased exponentially in almost all countries during the first and subsequent waves (Worldometer 2020). The clinical spectrum of SARS‐CoV‐2 pneumonia ranges from mild to severe and critical manifestations. Approximately 15% of patients with SARS‐CoV‐2 infection develop severe COVID‐19 pneumonia (Guan 2020). Enormous efforts are focused on finding treatments to reduce the need of invasive mechanical ventilation and/or the risk of death in these patients.

Some authors have proposed that patients at high risk of COVID‐19 may experience a “cytokine storm”; a complex milieu of immune mis‐firing characterised by an early interferonopathy followed by hypercytokinaemia with high inflammatory markers and low reparative growth factors (Bastard 2020; Galani 2020; Lucus 2020; Mehta 2020; Pedersen 2020). In this milieu, Interleukin 6 (IL‐6) stands out as a particularly important biomarker (Chen 2020; Herold 2020; Laguna‐Goya 2020; Stukas 2020). IL‐6 levels or C‐reactive protein (CRP), a marker of IL‐6 driven inflammation, are associated with the severity of the disease (Caricchio 2020; Galvan‐Roman 2021; Knight 2020; Manson 2020; Webb 2020).

Description of the intervention

IL‐6 blocking agents are a class of therapeutic agents directed against the IL‐6 peptide or receptor. Available IL‐6 blocking agents are classified as anti‐IL‐6 receptor monoclonal antibodies (e.g. sarilumab, tocilizumab, levilimab) or anti‐IL‐6 monoclonal antibodies (siltuximab, olokizumab, clazakizumab).

How the intervention might work

IL‐6 blockers are beneficial in some hyperinflammatory diseases, such as rheumatoid arthritis (Scott 2017), giant cell arteritis (Stone 2017), and cytokine release syndrome induced by chimeric antigen receptor T‐cell therapy (Kotch 2019). SARS‐CoV‐2 infection induces a dose‐ and time‐dependent production of cytokines, including IL‐6 (Kang 2020).

The immunosuppressive effect of IL‐6 blockers might be valuable in patients with COVID‐19 who are characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance (Campochiaro 2020).

Why it is important to do this review

Given the urgent need for an effective treatment for COVID‐19 globally, patients have been treated with several costly immune‐modulating compounds including JAK (Janus kinase) inhibitors (Cao 2020; Kalil 2021), and specific cytokine blockers (Guaraldi 2020). The main immunomodulatory therapies that have been explored are JAK inhibition (broad suppression of inflammatory cytokines) and targeted inhibition of IL‐1 and IL‐6 (CORIMUNO‐19 Collaborative group 2021). Policymakers, scientific experts and the public need high‐quality, up‐to‐date evidence evaluating the effectiveness and safety of IL‐6 blocking agents for treating COVID‐19. This is a high‐priority question, for which the existing evidence is inconclusive (Solis‐García Del Pozo 2020). A living systematic review is an optimal approach to track and assess the effectiveness of IL‐6 blocking agents use in patients with COVID‐19.

This evidence synthesis will be updated weekly on the COVID‐NMA platform (covid-nma.com). This published Cochrane Review will be updated when new evidence emerges with potential to change the certainty of the evidence or the review authors’ conclusions, or at least every six months if new evidence is available. The process of the living systematic review is described in Appendix 1.

Objectives

To assess the effects of IL‐6 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in patients with COVID‐19.

This review is part of a larger project: the COVID‐NMA project (Boutron 2020a). The COVID‐NMA project provides decision‐makers with a complete, high‐quality and up‐to‐date mapping and synthesis of evidence on interventions for preventing and treating COVID‐19. We developed a master protocol on the effect of all interventions for preventing and treating COVID‐19 (Boutron 2020b). Our results are made available and updated weekly on the COVID‐NMA platform at covid-nma.com.

This living review focuses on SARS‐CoV‐2 and does not consider studies evaluating treatment with IL‐6 blocking agents for other coronavirus infections affecting humans.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) of any design with no restrictions on language. The following trial designs were eligible for inclusion: parallel group, cluster, cross‐over and factorial. Early‐phase clinical trials, single‐arm trials, non‐randomised studies and modeling studies of interventions for COVID‐19 were excluded as were prognosis studies, systematic reviews and meta‐analyses, and diagnostic test accuracy studies.

The protocol of this review is available on PROSPERO (CRD42020214700).

Types of participants

We included trials evaluating children or adults with suspected, probable or confirmed ambulatory or hospitalised COVID‐19 (see classification in Appendix 2; (WHO 2020b)).

Types of interventions

We included the following IL‐6 blocking agents with no restriction on dose, frequency, or mode of administration.

Tocilizumab (humanised monoclonal antibody against the IL‐6 receptor)
Sarilumab (human monoclonal antibody against the IL‐6 receptor)
Clazakizumab (humanised rabbit monoclonal antibody against IL‐6)
Olokizumab (humanised monoclonal antibody against IL‐6)
Siltuximab (chimeric monoclonal antibody against IL‐6)
Levilimab (human monoclonal antibody against the IL‐6 receptor)

Comparator(s)

We considered the following types of comparators in this review.

Standard care alone or with placebo.
Standard of care as defined by trialists.

Types of outcome measures

Our outcome selection was based on the CORE outcome sets developed by the WHO (WHO Working Group 2020), and advice from content experts.

We predefined the following critical and important outcome measures.

Critical outcomes

The following outcomes with related time points reported as days (D) of follow‐up were considered:

clinical improvement (D28 / ≥ D60) defined as a hospital discharge or improvement on the scale used by trialists to evaluate clinical progression and recovery. We recorded the scale and the threshold used by authors to define improvement as appropriate;
WHO Clinical Progression Score of level 7 or above (i.e. mechanical ventilation +/‐ additional organ support (extra corporeal membrane oxygenation (ECMO), vasopressors or dialysis) OR death (D28 / ≥ D60);
all‐cause mortality (D28 / ≥ D60);

We reported all assessments performed at D60 and later under ≥ D60

Safety outcomes

Incidence of any adverse events (AEs)
Incidence of serious AEs (SAEs)

For each time point, we considered time of randomization as D0. However, if not reported, we considered D0 as reported by the authors.

When outcomes are assessed at time points other than those selected by the review, we chose the closest (e.g. D15 for D28).

Important outcomes

Time to clinical improvement
Time to WHO Clinical Progression Score of level 7 or above
Time to death

We present all critical and important outcomes in Table 1; Table 2.

Summary of findings 1. Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19.

Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19
Patient or population: participants with mild/moderate/severe/critical COVID‐19 Settings: Brazil, China, France, Italy, UK, USA Intervention: tociliuzumab Comparison: standard care/placebo
Outcomes	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with standard care/placebo	Risk with tocilizumab
Clinical improvement D28	515 per 1000	545 per 1000 (515 to 581)	RR 1.06 (1.00 to 1.13)	5585 (7 RCTs)	⊕⊕⊕⊝ moderate¹	Data at D ≥ 60 was not available Clinical improvement was defined variably as an improvement from baseline in > 2 categories on a 7‐category ordinal scale (2 studies); a decrease of at least 2 points on an ordinal clinical improvement scale (1 study); or hospital discharge or ready to discharge (7 studies)
WHO progression score (level 7 or above) D28	262 per 1000	260 per 1000 (147 to 457)	RR 0.99 (0.56 to 1.74)	712 (3 RCTs)	⊕⊕⊝⊝ low^2,3	Data at D ≥ 60 was not available
All‐cause mortality D28	291 per 1000	259 per 1000 (239 to 283)	RR 0.89 (0.82 to 0.97)	6363 (8 RCTs	⊕⊕⊕⊕ high⁴
All‐cause mortality D60	133 per 1000	114 per 1000 (70 to 186)	RR 0.86 (0.53 to 1.40)	519 (2 RCTs)	⊕⊕⊝⊝ low^5,6
Adverse events	457 per 1000	562 per 1000 (397 to 786)	RR 1.23 (0.87 to 1.72)	1534 (7 RCTs)	⊕⊝⊝⊝ very low^7,8,9
Serious adverse events	149 per 1000	132 per 1000 (111 to 157)	RR 0.89 (0.75 to 1.06)	2312 (8 RCTs)	⊕⊕⊕⊝ moderate⁷
Time to clinical improvement 28 to 90 days follow‐up	High		HR 1.23 (1.08 to 1.39)	2118 (6 RCTs)	⊕⊕⊕⊝ moderate^{1, 13}
	889 per 1000	933 per 1000 (917 to 957
Time to WHO progression score (level 7 and above) 28 to 90 days follow‐up	Low		HR 0.62 (0.42 to 0.91)	762 (3 RCTs)	⊕⊕⊕⊝ moderate^10,^{11, 13}
	123 per 1000	78 per 1000 (54 to 113)
Time to death follow‐up 28 to 90 days	Low		HR 0.65 (0.51 to 0.83)	1152 (3 RCTs)	⊕⊕⊝⊝ low^{2, 12, 13}
	37 per 1000	24 per 1000 (19 to 31)
*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; RR: Risk Ratio; HR: Hazard Ratio: WHO: World Health Organization
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.

