Table 2.

Summary of COVID-19 therapy studies: Compounds with anti-viral properties

No	Drug/treatment	Author	Year	Study aim	Study type	Study design	Status	Main findings	Limitations
1.	Remdesivir	Grein et al [40].	2020	To describe outcomes in a cohort of patients hospitalised for severe COVID-19 who were treated with remdesivir on a compassionate-use basis	Open label program.	Compassionate use of remdesivir approved by manufacturer for hospitalised COVID-19 patients with RT-PCR confirmed infection and needing oxygen support. 61 patients received remdesivir treatment; 8 excluded due to missing data and findings of 53 patients reported.	Complete	Clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomised, placebo-controlled trials of remdesivir therapy.	Short follow-up (median 18 d, interquartile range [IQR] = 13-23), small cohort, no control group. Study funded by manufacturers of remdesivir.
		Wang Y. et al [41].	2020	To assess the effectiveness and safety of intravenous remdesivir in adults admitted to hospital with severe COVID-19.	Double-blinded, multicentre, placebo-controlled RCT.	237 patients admitted to 10 hospitals in Wuhan with laboratory-confirmed COVID-19 and classified as severe were randomly assigned in a 2:1 ratio to remdesivir (n = 158) or placebo (n = 79) groups.	Complete	Remdesivir was not associated with statistically significant clinical benefits (hazard ratio [HR] = 1.23 95% confidence interval [CI] = 0.87-1.75]), yet there was a numerical reduction in time to clinical improvement in those treated earlier with remdesivir which requires confirmation in larger studies.	Failed to complete full enrolment (owing to the end of the outbreak), insufficient power to detect assumed differences in clinical outcomes, initiation of treatment quite late in COVID-19, and the absence of data on infectious virus recovery or on possible emergence of reduced susceptibility to remdesivir. One author served as a non-compensated consultant to manufacturers of remdesivir.
		Beigel et al [42]	2020	To evaluate the clinical efficacy and safety of remdesivir among hospitalised adults with laboratory-confirmed COVID-19.	Double-blinded, multicentre, placebo-controlled RCT.	1062 hospitalised patients across 60 international trial sites randomly assigned in a 1:1 ratio to remdesivir (n = 538) or placebo (n = 521) groups.	Complete	Remdesivir was superior to placebo in shortening the time to recovery (relative risk [RR] 1.29 95% CI = 1.12-1.49) in adults hospitalised with COVID-19 and evidence of lower respiratory tract infection.	Report based on preliminary findings. Primary outcome changed early in the trial.
		Spinner et al [43]	2020	To evaluate the efficacy and adverse events of remdesivir administered for 5 or 10 day (d) vs standard care in hospitalized patients with moderate COVID-19	Randomised, open label, multicentre trial	584 hospitalised patients across 105 international sites randomly assigned in a 1:1:1 ratio to receive up to a 5-d course of remdesivir (n = 191) up to a 10-d course of remdesivir (n = 193), or standard care (n = 200).	Complete	On day 11, patients in the 5-d remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio [OR] = 1.65 95% CI = 1.09-2.48; P = 0.02). The clinical status distribution on day 11 between the 10-d remdesivir and standard care groups was not significantly different (P = 0.18)	Based on preliminary data leading to change in protocol, open-label design may have led to biases. Effects on viral load not assessed and decisions on discharge may have been driven by factors other than clinical improvement.
2.	Convalescent plasma	Salazar et al [44]	2020	To provide additional data on initial clinical observations of patients’ clinical course and subsequent improvement after receiving convalescent plasma therapy for COVID-19	Therapy study.	25 patients hospitalised with severe/critical COVID-19 transfused with Convalescent-Phase Donor Plasma using either the emergency investigational new drug (eIND) or investigational new drug (IND) applications approved by the US FDA.	Complete	At day 7 post-transfusion with convalescent plasma, 9 patients had at least a 1-point improvement in clinical scale, and 7 of those were discharged. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged. No adverse events as a result of plasma transfusion was observed.	Small case series with no control group. All patients received adjunct therapy (azithromycin, ribavirin, remdesivir. etc.) as patients were critically ill.