Sarilumab compared to standard care for severe/critical COVID‐19
Patient or population: participants with severe/critical COVID‐19 Settings: Brazil, China, France, Italy, UK, USA Intervention: sarilumab Comparison: standard care
Outcomes	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
Clinical improvement D28	‐	‐	‐	‐	‐	Outcome of interest not reported
WHO progression score (level 7 or above) D28	‐	‐	‐	‐	‐	Outcome of interest not reported
All‐cause mortality D28	299 per 1000	230 per 1000 (129 to 407)	RR 0.77 (0.43 to 1.36)	880 (2 RCTs)	⊕⊕⊝⊝ low^1,2
All‐cause mortality D60 or above	105 per 1000	105 per 1000 (52 to 209)	RR 1.0 (0.5 to 2.0)	420 (1 RCT)	⊕⊕⊝⊝ low^{2, 3}
Adverse events	640 per 1000	672 per 1000 (563 to 799)	RR 1.05 (0.88 to 1.25)	420 (1 RCT)	⊕⊕⊕⊝ moderate^4,5
Serious adverse events	62 per 1000	73 per 1000 (48 to 110)	RR 1.17 (0.77 to 1.77)	880 (2 RCTs)	⊕⊕⊝⊝ low^2,4
Time to clinical improvement follow‐up 90 days	Moderate		HR 1.28 (0.88 to 1.87)	880 (2 RCTs)	⊕⊕⊝⊝ low^6,7,9	Clinical improvement defined as hospital discharge
Time to clinical improvement follow‐up 90 days	460 per 1000	546 per 1000 (419 to 684)	HR 1.28 (0.88 to 1.87)	880 (2 RCTs)	⊕⊕⊝⊝ low^6,7,9	Clinical improvement defined as hospital discharge
Time to WHO progression score (level 7 and above)	‐	‐	‐	‐	‐	Outcome of interest not reported
Time to death follow‐up 90 days	Moderate		HR 0.55 (0.33 to 0.91)	460 (1 RCT)	⊕⊕⊝⊝ low^{1, 5,8,9}
Time to death follow‐up 90 days	330 per 1.000	198 per 1000 (124 to 305)	HR 0.55 (0.33 to 0.91)	460 (1 RCT)	⊕⊕⊝⊝ low^{1, 5,8,9}
*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; RR: Risk Ratio; HR: Hazard Ratio, WHO:World Health Organization
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.

Study	1.Randomisation	2.Deviations from intervention	3.Missing outcome data	4.Measurement of the outcome	5.Selection of the reported results	Overall risk of bias
Hermine CORIMUNO‐19 2020	Low	Some concerns¹	Low	Some concerns²	Low	Some concerns
Rosas COVACTA 2021	Low	Low	Low	Low	Low	Low
Salama EMPACTA 2020	Low	Low	Low	Low	Low	Low
Salvarani 2020	Low	Some concerns³	Low	Some concerns⁴	Some concerns⁵	Some concerns
Stone 2020	Low	Low	Low	Low	Low	Low
Horby RECOVERY 2021	Low	Low	Low	Some concerns⁶	Low	Some concerns
Veiga TOCIBRAS 2021	Low	Some concerns⁷	Low	Some concerns⁸	Low	Some concerns

Study	1.Randomisation	2.Deviations from intervention	3.Missing outcome data	4.Measurement of the outcome	5.Selection of the reported results	Overall risk of bias
Hermine CORIMUNO‐19 2020	Low	Some concerns ¹	Low	Some concerns ²	Low	Some concerns
Rosas COVACTA 2021	Low	Low	Low	Low	Low	Low
Salama EMPACTA 2020	Low	Low	Low	Low	Low	Low
Salvarani 2020	Low	Some concerns³	Low	Some concerns⁴	Low	Some concerns
Stone 2020	Low	Low	Low	Low	Low	Low
Wang 2020	Some concerns ⁵	Some concerns ⁶	Low	Some concerns ⁷	Some concerns⁸	High
Gordon REMAP‐CAP 2021	Low	Some concerns ⁹	Low	Some concerns¹⁰	Low	Some concerns
Veiga TOCIBRAS 2021	Low	Some concerns¹¹	Low	Some concerns ¹²	Low	Some concerns

Study	1.Randomisation	2.Deviations from intervention	3.Missing outcome data	4.Measurement of the outcome	5.Selection of the reported results	Overall risk of bias
Hermine CORIMUNO‐19 2020	Low	Some concerns ¹	Low	Low	Low	Some concerns
Salama EMPACTA 2020	Low	Some concerns ²	Low	Low	Low	Some concerns
Stone 2020	Low	Low	Low	Low	Low	Low

NCT04315298
Trial name or title	Evaluation of the efficacy and safety of sarilumab in hospitalized patients With COVID‐19
Methods	RCT, placebo‐controlled, double‐blind study Date of study: March 2020 Location: USA Phase 2/3
Participants	Randomised: 1912 participants Inclusion criteria Laboratory‐confirmed SARS‐CoV‐2 infection as determined by polymerase chain reaction (PCR), result from any specimen (or other commercial or public health assay) within 2 weeks prior to randomisation and no alternative explanation for current clinical condition Hospitalised with illness of any duration with evidence of pneumonia, requires supplemental oxygen and/or assisted ventilation and meets one of the following: Phase 2 and phase 3 cohort 1: meets 1 of the following criteria at baseline: severe disease or critical disease or multi‐system organ dysfunction or immunocompromised Phase 3 cohort 2: patients must be receiving mechanical ventilation to treat respiratory failure due to COVID‐19: ability to provide informed consent signed by study patient or legally acceptable representative willingness and ability to comply with study‐related procedures/assessments Exclusion criteria In the opinion of the investigator, not expected to survive for more than 48 hours from screening Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 2000 mm³; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN); platelets <50,000 per mm^3. Treatment with anti‐IL 6, anti‐IL‐6R antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period Current treatment with the simultaneous combination of leflunomide and methotrexate Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections Participation in a double‐blind clinical research study evaluating an investigational product (IP) or therapy within 3 months and less than 5 half‐lives of IP prior to the screening visit. (The use of remdesivir, hydroxychloroquine, or other treatments being used for COVID‐19 treatments in the context of an open‐label study, emergency use authorisation (EUA), compassionate use protocol or open‐label use is permitted) Any physical examination findings, and/or history of any illness, concomitant medications or recent live vaccines that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study Known systemic hypersensitivity to sarilumab or the excipients of the drug product Phase 3 cohort 2 only Known or suspected history of immunosuppression or immunodeficiency disorder Patients who require renal replacement therapy for acute kidney injury at randomisation or who required renal replacement therapy within 72 hours prior to randomisation Patients who have circulatory shock requiring vasopressors at randomisation or within 24 hours prior to randomisation Use of extracorporeal life support (e.g. ECMO) or, in the opinion of the investigator, there is a high likelihood that extracorporeal life support will be initiated within 48 hours after randomisation
Interventions	Intervention: sarilumab (low, mild or high dose, dosage not stated) Control interventions: placebo
Outcomes	Primary outcome Proportion of patients with at least 1‐point improvement in clinical status (day 4) Secondary outcomes Time to improvement (up to day 29) Number of patients requiring initiation of mechanical ventilation (up to day 29) Number of patients requiring non‐invasive ventilation Number of deaths (up to day 29)
Starting date	Study start date: 18 March 2020 Study completion date: 2 September 2020
Contact information	Regeneron Pharmaceuticals
Notes	Completed

EUCTR‐2020‐001162‐12‐FR
Trial name or title	An adaptive phase 3, randomized, double‐blind, placebo‐controlled, study assessing efficacy and safety of sarilumab for hospitalized patients with COVID‐19
Methods	RCT, placebo‐controlled, double‐blind study Date of study: March 2020 Location: Canada, France, Germany, Israel, Italy, Japan, Russian Federation, Spain Phase 2/3
Participants	Randomised: 460 participants Inclusion criteria Severe disease Multisystem organ dysfunction or critical disease Laboratory‐confirmed SARS‐CoV‐2 infection Exclusion criteria Unlikely to survive for > 48 hours from screening Presence of neutropenia less than 2000/mmˆ3, AST or ALT greater than 5 X ULN, platelets less than 50,000/mmˆ3 Prior immunosuppressive therapies Use of chronic oral corticosteroids for non‐COVID‐19 related condition Past or current history of autoimmune or inflammatory disease(s) Known or suspected history of tuberculosis Suspected or known active systemic bacterial or fungal infections
Interventions	Intervention: sarilumab (IV, 200 mg) Control interventions: placebo (IV)
Outcomes	Primary outcome Secondary outcomes Time to clinical improvement Change in 7‐point ordinal scale (baseline to days 3, 5, 8, 11,15, and 29) Clinical status using the 7‐point ordinal scale Mortality (baseline to day 60) Adverse events (baseline to day 60)
Starting date	Study start date: 26 March 2020 Study completion date: 29 September 2020
Contact information	Sanofi‐Aventis France, Public‐Registry‐MA‐France@sanofi.com
Notes	Completed

NCT04380519
Trial name or title	Study of the efficacy and safety of a single administration of olokizumab and RPH‐104 with standard therapy in patients with severe severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection (COVID‐19)
Methods	RCT, placebo‐controlled, double‐blind study Date of study: May 2020 Location: Russian Federation Phase 2/3
Participants	Randomised: 372 participants Inclusion criteria Signed and dated patient's Informed consent for participation in this study, or record of a medical board decision justifying patient's participation in case of patient is unable to state his/her will. Having either of the following COVID‐associated respiratory syndromes: pneumonia with oxygenation parameters SpO₂ ≤ 93% (on room air) or respiratory rate greater than 30/min; ARDS (PaO₂/FiO₂ ≤ 300 mmHg or SpO₂/FiO₂ ≤ 315 if PaO₂ is not available). COVID‐19 diagnosis based on: laboratory‐confirmed SARS‐CoV‐2 infection as determined by PCR method; or bilateral changes in the lungs typical for COVID‐19, based on chest computed tomography results. Exclusion criteria Hypersensitivity to the study drugs (RPH‐104 and/or OKZ), and/or its components Presence of any of the following laboratory abnormalities: absolute neutrophil counts < 0.5 x 10^9 L white blood cell count < 2 x 10^9 L platelet count < 50 x 10^9 L ALT and/or AST ≥ 3.0 x ULN Severe renal failure: creatinine clearance < 30 mL/min Septic shock (to maintain mean arterial pressure ≥ 65 mm Hg and lactate ≥ 2 mmol/L in the absence of hypovolaemia, vasopressors are necessary) Progression of disease up to the death in the following 24 hours regardless of treatment, as per Investigator's opinion History of perforation of gastrointestinal tract, history of diverticulitis Plasma infusion from convalescent COVID‐19 donors within 4 weeks prior to patient inclusion and/or planned infusion during the study Recent (less then 5 half‐lives) administration of tocilizumab or sarilumab; Recent (less then 5 half‐lives) or planned during the current study period use of the following drugs: immunosuppressive biologics over than OKZ or RPH‐104, including but not limited, Interleukin‐1 (IL‐1) inhibitors (rilonacept, anakinra, canakinumab), IL‐6 inhibitors (except tocilizumab and sarilumab), IL‐17A inhibitors (secukinumab), tumour necrosis factor α (TNFα) inhibitors (adalimumab, infliximab, etanercept), anti‐B‐cell therapy and others other immunosuppressors except methotrexate dosed up to 25 mg per week, including but not limited: high‐dose glucocorticoids (> 1 mg/kg of prednisolone equivalent), oral and parental; JAK inhibitors, cyclophosphamide, and others Concurrent participation in another clinical trial Pregnancy or lactation History of active tuberculosis, active tuberculosis suspected by Investigator
Interventions	Intervention RPH‐104 (SC, 80 mg, single injection) Olokizumab (SC, 64 mg, single injection) Control interventions Placebo
Outcomes	Primary outcome Secondary outcomes Changes of patients' clinical status on a 6 points ordinal scale (day 2 until day 15, day 29) Mortality (day 1 until day 29) Time to clinical improvement of clinical status (day 1 until day 29)
Starting date	Study start date: 23 April 2020 Study completion date: 24 July 2020
Contact information	R‐Pharm, Mikhail Samsonov
Notes	Completed

NCT04397562
Trial name or title	A clinical trial of the efficacy and safety of levilimab (BCD‐089) in patients with severe COVID‐19
Methods	RCT, placebo‐controlled, double‐blind study Date of study: May 2020 Location: Russian Federation Phase 3
Participants	Randomised: 206 participants Inclusion criteria Signed informed consent (participant; legally authorised representative) or signed conclusion of panel of independent medical doctors Males and non‐pregnant females aged 18 years or older at the IC date Positive test for SARS‐CoV2 nucleic acid (RNA) at the IC date Admitted as inpatient to a hospital with radiologically‐confirmed pneumonia Severe form of COVID‐19. Participants meeting any of the following criteria: total respiratory rate > 30 breaths per minute; SpO₂ ≤ 93%; PaO₂ /FiO₂ ≤ 300 mmHg; chest imaging (X‐ray, CT, US) showed lesion progression within 24 to 48 hours > 50%; decrease of consciousness level, psychomotor agitation/irritability haemodynamically unstable (systolic blood pressure < 90 mmHg or diastolic blood pressure < 60 mmHg or urine output < 20 mL/hour) arterial lactate > 2 mmol/L; qSOFA (quick sequential organ failure assessment score) > 2. Participants meeting 3 following criteria: low blood pressure (SBP ≤ 100 mmHg); high respiratory rate (≥ 22 breaths/min); altered mentation (Glasgow Coma Scale ≤ 14). Exclusion criteria Critical COVID‐19. Participants meeting any of the following: respiratory failure and requiring invasive mechanical ventilation (tracheal intubation); septic shock; multiple organ failure; life expectancy < 24 hours in the opinion of the investigator; unlikely to remain at the investigational site beyond 48 hours; use of other monoclonal antibodies for COVID‐19 treatment; current treatment with immunosuppressive agents (including corticosteroids); participating in other drug clinical trials at the IC date or within 60 days after randomisation (participation in COVID‐19 anti‐viral trials may be permitted if approved by Sponsor). Laboratory values: ALT / AST > 10 ULN at screening platelets < 50 х 109/L at screening absolute neutrophil count < 1 х 109/L at screening suspected active bacterial, fungal, viral, or other infection (besides COVID‐19) confirmed active TB history of allergic reaction to monoclonal antibodies Pregnancy or breastfeeding Any illness or laboratory findings that, in the opinion of the study investigator, might pose an additional risk to the patient by their participation in the study
Interventions	Intervention: levilimab (SC, 324 mg) Control interventions: standard of care
Outcomes	Primary outcome Secondary outcomes Patients reporting each category of 7‐Category Ordinal Scale of Clinical Status (day 30) Proportion of patients transferred to the ICU (day 60)
Starting date	Study start date: 29 April 2020 Study completion date: 3 August 2020
Contact information	Biocad
Notes	Completed

NCT04479358
Trial name or title	Low‐dose tocilizumab versus standard of care in hospitalized patients with COVID‐19
Methods	RCT, active‐controlled, open‐label study Date of study: July 2020 Location: USA Phase 2
Participants	Randomised: 332 participants Inclusion criteria Adults ≥ 18 years of age Approval from the patient's primary inpatient service Hospitalised Fever, documented in electronic medical record and defined as: T ≥ 38 degrees C by any conventional clinical method (forehead, tympanic, oral, axillary, rectal) Positive test for active SARS‐CoV‐2 infection Radiographic evidence of infiltrates on chest radiograph (CXR) or computed tomography (CT) Ability to provide written informed consent on the part of the participant or, in the absence of decisional capacity of the participant, an appropriate surrogate (e.g. a legally authorised representative). Exclusion criteria Concurrent use of invasive mechanical ventilation Concurrent use of vasopressor or inotropic medications Previous receipt of tocilizumab or another anti‐IL6R or IL‐6 inhibitor in the year prior Known history of hypersensitivity to tocilizumab Diagnosis of end‐stage liver disease or listed for liver transplant. Elevation of AST or ALT in excess of 10 times the upper limit of normal Neutropenia (absolute neutrophil count < 500/uL) Thrombocytopenia (platelets < 50,000/uL). On active therapy with a Bruton's tyrosine kinase‐targeted agent, which include the following: acalabrutinib; ibrutinib; zanubrutinib. On active therapy with a JAK2‐targeted agent, which include the following: tofacitinib, baricitinib, upadacitinib, ruxolitinib Any of the following biologic immunosuppressive agent (and any biosimilar versions thereof) administered in the past 6 months or less: abatacept, adalimumab, alemtuzumab, atezolizumab, belimumab, blinatumomab, brentuximab, certolizumab, daratumumab, durvalumab, eculizumab, elotuzumab, etanercept, gemtuzumab, golimumab, ibritumomab, infliximab, inotuzumab, ipilimumab, ixekizumab, moxetumomab, nivolumab, obinutuzumab, ocrelizumab, ofatumumab, pembrolizumab, polatuzumab, rituximab, rituximab, sarilumab, secukinumab, tocilizumab, tositumumab, tremelimumab, urelumab, ustekinumab History of bone marrow transplantation (including chimeric antigen receptor T‐cell) or solid organ transplant Known history of Hepatitis B or Hepatitis C (patients who have completed curative‐intent anti‐HCV treatments are not excluded from trial) Positive result on hepatitis B or C screening Known history of mycobacterium tuberculosis infection at risk for reactivation Known history of gastrointestinal perforation Active diverticulitis Multi‐organ failure as determined by primary treating physicians Any other documented serious, active infection besides COVID‐19 ‐ including but not limited to: lobar pneumonia consistent with bacterial infection, bacteraemia, culture‐negative endocarditis, or current mycobacterial infection ‐ at the discretion of primary treating physicians Pregnant patients or nursing mothers Patients who are unable to discontinue scheduled antipyretic medications, either as monotherapy (e.g. acetaminophen or ibuprofen (aspirin is acceptable)) or as part of combination therapy (e.g. hydrocodone/acetaminophen, aspirin/acetaminophen/caffeine [Excedrin®]) CRP < 40 mg/L
Interventions	Intervention: ·tocilizumab (IV, 8 mg/kg, up to a maximum dose 800 mg, up to 1 additional dose may be given if clinical symptoms worsen or show no improvement) Control interventions: placebo
Outcomes	Primary outcome Secondary outcomes Mortality (28 days) Time to non‐elective invasive mechanical ventilation (up to day 28) Adverse events (28 days)
Starting date	Study start date: 10 September 2020
Contact information	University of Chicago Medicine, Pankti D Reid, pankti.reid@uchospitals.edu
Notes	Completed

IRCT20200525047570N1
Trial name or title	A comparative study of the effects of tocilizumab, interferon‐gamma and vitamin C on the recovery of critically ill Covid‐19 patients and cytokine storm
Methods	RCT, active‐controlled, open‐label study Date of study: July 2020 Location: Iran Phase 2
Participants	Randomised: 60 participants Inclusion criteria Lack of a specific clinical disease Non‐use of a particular drug No pregnancy Exclusion criteria A specific clinical disease Taking a particular drug Pregnancy
Interventions	Intervention: tocilizumab‎ (SC, 62 mg/0.9 mL, 1 time a week for 2 weeks) Control interventions: standard of care
Outcomes	Primary outcome Secondary outcomes
Starting date	Study start date:‐
Contact information	Tabriz University of Medical Sciences, Negin Hadisi, +98 44 4432 6311, nhadisi72@yahoo.com
Notes	Completed