		Abolghasemi et al [45]	2020	To explore the efficacy of administrating convalescent plasma to COVID-19 patients in a nonrandomized multi-centre clinical trial.	Multicentre clinical trial	189 hospitalised patients across 6 sites were assigned to convalescent plasma group (n = 115) or control group (n = 74)	Complete	98 (98.2%) of patients who received convalescent plasma were discharged from hospital compared to 56 (78.7%) patients in control group. Length of hospitalization days was significantly lower (9.54 d) in convalescent plasma group com- pared with that of control group (12.88 d). Only 8 patients (7%) in convalescent plasma group required intubation while that was 20% in control group.	Not randomised. This led to bias of clinicians and the control group was smaller and consisted of milder patients. Standard therapy allowed in both groups and not standardized.
		Alsharidah et al [46]	2021	To assess the effectiveness of CCP in both moderate and severe COVID-19 cases compared to the standard treatment alone.	Multicentre, prospective cohort study	135 hospitalised patients across 4 sites with moderate to severe COVID-19 were enrolled and compared to 233 patients receiving standard care.	Complete	Among those with moderate COVID-19 disease, time to clinical improvement was 7 d in the CCP group, vs 8 d in the control group (P = 0.006). 30-d mortality rate was also significantly lower. For severe COVID-19 disease, time to clinical improvement was 7 d in the CCP group, vs 15.5 d in the control group (P = 0.003). There were no serious adverse effects.	Lack of randomisation, clinical treatment and management not standardised, did not exclude donors who were negative for IgG antibodies.
		Li L. et al [47]	2020	To evaluate the efficacy and adverse effects of convalescent plasma added to standard treatment, compared with standard treatment alone, for patients with severe or life-threatening COVID-19.	Multicentre, open label, randomised clinical trial.	103 patients with laboratory-confirmed COVID-19 and classified as severe/critical, randomly assigned to convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity.	Complete	Clinical improvement occurred within 28 d in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% 95% CI = -10.4% to 28.0%; HR = 1.40, 95% CI = 0.79-2.49). There was no significant difference in 28-d mortality (15.7% vs 24.0%; OR = 0.59, 95% CI = 0.22-1.59]) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28: HR = 1.61 95% CI = 0.88-2.95]). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care.	Small sample size and study terminated early due to lack of new cases emerging in Wuhan. Possibility for study to be underpowered to detect a clinically important benefit of convalescent plasma therapy. Median time between the onset of symptoms and randomization was 30 d. This was an open-label study, the primary outcome was based to some degree on physicians’ clinical management decisions. Standard therapy allowed in both groups and not protocolized.
		Agarwal et al [48]	2020	To investigate the effectiveness and safety of convalescent plasma in patients with moderate COVID-19 admitted to hospitals across India to limit progression to severe disease	Open label phase 2 multicentre RCT	464 patients across 39 sites in India randomly assigned 1:1 to receive convalescent plasma (n = 235) or standard care (n = 229)	Complete	Progression to severe disease or all-cause mortality at 28 d after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008, 95% CI = −0.062 to 0.078); RR = 1.04, 95% CI = 0.71 to 1.54). No difference in inflammatory markers.	Open label susceptible to anchoring bias, testing for biomarkers were from different manufacturers, bias in enrolment numbers between sites due to pandemic at different stages across India.
		Zeng Q.L et al [49]	2020	To retrospectively collect and analyse data of patients who received and did not receive convalescent plasma therapy to evaluate its efficacy.	Retrospective, observational study.	Extracted the epidemiological, demographic, clinical, laboratory, management, and outcome data of 21 COVID-19 patients who received (n = 6) and did not receive (n = 15) convalescent plasma.	Complete	All 6 critically ill patients who received plasma transfusion at a median of 21.5 d after first detection of viral shedding tested negative for SARS-CoV-2 RNA 3 d after infusion, yet 5 died eventually. Convalescent plasma treatment can discontinue SARS-CoV-2 shedding but cannot reduce mortality in critically end-stage COVID-19 patients, and treatment should be initiated earlier.	Limited number of patients due to end of outbreak in Wuhan. The amount of viral antibodies given to each patient was unknown and not standardized, which may lead to different clinical outcomes.
3.	Hydroxychloroquine (HCQ)/chloroquine (CQ)	Mahévas et al [50]	2020	To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (COVID-19) pneumonia who require oxygen.	Observational comparative study.	Data of 181 patients with severe COVID-19 who required oxygen split into those who did receive hydroxychloroquine (n = 92) and those who did not (n = 89). Analysed for 21 d survival.	Ongoing	The survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted HR = 0.9, 95% CI = 0.4-2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (HR = 1.2, CI = 0.4. to 3.3).	Not randomised causing potential for bias, prognostic variables not balanced, small sample.