NCT04690920
Trial name or title	Theranostic Implication of complementary medicines against interleukin receptors and Gp‐130 proteins
Methods	RCT, active‐controlled, open‐label study Date of study: December 2020 Location: Pakistan Phase ‐
Participants	Randomised: 200 participants Inclusion criteria Admitted diagnosed cases of COVID‐19 infection on real time polymerase chain reaction (RT‐PCR) Both males and females were included All participants were on oxygen therapy Exclusion criteria Asthmatics Pulmonary fibrosis Chronic obstructive pulmonary disease (COPD) Allergic to remdesivir Allergic to Actemra Refused to take consent
Interventions	Intervention Tocilizumab Remdesivir Control interventions Standard of care No intervention
Outcomes	Primary outcome Secondary outcomes Oxygen demand (7 to 15 days) Viral load (7 to 15 days)
Starting date	Study start date: 23 July 2020
Contact information	The University of Lahore, Arif Malik
Notes	Completed

IRCT20200510047383N1
Trial name or title	Evaluation of the effect of tocilizumab on outcomes of the severe COVID‐19 patients
Methods	RCT, active‐controlled, double‐blind study Date of study: May 2020 Location: Iran Phase 3
Participants	Randomised: 100 participants Inclusion criteria COVID‐19 disease confirmed by chest CT and PCR No pregnancy No breastfeeding Negative PPD No bacterial pneumonia (negative sputum and urine culture) Not use of atorvastatin, alprazolam , amlodipine, MTX, hydroxychloroquine , Informed consent Exclusion criteria Disapproval of COVID‐19 disease by chest computed tomography and PCR positive PPD Bacterial pneumonia (negative sputum and urine culture) pregnancy Breastfeeding Use of atorvastatin, alprazolam, amlodipine, MTX, hydroxychloroquine by the patient Lack of Informed consent
Interventions	Intervention: tocilizumab (8 mg per kilogram of body weight tocilizumab up to a maximum dose of 800 mg) Control interventions: standard of care
Outcomes	Primary outcome Mortality Secondary outcomes
Starting date	Study start date: 21 May 2020
Contact information	Arak University of Medical Sciences, Mohammadreza Bozorgmanesh, +98 86 3223 1350, mhmmdrz_bzrgmnsh@yahoo.com
Notes	Completed

IRCT20081027001411N4
Trial name or title	Effect of TOCILIZUMAB (ACTEMRA) on treatment of COVID‐19
Methods	RCT, active/placebo‐controlled, double‐blind study Date of study: June 2020 Location: Iran Phase 2
Participants	Randomised: 40 participants Inclusion criteria COVID‐19 patient confirmed by positive PCR ‎test for SARS‐CoV‐19 or abnormal CT scan finding (bilateral, sub pleural, peripheral ground glass ‎opacities) Blood oxygen saturation < 90%, respiratory rate > 24 breaths/minute, high CRP rate, lymphopenia < 1100 and not responding to standard COVID‐19 treatment Exclusion criteria History of diabetes, high blood pressure, malignancies, positive pro‐calcitonin and active infection (Including latent or active TB infection), Taking immunosuppressive drugs and corticosteroids and abnormal liver enzymes
Interventions	Intervention: tocilizumab (8 mg/kg, if the patient’s condition is not stable 2 doses by 12 hours will be administrated, maximum dose: 800 mg) Control interventions Placebo Standard of care
Outcomes	Primary outcome Mortality Secondary outcomes
Starting date	Study start date:‐
Contact information	Tehran University of Medical Sciences, Ahmadreza Jamshidi, +98 21 8822 0065, jamshida@sina.tums.ac.ir
Notes	Completed

NCT04330638
Trial name or title	Treatment of COVID‐19 patients with anti‐interleukin drugs
Methods	RCT, active‐controlled, open‐label study Date of study: April 2020 Location: Belgium Phase 3
Participants	Randomised: 342 participants Inclusion criteria Recent ( ≥ 6 days of flu‐like symptoms or malaise yet ≤ 16 days of flu‐like symptoms or malaise prior to randomisation) infection with COVID‐19. Confident COVID‐19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID‐19 within this period. In some patients, it may be impossible to get a confident laboratory confirmation of COVID‐19 diagnosis after 24 hours of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (< 24 hours) chest‐CT scan (confirmed by a radiologist and pulmonary physician as probable COVID‐19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable COVID‐19 infected. In all cases, this needs confirmation by later seroconversion. Presence of hypoxia defined as PaO₂/FiO₂ below 350 while breathing room air in upright position or PaO₂/FiO₂ below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation signs of cytokine release syndrome defined as ANY of the following: serum ferritin concentration > 1000 mcg/L and rising since last 24 hours; single ferritin above 2000 mcg/L in patients requiring immediate high‐flow oxygen device or mechanical ventilation; lymphopenia defined as < 800 lymphocytes/microlitre) and 2 of the following extra criteria: ferritin > 700 mcg/L and rising since last 24 hours; increased LDH (above 300 IU/L) and rising last 24 hours; D‐dimers > 1000 ng/mL and rising since last 24 hours; CRP above 70 mg/L and rising since last 24 hours and absence of bacterial infection<, if 3 of the above are present at admission, no need to document 24 hour rise Chest X‐ray or CT scan showing bilateral infiltrates within last 2 days Admitted to specialised COVID‐19 ward or an ICU ward taking care of COVID‐19 patients Age ≥ 18 years Male or female Willing and able to provide informed consent or legal representative willing to provide informed consent Exclusion criteria Patients with known history of serious allergic reactions, including anaphylaxis, to any of the study medications, or any component of the product. Mechanical ventilation > 24 hours at randomisation Patient on ECMO at time of screening Clinical frailty scale above 3. (This frailty score is the patient status before first symptoms of COVID‐19 episode.) Active bacterial or fungal infection Unlikely to survive beyond 48 hours Neutrophil count below 1500 cells/microlitre Platelets below 50.000/microlitre Patients enrolled in another investigational drug study ·Patients on high dose systemic steroids (> 20 mg methylprednisolone or equivalent) for COVID‐19 unrelated disorder Patients on immunosuppressant or immunomodulatory drugs Patients on current anti‐IL1 or anti‐IL6 treatment Signs of active tuberculosis Serum transaminase levels > 5 times upper limit of normal Bowel perforation or diverticulitis Pregnant or breastfeeding females (all female participants deemed of childbearing potential by the investigator must have negative pregnancy test at screening) Women of childbearing potential must have a negative serum pregnancy test pre‐dose on day 1. Women of childbearing potential must consistently and correctly use (during the entire treatment period and 3 months after last treatment) 1 highly effective method for contraception.
Interventions	Intervention Anakinra (SC, 100 mg for 28 days or until hospital discharge) Siltuximab (IV, 11 mg/kg, single dose) Tocilizumab (IV, 8 mg/kg with a maximum infusion of 800 mg/injection, single dose) Anakinra + siltuximab Anakinra + tocilizumab Control interventions Usual care
Outcomes	Primary outcome Time to clinical improvement (day 15) Secondary outcomes Adverse events (28 days) Serious adverse events (28 days) Mortality (28 days, 10 to 20 weeks) Time to 1st use of high‐flow oxygen devices, non‐invasive or invasive mechanical ventilation in non‐ventilated patients (28 days)
Starting date	Study start date: 3 April 2020
Contact information	University Hospital, Ghent, Anja Delporte, +32‐9‐3320228, anja.delporte@uzgent.be
Notes	Ongoing

NL8504
Trial name or title	Pre‐emptive tocilizumab in hypoxic COVID‐19 patients, a prospective randomized trial
Methods	RCT, active‐controlled, open‐label study Date of study: April 2020 Location: the Netherlands
Participants	Randomised: 354 participants Inclusion criteria Patients 18 years and older Patients with a diagnosis of COVID‐19 based on a compatible clinical presentation AND a positive SARS‐CoV‐2 PCR on a respiratory sample such as a nasopharyngeal swab, sputum, or BAL fluid Clinical features compatible with hyperinflammation: ‐ hypoxia, without other explanation for hypoxia than COVID‐19 OR ‐ ferritin > 2000 μg/L or doubling of serum ferritin in 20 to 48 hours. Hypoxia is defined according to ASTCT CRS Consensus grading: grade II. (Lee 2019). Inclusion of patients already requiring oxygen administration prior to COVID‐19 should be discussed with the study team. Written informed consent. Patient is capable of giving informed consent. Exclusion criteria Pregnancy Allergy to tocilizumab
Interventions	Intervention: ·tocilizumab (IV, 8 mg/kg, maximum dose 800 mg, which can be repeated at the same dose after 8 hours if the hypoxia has not improved) Control interventions: standard of care (unclear)
Outcomes	Primary outcome Mortality (30 days from randomisation) Secondary outcomes Percentage of patients who need ICU care Percentage of patients who develop respiratory failure and need mechanical ventilation.
Starting date	Study start date: 6 April 2020
Contact information	UMCG, Margriet Dijkstra, +31 50 3610468, m.j.dijkstra‐tiekstra@umcg.nl
Notes	Ongoing

NCT04348500
Trial name or title	Clazakizumab (anti‐IL‐ 6 monoclonal) compared to placebo for COVID19 disease
Methods	RCT, placebo‐controlled, double‐blind study Date of study: April 2020 Location: USA Phase 2
Participants	Randomised: 17 participants Inclusion criteria Age > 18 at the time of screening. Participant must be able to understand and provide informed consent. Hospitalised with COVID19+ disease (confirmed by PCR assay from any specimen (e.g. respiratory, blood, urine, stool, other bodily fluid). Not on mechanical ventilation and/or ECMO Evidence of pulmonary involvement with at least 2 of the following: oxygen saturation at rest in ambient air with SpO₂ ≤ 94%; tachypnoea with resting respiration rate > 25 breaths/minute; PaO₂/FiO₂ ≤ 300 mmHg; chest imaging (radiograph, CT scan, or lung ultrasound) with abnormalities consistent COVID‐19 pneumonia CRP > 35 mg/L Exclusion criteria Previous hypersensitivity or allergic reactions to clazakizumab Lactating or pregnant females. Participants with latent TB and who are not receiving treatment. Participants with active TB A significantly abnormal general serum screening lab result defined as a WBC < 3.0 X 103/ml, a Hgb < 8.0 g/dL, a platelet count < 50 X 103/ml, an SGOT or SGPT > 5X upper limit normal Participation in another clinical trial investigating COVID‐19 aimed agents
Interventions	Intervention: clazakizumab (IV, 25 mg in 50 cc NS x 1 dose) Control interventions: placebo
Outcomes	Primary outcome Adverse events (14 days) Secondary outcomes Mortality (28 days, 60 days)
Starting date	Study start date: 24 April 2020
Contact information	Cedars‐Sinai Medical Center, Stanley Jordan, MD
Notes	Ongoing

NCT04357808
Trial name or title	Efficacy of subcutaneous sarilumab in hospitalised patients with moderate‐severe COVID‐19 infection (SARCOVID)
Methods	RCT, active‐controlled, open‐label study Date of study: April 2020 Location: Spain Phase 2
Participants	Randomised: 30 participants Inclusion criteria Age > 18 years Laboratory‐confirmed SARS‐CoV‐2 infection as determined by PCR or other validated commercial or public health assay Documented interstitial pneumonia requiring admission and at least 2 of the following: fever ≥ 37.8ºC (tympanic); IL‐6 in serum ≥ 25 ng / mL (in the absence of a previous dose of prednisone or equivalent > 1 mg / kg) or PCR > 5 mg/dL; lymphocytes < 600 mm^3; ferritin > 300 mcg / L that doubles in 24 hours; ferritin > 600 mcg / L in the 1st determination and LDH > 250 U/L; D‐dimer ( > 1 mg / L). Informed verbal or administration consent under urgent conditions, documented in the electronic medical record Exclusion criteria Patients who require mechanical ventilation at the time of inclusion AST / ALT values > 5 folds upper normal limit. Neutrophil count below 500 cells / mm³ Platelet count below 50,000 cells / mm³ Documented sepsis or high suspicion by pathogens other than COVID‐19 Presence of comorbidities that according to clinical judgment could lead to an unfavourable result. Complicated diverticulitis or intestinal perforation Current skin infection (e.g. uncontrolled dermopiodermitis) Immunosuppressive anti‐rejection therapy Pregnancy or lactation Previous treatment with tocilizumab or sarilumab Patients participating in some other clinical trial for SARS‐CoV‐2 infection Patients with known hypersensitivity or contraindication to sarilumab or excipients
Interventions	Intervention: sarilumab (SC, 2 x 200 mg, single dose) Control interventions: standard of care
Outcomes	Primary outcome Mean change in clinical status assessment using the 7‐point ordinal scale (7 and 14 days from enrolment) Mortality (30 days from enrolment) Secondary outcomes Time to invasive mechanical ventilation (30 days from enrolment) Non‐serious adverse events (30 days from enrolment)
Starting date	Study start date: 13 April 2020
Contact information	Fundación de Investigación Biomédica ‐ Hospital Universitario de La Princesa, Rosario Garcia de Vicuña, MD PhD
Notes	Ongoing

NCT04359901
Trial name or title	Sarilumab for patients with moderate COVID‐19 disease
Methods	RCT, active‐controlled, open‐label study Date of study: April 2020 Location: USA Phase 2
Participants	Randomised: 120 participants Inclusion criteria Positive testing for novel coronavirus SARS‐CoV‐2019 Patients with moderate COVID‐19 disease as defined clinically: score of 1 to 3 (out of 3) on a modified Brescia COVID respiratory severity score (BCRSS), elements of which include wheezing or inability to speak complete sentences without effort, respiratory rate ≥ 22, O₂ saturation ≤ 90% on room air (or O₂ saturation ≤ 94% on ≥ 2L supplemental oxygen; either is equal to 1 point on the score) all within a 24‐hour period prior to enrolment, and/or any worsening of chest X‐ray (CXR) findings after COVID‐19 diagnosis i. Initial CXR at the time of COVID‐diagnosis, or anytime thereafter. Change from baseline CXR prior to COVID‐diagnosis would not qualify. the BCRSS risk calculation score is available at: mdcalc.com/brescia-covid-respiratory-severity-scale-bcrss-algorithm Exclusion criteria Critical disease, defined by need for mechanical ventilation and/or ICU admission Expected death within 48 hours Patients currently taking prednisone > 10 mg/day or on treatment with biologics for chronic inflammatory diseases use of chronic inhaled steroids is NOT an exclusion Receipt of any IL‐6 inhibitor within 3 months prior to enrolment in the trial Pregnancy, due to lack of foetal monitoring capabilities Patients enrolled in other interventional clinical trials. Patients enrolled in non‐interventional studies or receiving non‐FDA‐approved drugs for compassionate use are not excluded. Patients whose goal of care is comfort measures only Inability to provide informed consent, or absence of a legally authorised representative to provide informed consent. Severe psychiatric disease that prevents compliance with typical medical care Participation in another interventional clinical trial for COVID‐19
Interventions	Intervention: sarilumab (SC,400 mg) Control interventions: standard of care
Outcomes	Primary outcome · Intubation or death (within 14 days of enrolment) Secondary outcomes
Starting date	Study start date: 10 April 2020
Contact information	Westyn Branch‐Elliman, VA Boston Healthcare System, Sara Schiller, MPH, 857‐364‐2012, Sara.Schiller1@va.gov
Notes	Ongoing

NCT04363502
Trial name or title	Use of the interleukin‐6 inhibitor clazakizumab in patients with life‐threatening COVID‐19 infection
Methods	RCT, placebo‐controlled, double‐blind study Date of study: April 2020 Location: USA Phase 2
Participants	Randomised: 30 participants Inclusion criteria At least 18 years of age ·Confirmed COVID‐19 disease (by Cobas severe acute respiratory syndrome (SARS)‐CoV‐2 real time RT‐PCR using nasopharyngeal swab sample, or equivalent test available to be performed by the Johns Hopkins Medical Laboratories Services). Effort will be made to have the confirmatory test result < 72 hours prior to enrolment however given overall clinical demand this may not be feasible in all cases Respiratory failure manifesting as: acute respiratory distress syndrome (defined by a P/F ratio of < 200), OR SpO₂ < 90% on 4L (actual or expected given higher O₂ requirement) OR increasing O₂ requirements over 24 hours, plus 2 or more of the following predictors for severe disease: CRP > 35 mg/L; ferritin > 500 ng/mL; D‐dimer > 1 mcg/L; neutrophil‐lymphocyte ratio > 4; LDH > 200 U/L; increase in troponin in patient w/out known cardiac disease. Has a consent designee willing to provide informed consent on behalf of the patient (this assumes that a mechanically ventilated patients lacks capacity to consent on his/her own behalf. Should it be deemed that the patient has capacity to consent, consent may be obtained from the patient) Women of childbearing potential must be willing and able to use at least 1 highly effective contraceptive method for a period of 5 months following the study drug administration. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as: combined (oestrogen and progestogen containing) hormonal contraception combined (oestrogen and progestogen containing) hormonal contraception (oral, intravaginal, or transdermal); progestogen‐only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); IUD; IUS; vasectomised partner; bilateral tubal occlusion; true abstinence. when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence, such as calendar, ovulation, symptothermal, postovulation methods, and withdrawal are not acceptable methods of contraception. Men must be willing to use a double‐barrier contraception from enrolment until at 5 months after the last dose of study drug, if not abstinent Exclusion criteria Evidence of irreversible injury deemed non‐survivable even if the pulmonary failure recovers (for example severe anoxic brain injury) Known active inflammatory bowel disease Known active, untreated diverticulitis Known untreated bacteraemia Pregnancy. (The protocol will exclude pregnant participants given the lack of overall data on use of clazakizumab in pregnancy however the study team would consider a protocol revision should more than 3 potential pregnant study participants be excluded on this basis). Known hypersensitivity to the clazakizumab Use of other IL‐6 inhibitor investigational drugs at the time of enrolment
Interventions	Intervention: clazakizumab (IV, 25 mg, if the CRP does not decrease by 50% within 36 to 48 hours after the 1st dose, a 2nd dose of 25 mg clazakizumab will be given no later than day 3) Control interventions: placebo
Outcomes	Primary outcome Secondary outcomes
Starting date	Study start date: 7 May 2020
Contact information	Johns Hopkins University, Nada Alachkar, MD, 4106149225, nalachk1@jhmi.edu
Notes	Ongoing