		Gautret et al [51]	2020	To evaluate the effect of HCQ on respiratory viral loads.	Clinical trial	36 hospitalised patients with laboratory-confirmed COVID-19 in multiple hospitals served as either the treatment group (n = 26) or control (n = 16).	Ongoing	Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and 8 had lower respiratory tract infection symptoms. Twenty cases were treated in this study (6 lost to follow-up) and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported in the literature for untreated patients. Azithromycin added to HCQ was significantly more efficient for virus elimination (P < 0.001).	Based on preliminary findings. Study had a small sample size, limited long-term outcome follow- up, and dropout of 6 patients from the study.
		The RECOVERY Collaborative Group [52]	2020	To report the results of a comparison between hydroxychloroquine and usual care involving patients hospitalized with COVID-19.	Open-label RCT	4716 patients from 176 UK sites from randomly assigned to receive hydroxychloroquine (n = 1561) or standard care (n = 3155).	Complete	Death within 28 d occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (RR = 1.09; 95% CI = 0.97-1.23; P = 0.15). patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 d than those in the usual-care group (59.6% vs 62.9%; RR = 0.90; 95% CI = 0.83-0.98)	Does not investigate use as prophylaxis or in patients with less severe infection.
		Borba et al [53]	2020	To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19.	Parallel, double-masked, randomised, phase 2b clinical trial	81 patients hospitalised with severe COVID-19 randomised at a 1:1 ratio into high dosage (n = 41) or low dosage (n = 40) groups.	Ongoing	Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low dosage and high dosage groups, respectively. Lethality until day 13 was 39.0% in the high dosage group (16 of 41) and 15.0% in the low dosage group (6 of 40). The high dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37, 18.9%) compared with the low-dosage group (4 of 36, 11.1%). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).	Patients enrolled before laboratory confirmation of COVID-19 diagnosis. Based on preliminary findings. Small sample size, single centre, and lack a placebo control group.
		Boulware et al [54]	2020	To evaluate postexposure prophylaxis with HCQ after exposure to COVID-19.	Randomized, double-blind, placebo-controlled clinical trial.	821 asymptomatic adult participants with known exposure to a person with laboratory-confirmed COVID-19 randomised into HCQ group (n = 414) or placebo group (n = 407).	Complete	The incidence of new illness compatible with COVID-19 did not differ significantly between participants receiving HCQ (49 of 414, 11.8%) and those receiving placebo (58 of 407, 14.3%); the absolute difference was -2.4 percentage points (95% CI = 7.0-2.2; P = 0.35). Side effects were more common with HCQ than with placebo (40.1% vs 16.8%).	An a priori symptomatic case definition was used to define probable COVID-19 as diagnostic testing was lacking for vast majority of participants. Data obtained through participant self-report.
		Huang et al [55]	2020	To evaluate the efficacy and safety of CQ in hospitalized patients with COVID-19.	RCT	22 hospitalised patients with RT-PCR confirmed COVID-19 randomly assigned into treatment with CQ (n = 10) and treatment with Lopinavir/Ritonavir, which served as a control group (n = 12).	Ongoing	At day 14, all 10 patients (100%) from the CQ group were discharged compared to 6 patients (50%) from the Lopinavir/ Ritonavir group. The incidence rate of lung improvement based on CT imaging from the CQ group was more than double to that of the Lopinavir/Ritonavir group (RR 2.21, 95% CI = 0.81-6.62). 5 patients in the CQ group experienced a total of 9 adverse events.	Based on preliminary findings. Small sample size.
		Tang et al [56]	2020	To assess the efficacy and safety of HCQ plus standard of care compared with standard of care alone in adults with COVID-19.	Multicentre, open label, randomised controlled trial.	150 hospitalised patients with laboratory-confirmed COVID-19 randomised to HCQ plus standard of care (n = 75) and standard of care alone (n = 75) groups.	Complete	Administration of HCQ did not result in a significantly higher probability of negative conversion than standard of care alone (difference between groups was 4.1% 95% CI = 10.3%-18.5%) in patients admitted to hospital with mainly persistent mild to moderate COVID-19. Adverse events were higher in HCQ recipients than in non-recipients.	Possibility of biased investigator determined assessments and unbalanced dosage adjustment. Cannot provide evidence on the effect of HCQ on disease progression or regression because 148/150 (99%) patients in trial had mild to moderate disease.