NCT04377750
Trial name or title	The use of tocilizumab in the management of patients who have severe COVID‐19 with suspected pulmonary hyperinflammation
Methods	RCT, placebo‐controlled, open‐label study Date of study: May 2020 Location: Israel Phase 4
Participants	Randomised: 500 participants Inclusion criteria Any gender Age 18 and older Informed consent for participation in the study Virological diagnosis of Sars‐CoV2 infection (PCR) Acute respiratory failure Radiographic pneumonia, defined as any/ changing new lung infiltrate Patient breathing spontaneously, required more than 50% oxygen and MEWS score > 7 If intubated, intubated less than 24 hours with PaO₂/FiO₂ ratio ≤ 200 and PEEP ≥ 5 cm H₂O Exclusion criteria Known hypersensitivity to tocilizumab or its excipients Patient with a life expectancy of less than 6 months. Known active infections or other clinical condition that contra‐indicate tocilizumab and cannot be treated or solved according to the judgement of the clinician. Neutrophils < 500 / mmc Platelets < 40.000 / mmc
Interventions	Intervention: tocilizumab(IV, 8 mg/kg up to total dose of 800 mg) Control interventions: placebo
Outcomes	Primary outcome Mortality (30 days) Secondary outcomes
Starting date	Study start date: 8 April 2020
Contact information	Hadassah Medical Orginisation, Reuven Pizov, Prof., 972‐50‐6265542, pizovr@hadassah.org.il
Notes	Ongoing

PERMALINK

Interleukin‐6 blocking agents for treating COVID‐19: a living systematic review

Lina Ghosn

Anna Chaimani

Theodoros Evrenoglou

Mauricia Davidson

Carolina Graña

Christine Schmucker

Claudia Bollig

Nicholas Henschke

Yanina Sguassero

Camilla Hansen Nejstgaard

Sonia Menon

Thu Van Nguyen

Gabriel Ferrand

Philipp Kapp

Carolina Riveros

Camila Ávila

Declan Devane

Joerg J Meerpohl

Gabriel Rada

Asbjørn Hróbjartsson

Giacomo Grasselli

David Tovey

Philippe Ravaud

Isabelle Boutron

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Comparator(s)

Types of outcome measures

Critical outcomes

Safety outcomes

Important outcomes

Summary of findings 1. Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19.

Summary of findings 2. Sarilumab compared to standard care for severe/critical COVID‐19.

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Domain 2. Risk of bias due to deviations from intended interventions.

A. Cross‐over from the control group to the intervention group

B. Cointerventions

Domain 2. Analysis to estimate the effect of assignment

Domain 4. Risk of bias in measurement of the outcome

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Assessing risk of bias due to missing results in the synthesis

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

EUCTR2020‐002037‐15‐ES
Trial name or title	Multicenter, randomized, open‐label study to evaluate the efficacy and safety of SOC + sarilumab versus standard of care for the early treatment of COVID‐19‐pneumonia in hospitalized patients
Methods	RCT, active‐controlled, open‐label study Date of study: May 2020 Location: Spain Phase 2
Participants	Randomised: 200 participants Inclusion criteria Patients willing to provide written informed consent to participate in this study. Witnessed oral consent will be accepted in order to avoid paper handling. Written consent by patient or representatives will be obtained as soon as possible. The patient is at least 18 years of age. The patient is positive for novel coronavirus by real‐time RT‐PCR The patient is hospitalised for COVID‐19 without either mechanical ventilation (invasive or non‐invasive) or oxygen mask with reservoir bag and at least 1 of the following: radiographic evidence of pulmonary infiltrates by imaging (chest x‐ray, CT scan, etc.); OR clinical assessment (evidence of rales/crackles on exam); AND SpO₂ ≤ 94% on room air that requires supplemental oxygen. More than 7 days between the onset of symptoms (fever, dyspnoea, and/or cough) and treatment administration day. In the absence of fever, cough, or dyspnoea, other symptoms like asthenia, headache, or gastrointestinal symptoms may be considered The patients present progressive elevation of inflammatory parameters suggestive of a hyperinflammatory syndrome: presence of elevated IL‐6 (> 40 pg/mL); OR elevated D‐dimer (> 1.0 mcg/mL), or alternatively, progressive worsening in at least 2 of these inflammatory parameters in the prior 48 hours: CRP, LDH, serum ferritin, lymphopenia, or D‐dimer Exclusion criteria Requiring mechanical ventilation (invasive or non‐invasive) or oxygen mask with reservoir bag at screening Participation in any other clinical trial of an experimental treatment for COVID‐19 In the opinion of the clinical team, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Any incompatibility or allergy to the administration of sarilumab or corticosteroids
Interventions	Intervention: sarilumab (IV, 200 mg) Control interventions: standard of care
Outcomes	Primary outcome Progression to severe respiratory failure (from baseline up to day‐15) ICU admission (from baseline up to day‐15) Mortality (from baseline up to day‐15) Secondary outcomes Time to progression to severe respiratory failure
Starting date	Study start date: 25 May 2020
Contact information	Hospital Universitario Puerta de Hierro Majadahonda, 0034911917479, mariabelen.ruiz@salud.madrid.org
Notes	Ongoing

NCT04412291
Trial name or title	A study in patients with COVID‐19 and respiratory distress not requiring mechanical ventilation, to compare standard‐of‐care with anakinra and tocilizumab treatment the immunomodulation‐CoV assessment (ImmCoVA) study
Methods	RCT, active‐controlled, open‐label study Date of study: June 2020 Location: Sweden Phase 2
Participants	Randomised: 120 participants Inclusion criteria Laboratory‐confirmed SARS‐CoV‐2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay SARS‐CoV‐2 infection with duration at least 7 days (as determined by onset of symptoms) PaO₂ (or SpO₂)/FiO₂ < 26,8 kPa (200 mmHg) for at least 8 hours, corresponding to 5 litres/minute of Oxygen to maintain SpO₂ at 94% CRP > 70 mg/L with no non‐SARS‐CoV‐2 infections. Ferritin > 500 µg/L At least 2 points on a scale of 0 to 3 where 1 point is awarded for each value of; lymphocytes < 1x 10(9)/L; D‐dimer ≥ 0.5 mg/L and; LDH ≥ 8 microkatal/L Ability to provide informed consent signed by study patient Willingness and ability to comply with study‐related procedures/assessments Infertile females, willing to comply with effective contraceptive methods for up to 3 months after last dose of study drug. These may include birth control pills, surgical sterilisation of patient or partner or IUD. Non‐fertile woman is defined as more than 12 months of amenorrhoea without an alternative medical cause or, in case of ambiguities, an FSH level in the postmenopausal range Exclusion criteria Pregnancy or breast feeding Ongoing or completed mechanical ventilation In the opinion of the investigator, unlikely to survive for > 48 hours from screening In the opinion of the investigator, expected overall survival due to other comorbidities less than 3 months Chronic impairment of cardiac function NYHA II or higher Severe renal dysfunction eGFR < 30 ml/min Medical history including chronic liver disease with inflammation, fibrosis or cirrhosis including underlying diseases such as alcoholic liver disease, non‐alcoholic fatty liver disease, chronic viral hepatitis, alcoholic liver disease, autoimmune liver disease, haemochromatosis, Wilson's disease, alpha‐1 antitrypsin deficiency, cholangitis, or carcinoma Uncontrolled hypertension systolic BP >180 mm Hg, diastolic BP > 110 mm Hg History of hypersensitivity to the study drugs Presence of any of the following abnormal laboratory values at screening: ANC less than 2 x 109/L; AST or ALT greater than 5 x ULN; platelets < 100 x 109/L. Treatment with anakinra, anti‐IL 6, anti‐IL‐6R antagonists, JAKi in the past 30 days or plans to receive during the study period Current treatment with conventional synthetic DMARD)/immunosuppressive agents Use of chronic oral corticosteroids for a non‐COVID‐19‐related condition in a dose higher than prednisone 10 mg or equivalent per day History of, or current autoimmune or inflammatory systemic or localised disease(s) other than rheumatoid arthritis Acute systemic infection; verified by blood cultures systemic bacterial infection, systemic fungi‐infection or prosthesis‐related infection History of stem‐cell or solid organ transplantation Known active TB, history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections Diagnosis of, or suspicion of HIV infection, acute hepatitis A and/or chronic hepatitis B and/or C Previous history of gastrointestinal ulceration or diverticulitis. Patients who have received immunosuppressive antibody therapy within the past 3 months, including intravenous immunoglobulin or plans to receive during the study period Participation in any clinical research study evaluating an IPh or therapy within 3 months and less than 5 half‐lives of IP prior to the screening visit. The use of remdesivir in the context of a single‐arm remdesivir compassionate use protocol is permitted) Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study
Interventions	Intervention Anakinra (IV, anakinra 400 mg per day, divided in 4 doses of 100 mg, for 7 days) Tocilizumab (IV, 8 mg/kg for up to max 800 mg, single infusion, another dose of 8 mg/kg may be administered after earliest 2 days) Control interventions Standard of care
Outcomes	Primary outcome Secondary outcomes Mortality (up to day 29) Patients requiring initiation of mechanical ventilation (up to day 29) Mean change in the 8‐point ordinal scale (up to day 29) Time to clinical improvement (up to day 29)
Starting date	Study start date: 11 June 2020
Contact information	Karolinska University Hospital, Jonas Sundén‐Cullberg, +46‐8‐58580000, Jonas.sunden‐cullberg@sll.se
Notes	Ongoing

NCT04412772
Trial name or title	A RCT ‐ safety & efficacy of tocilizumab ‐ Tx of severe COVID‐19: ARCHITECTS
Methods	RCT, placebo‐controlled, double‐blind study Date of study: June 2020 Location: USA Phase 3
Participants	Randomised: 300 participants Inclusion criteria Hospitalised with COVID‐19 pneumonia, based on chest X‐ray or CT scan; AND Evidence of hyperinflammation: IL‐6 > 40pg/mL (if available);OR CRP > 2 mg/dL; OR Ferritin > 2000 ng/mL AND iv. 1 or more of the following: impending need for requiring invasive or non‐invasive mechanical ventilation; OR shock requiring vasopressor (without evidence of bacterial / fungal infection); OR need for ECMO; OR severe, refractor ARDS (PaO₂/FiO₂< 200 mmHg). Exclusion criteria Active tuberculosis infection based on history Suspected active bacterial, fungal, viral, or other infection (besides COVID‐19) In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Have received oral anti‐rejection or immunomodulatory drugs (including tocilizumab) with the past 6 months Participating in other drug clinical trials (participation in COVID‐19 trials allowed) Self‐reported pregnant or breastfeeding Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study ALT or AST > 10 x ULN detected within 24 hours at baseline ANC < 1000/mL at baseline Platelet count < 50,000/mL at baseline
Interventions	Intervention: tocilizumab (IV, 8 mg/kg for up to max 800 mg, single infusion, 1 additional dose may be given if clinical symptoms worsen) Control interventions: placebo
Outcomes	Primary outcome Clinical status on a 7‐point ordinal scale (up to day 28) Secondary outcomes Clinical improvement (up to day 28) Mechanical ventilation (up to day 28)
Starting date	Study start date: 12 June 2020
Contact information	Queen's Medical Centre, Todd Seto, tseto@queens.org
Notes	Ongoing

EUCTR2020‐001390‐76‐IT
Trial name or title	A phase 3, randomized, open‐labeled, multi‐center study comparing clinical efficacy and safety of intravenous sarilumab plus standard of care compared to standard of care, in the treatment of patients with severe COVID‐19 pneumonia.
Methods	RCT, active‐controlled, open‐label study Date of study: June 2020 Location: Italy Phase 3
Participants	Randomised: 171 participants Inclusion criteria Age = 18 years Signed informed consent provided by the patient, or by the patient’s legally authorised representative(s), as applicable. Orally provisions could be considered in emergency conditions if deemed necessary by the investigator (signature of the informed consent will occur if and as soon as clinical conditions improve). Virological diagnosis of SARS‐CoV‐2 infection (SARS‐CoV‐2 infection confirmed by PCR test or positive serology) Evidence of pulmonary infiltrates at CT scan or Chest Xray Oxygen saturation (SpO₂) at rest without oxygen supplementation < 93% or PaO₂/FiO₂ < 300 at rest in patients requiring oxygen supplementation (either Venturi mask or cPAP or NIV). Evidence of hyperinflammation defined as at least 2 of the following: blood lymphocytes < 1000/mm3; ferritin > 500 ng/mL; LDH > 300 U/L; D‐dimers > 1000 ng/mL; C‐reactive protein > 3 mg/dL. Indication to start antiviral therapy with either hydroxychloroquine or lopinavir/ritonavir as regular clinical practice (or patients who have already started/finished antiviral therapy for SARS‐CoV‐2) Men and women of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method (s) of contraception Exclusion criteria Known hypersensitivity to sarilumab or its excipients Known active infections or other clinical condition that contraindicate sarilumab and cannot be treated or solved according to the judgement of the clinician Patient being treated with immunomodulators or anti‐rejection drugs Pregnancy/lactation Neutrophils count < 500 cell/mm³ Platelets count < 50.000/mm³ ALT / AST> 5 times the upper limit of the normality Bowel diverticulitis or perforation Existence of any life‐threatening co‐morbidity or any other medical condition which, in the opinion of the investigator, makes the patient unsuitable for inclusion Severe hepatic dysfunction Creatinine clearance < 30 ml/min/1.73 m² Mechanical ventilation or ECMO Enrolment in another concurrent clinical interventional study Intake of an investigational drug within 3 months
Interventions	Intervention: ·sarilumab (IV, 400 mg) Control interventions: standard of care
Outcomes	Primary outcome Time to clinical improvement (every visit) Secondary outcomes Mortality (30 days from baseline) Time to death Time to mechanical ventilation or extracorporeal membrane oxygenation Serious adverse events
Starting date	Study start date: 27 April 2020
Contact information	Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, 0655170546, immunodeficienzevirali@inmi.it
Notes	Ongoing

CTRI/2020/05/025369
Trial name or title	A study on treatment of COVID‐19 patients with study drug along with standard of care
Methods	RCT, active‐controlled, open‐label study Date of study: May 2020 Location: India Phase 3
Participants	Randomised: 180 participants Inclusion criteria Male or female participants who are ≥ 18 years of age, on the day of signing informed consent. Patient or legally acceptable representative (LAR) willing to give informed consent before study procedure. Hospitalised with COVID‐19 infection confirmed per WHO criteria (including a positive PCR of any specimen; e.g. respiratory, blood, urine, stool, other bodily fluid). Moderate to severe COVID 19 infection (moderate disease – increased respiratory rate 15 to 30/minute and SpO₂ 90% to 94%; and severe disease ‐ respiratory rate ≥ 30/minute and/or SpO₂ < 90% on room air, or ARDS or septic shock Exclusion criteria Known severe allergic reactions to TCZ or other monoclonal antibodies Active tuberculosis (TB) infection Suspected or active bacterial, fungal, viral (except treated HCV or HBV infection), or other infection (besides COVID‐19). In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Have received oral anti‐rejection or immunomodulatory drugs (including TCZ) with in the past 6 months Participating in other drug clinical trials Pregnant or breastfeeding, or positive pregnancy test in a pre‐dose examination Treatment with an investigational drug within 5 half‐lives or 30 days (whichever is longer) of randomisation Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator’s judgment, precludes the patient safe participation in and completion of the study Definite diagnosis of rheumatic immune related diseases. Administration of steroids equivalent to methylprednisolone at a dose > 1 mg/kg/day) at screening/baseline Absolute neutrophil count < 500, platelet count < 50,000 per microlitre at screening/baseline AL) or (AST > 10 times upper limit of normal detected with‐in 24 hours at screening/baseline
Interventions	Intervention: tocilizumab (IV, 6 mg/kg for up to max 480 mg, single infusion) Control interventions: standard of care
Outcomes	Primary outcome Progressive COVID 19 disease from moderate to severe, or from severe disease to death (up to day 14) Secondary outcomes Time to clinical improvement (up to day 28) Clinical improvement (up to day 28) Incidence of mechanical ventilation (up to day 28) Incidence of intensive care (up to day 28) Mortality (days 7, 14, 21 and 28)
Starting date	Study start date: 30 May 2020
Contact information	Medanta Institute of Education and Research (MIER), 01244855100, pooja.sharma@medanta.org
Notes	Ongoing

NCT04494724
Trial name or title	Clazakizumab vs. placebo ‐ COVID‐19 infection
Methods	RCT, placebo‐controlled, double‐blind study Date of study: July 2020 Location: USA Phase 2
Participants	Randomised: 60 participants Inclusion criteria Age > 18 at the time of screening. Participant or LAR must be able to understand and provide informed consent. Hospitalised with coronavirus disease (COVID‐19) confirmed by PCR assay from any specimen (e.g. respiratory, blood, urine, stool, other bodily fluid) within the prior 72 hours. · CRP > 3.5 mg/dL · Evidence of pulmonary involvement with at least 2 of the following: oxygen saturation at rest in ambient air with peripheral capillary oxygen saturation (SpO₂) ≤ 94% tachypnoea with resting respiration rate > 25 breaths/minute Partial pressure of oxygen (PaO₂)/initial fraction of inspired oxygen (FiO₂) ≤ 300 mmHg Chest imaging (radiograph, CT, or ultrasound) with abnormalities consistent COVID‐19 pneumonia Exclusion criteria Previous hypersensitivity or allergic reactions to clazakizumab Lactating or pregnant females Patients with latent TB and who are not receiving treatment Patients with active TB Patients with known active inflammatory bowel disease, untreated diverticulitis, or gastrointestinal perforation Requiring mechanical ventilation or ECMO A significantly abnormal general serum screening lab result defined as a WBC count < 3.0 X 10^3/mL, a haemoglobin (Hgb) < 8.0 g/dL, a platelet count < 50 X 10^3/mL, an AST or ALT > 5 times ULN Participation in another clinical trial investigating COVID‐19‐aimed agents Presence of any medical or psychosocial condition, which the investigator believes, would hinder adherence to the study requirements.
Interventions	Intervention: clazakizumab (IV, 25 mg in 50 mL of 0.9% saline) Control interventions: placebo
Outcomes	Primary outcome Adverse events (during the first 24 hours) Secondary outcomes Mechanical ventilation and/or extracorporeal membrane oxygenation (14 days) Mortality (28 days, 60 days) Clinical improvement (28 days)
Starting date	Study start date: 13 July 2020
Contact information	Houston Methodist Hospital, Isioma Agboli, 713‐441‐6311, iagboli@houstonmethodist.org
Notes	Ongoing

NCT04577534
Trial name or title	Use of tocilizumab in the inflammatory phase of COVID‐19 / new coronavirus disease
Methods	RCT, active‐controlled, open‐label study Date of study: October 2020 Location: Finland Phase 3
Participants	Randomised: 90 participants Inclusion criteria Written informed consent obtained Hospitalised with COVID‐19 disease Age ≥ 18 years SARS CoV‐2 NhO posit Sp = 2 < /93% on ambient air or respiratory rate > 30 /min Any 2 of the 4: P‐IL‐6 > 2 x ULN / P‐ferritin > 2 x ULN / P‐FIDD > 1.5 mg/L / P‐ CRP > 40 mg/L without obvious presence of bacterial infection (normal values: P ‐IL‐6 < 5.9 ng/L; P‐ferritin, men 30 to 400 mickrog/l, women 13 to 150 mikrog/l; P‐FIDD (Fibrin degradation products, D‐dimer) <0.5 mg/L; P‐CRP < 10 mg/L). Exclusion criteria Known severe allergic reactions to monoclonal antibodies Active confirmed tuberculosis with ongoing treatment or obvious tuberculosis or obvious other bacterial, fungal or viral infection (besides COVID‐19) In the opinion of the clinical team, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments Long‐term oral anti‐rejection or immunomodulatory drugs (including corticosteroids equivalent to methylprednisolone 15 mg/day) Pregnant or lactating women. If needed, exclusion of pregnancy should be performed by laboratory test (U‐hCG‐O). Participating in other drug clinical trials Absolute neutrophil count < 1 x 10E9/L Platelet count < 50 x 10E9/L ALT > 10 x ULN
Interventions	Intervention: tocilizumab‎ (IV, single infusion according to weight of patient) Control interventions: standard of care
Outcomes	Primary outcome Clinical status (28 days) Secondary outcomes Time to clinical improvement (28 days) Time to decline of at least 2 categories (28 days) Mechanical and/or non‐invasive ventilation (28 days) ICU stay (28 days) Mortality (28 days)
Starting date	Study start date: 14 August 2020
Contact information	Turku University Hospital, Jarmo Oksi, +358 40 5414813, jarmo.oksi@utu.fi
Notes	Ongoing

EUCTR2020‐001290‐74‐ES
Trial name or title	Efficacy and safety of sarilumab in the early treatment of hospitalized patients with mild‐moderate pneumonia and COVID19 infection versus standard of care
Methods	RCT, active‐controlled, open‐label study Date of study: April 2020 Location: Spain Phase 3
Participants	Randomised: 216 participants Inclusion criteria More than18 years Diagnostic confirmation of COVID19 infection (PCR) and radiological diagnosis of pneumonia MEWS less than 3 and CURB 65 less than or equal to 1, IL6 greater than or equal to 20 pg / mL Exclusion criteria AST / ALT> 5 X LSN‐ neutrophils < 500 cell / mm³ Lymphocytes < 400 cell Platelets < 50,000 cell / mm³ Creatinine clearance (CCL) < 30 mL / min Documented sepsis and active infection by other pathogens other than COVID‐19‐ Presence of comorbidities that may lead to a poor prognosis according to clinical criteria Complicated diverticulitis or intestinal perforation Ongoing skin infection (e.g. uncontrolled pyodermitis with antibiotic treatment) Anti‐rejection immunosuppressive therapy Other biological treatments At the investigator's discretion, survival less than 48 hours from screening Treatment with anti‐IL 6, anti‐IL‐6R antagonists or with Janus kinase inhibitors (JAKi) in the last 30 days or plans to receive during the study period Current treatment with conventional synthetic disease modifying antirheumatic drugs (DMARDs) / immunosuppressive agents History of current systemic or localised autoimmune or inflammatory diseases, other than rheumatoid arthritis Known active TB, history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections Patients who have received immunosuppressive antibody therapy in the last 5 months, including intravenous immunoglobulin, or who plan to receive it during the study period. Participation in any clinical research study evaluating a research product or therapy (PI) within 3 months and less than 5 PI half lives before the screening visit. (The use of remdisivir in the context of a compassionate use remdisivir one‐arm is allowed.) Pregnancy Hypersensitivity to sarilumab and / or to some of its excipients. Any finding of the physical examination and/or history of any disease that, in the opinion of the study investigator, may confuse the study results or represent an additional risk for the patient due to their participation in the study.
Interventions	Intervention: sarilumab Control interventions: usual care
Outcomes	Primary outcome Time to clinical improvement (28 days) Secondary outcomes Mortality (28 days) Mechanical ventilation Time to death Serious adverse events
Starting date	Study start date: 11 April 2020
Contact information	Consorci PSMAR, Ana Aldea, +34933160490, aaldea@imim.es
Notes	Ongoing

EUCTR2020‐001767‐86‐IE
Trial name or title	An open‐label, multi‐centre, randomised trial comparing different doses of single‐dose tocilizumab in adults with severe, non‐critical, PCR‐confirmed COVID‐19 infection with evidence of progressive
Methods	RCT, active‐controlled, open‐label study Date of study: April 2020 Location: Ireland Phase 2
Participants	Randomised: 90 participants Inclusion criteria Confirmed SARS‐CoV2 infection (as defined by positive PCR) Evidence of hyper inflammatory state as evidenced by at least 3 of the following: documented temperature > 38°C in the past 48 hours; IL6 > 40 pg/mL, or in its absence D‐dimer > 1.5 μgFEU/mL; elevated CRP (> 100 mg/L) and/or a 3‐fold increase since presentation; elevated ferritin X 5 ULN; elevated LDH (above the ULN); elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging Moderate to severe respiratory failure as defined by PaO₂/FiO₂≤ 300 mmHg Aged 18 years or older Exclusion criteria Primary or secondary immunodeficiency Use of significant immunosuppressive therapy in the last 3 months (not including hydroxychloroquine or short course of corticosteroids (defined as < 400mg cumulative dose) Active malignancy requiring treatment Known active current or history of recurrent bacterial,mycobacterial, fungal or viral infections including history of untreated latent TB History of diverticulitis or chronic ulcerative GI disease that might predispose to GI perforation Severe allergic reaction to monoclonal antibodies Pregnancy or breast feeding AST/ALT with values greater than 10 times normal levels or history of significant liver disease that in the opinion of the investigator precludes use of an investigational agent Neutrophils < 0.5 x 109/L Platelets < 50 x 109/L Documented, uncontrolled sepsis caused by pathogen(s) other than COVID‐19 Presence of co‐morbidities (including cognitive impairment and/or frailty) that, in the opinion of the investigator, should preclude use of an investigational agent Current skin or soft tissue infection not controlled by antibiotics Body weight ≤ 30kg
Interventions	Intervention: tocilizumab (IV, single dose, different doses) Control interventions: standard of care
Outcomes	Primary outcome Progression to intubation and ventilation, non‐invasive ventilation or death (day 8) Secondary outcomes Serious adverse events (day 8) Mortality (day 14 and 28) Time to viral negative conversion
Starting date	Study start date: 25 June 2020
Contact information	University College Dublin, crc.monitoring@ucd.ie
Notes	Ongoing

NCT04659772
Trial name or title	A study to evaluate clazakizumab in patients with life‐threatening COVID‐19 infection.
Methods	RCT, placebo‐controlled, blind‐label study Date of study: December 2020 Location: USA Phase 2
Participants	Randomised: 30 participants Inclusion criteria ≥ 18 years of age. Confirmed COVID‐19 disease (by Cobas SARS‐CoV‐2 real time RT‐PCR using nasopharyngeal swab sample, or equivalent test available to be performed by Mayo Clinic clinical laboratory). Effort will be made to have the confirmatory test result < 72 hours prior to enrolment however given overall clinical demand this may not be feasible in all cases. Respiratory failure manifesting as: acute respiratory distress syndrome (defined by a P/F ratio of < 200), OR SpO₂ < 90% on 4L (actual or expected given higher O₂ requirement) OR increasing O₂ requirements over 24 hours, PLUS 2 or more of the following predictors for severe disease: CRP > 35 mg/L; ferritin > 500 ng/mL; D‐dimer > 1 mcg/L; neutrophil‐lymphocyte ratio > 4; LDH > 200 U/L; increase in troponin in patient w/out known cardiac disease. Has a consent designee willing to provide informed consent on behalf of the patient (this assumes that a mechanically‐ventilated patients lacks capacity to consent on his/her own behalf. Should it be deemed that the patient has capacity to consent, consent may be obtained from the patient) Women of childbearing potential must be willing and able to use at least 1 highly effective contraceptive method for a period of 5 months following the study drug administration. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as: combined (oestrogen and progestogen containing) hormonal contraception combined (oestrogen and progestogen containing) hormonal contraception (oral, intravaginal, or transdermal); progestogen‐only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); IUD; IUS; vasectomised partner; bilateral tubal occlusion; true abstinence. when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence, such as calendar, ovulation, symptothermal, postovulation methods, and withdrawal are not acceptable methods of contraception. Men must be willing to use a double‐barrier contraception from enrolment until at 5 months after the last dose of study drug, if not abstinent A participant, or an appropriate representative to the participant, will have the opportunity to consent with regard to the inclusion criteria above Exclusion criteria < 18 years of age Evidence of irreversible injury deemed non‐survivable even if the pulmonary failure recovers (for example severe anoxic brain injury) Known active inflammatory bowel disease Known active, untreated diverticulitis Known untreated bacteraemia Pregnancy (the protocol will exclude pregnant participants given the lack of overall data on use of clazakizumab in pregnancy however the study team would consider a protocol revision should more than 3 potential pregnant study participants be excluded on this basis) Known hypersensitivity to the clazakizumab Vulnerable participants will not be excluded. This study is designed to include any patients deemed at risk for imminent death, and the opportunity to enrol will not be withheld provided the participant meets the above inclusion and exclusion criteria
Interventions	Intervention: clazakizumab(IV, single dose, 25 mg, repeated dose for patients who fail expected decrease in inflammatory markers) Control interventions: placebo
Outcomes	Primary outcome Adverse events (60 days) Secondary outcomes
Starting date	Study start date: ‐
Contact information	Mayo Clinic in Arizona, Ayan Sen
Notes	Ongoing