Table 1.

Studies included in clinical review

Author	Population	Design	Drug (class)	Study endpoints	Outcomes		Limitations
Borba et al. 2020 [13]	Hospitalized patients with clinical suspicion of COVID-19, aged 18 years or older, with respiratory rate higher than 24 rpm and/or heart rate higher than 125 bpm (in the absence of fever) and/or peripheral oxygen saturation lower than 90% in ambient air and/or shock.	RCT	Chloroquine diphosphate (Antimalarial)	Reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group.	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%).		Small sample size.
							Single-center design.
							Lack of a placebo control group.
							Absence of exclusion criteria based on the QTc interval at baseline.
Tang et al. 2020 [14]	Patients 18 years and older with mild or moderate ongoing SARS CoV-2 infection.	RCT	Hydroxychloroquine (Antimalarial)	Negative conversion of SARS CoV-2 by 28 days.	The probability of negative conversion in the standard of care plus hydroxychloroquine group was 85.4% (95% CI 73.8–93.8) versus 81.3% in the standard of care group (95% CI 71.2–89.6), however this difference were not significant.		Open label trial.
				Clinical improvement by 28 days.			Non-computerized randomization protocol.
							Did not enroll participants with severe disease.
							Underpowered sample size.
Sarma et al. 2020 [27]	Patients with lab-confirmed COVID-19 of any age.	Meta-analysis	Hydroxychloroquine (Antimalarial)	Clinical cure.	Two studies reported possible benefit in “time to body temperature normalization” and one study reported less “cough days” in the HCQ arm. Treatment with HCQ resulted in a smaller number of cases showing radiological progression of lung disease (OR 0.31, 95% CI 0.11–0.9). No difference was observed in virologic cure (OR 2.37, 95% CI 0.13–44.53), death or clinical worsening of disease (OR 1.37, 95% CI 1.37–21.97) and safety (OR 2.19, 95% CI 0.59–8.18), when compared to the control/ conventional treatment.		Limited number of clinical studies with limited number of participants.
				Virologic cure on day 6 to 7 post-initiation of therapy.
				Death or clinical worsening of disease condition during treatment.			Lack of control/conventional/standard group.
				Radiological progression during drug treatment.
				Recurrence of infection during treatment.			Did not specify whether the studies included assessed patients with mild, moderate or severe COVID-19.
				Safety and tolerability of HCQ.
Cavalcanti et al. 2020 [15]	Hospitalized patients with suspected or confirmed mild/moderate COVID-19 with 14 or fewer days since symptom onset, who were receiving either no supplemental oxygen or a maximum of 4 L/min of supplemental oxygen.	RCT	Hydroxychloroquine (Antimalarial) ± Azithromycin (Antibiotic)	Clinical status at 15 days evaluated using a 7-level ordinal scale.	There was no significant difference in seven-point ordinal scale at 15 days between those treated with hydroxychloroquine and standard care (OR 1.21, 95% CI 0.69–2.11, p = 1.00), or between those treated with hydroxychloroquine + azithromycin and standard care (OR 0.99, 95% CI 0.57–1.73, p = 1.00).		Not blinded.
					There were no significant differences in six-level ordinal outcome at day 7, the number of days free from respiratory support, use of high-flow nasal cannula or non-invasive ventilation, use of mechanical ventilation, duration of hospital stay, in-hospital death, thromboembolic complications, or acute kidney injury between the groups.		Some patients concomitantly treated with other pharmacologic agents.
					Prolongation of QT interval and elevation of liver enzymes was more frequent in the experimental groups.		Some patients were previously treated with hydroxychloroquine ± azithromycin at other hospitals prior to enrollment in this trial.
Boulware et al. 2020 [16]	Adults with household or occupational exposure to someone with confirmed COVID-19 at a distance of less than 6 ft. for more than 10 min without a face mask and/or eye shield.	RCT	Hydroxychloroquine (Antimalarial)	Laboratory confirmed COVID-19 or illness compatible with COVID-19 within 14 days.	The incidence of new illness compatible with COVID-19 did not significantly differ between participants receiving HCQ (11.8%) and placebo (14.3%) (p = .35). There was no meaningful difference in the effectiveness according to the time of starting post-exposure prophylaxis.		Use of an a priori symptomatic case definition in some patients as opposed to diagnostic testing.
Beigel et al. 2020 [17]	Adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement.	RCT	Remdesivir (Antiviral)	Time to recovery defined by either discharge from the hospital or hospitalization for infection-control purposes only.	The remdesivir group had a median recovery time of 11 days (95% CI 9–12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; p < .001)		Preliminary data.
					The remdesivir group had higher odds of improvement in the 8-level ordinal scale score at day 15 compared to placebo (OR 1.50, 95% CI 1.18–1.91.
					Mortality was numerically lower in the remdesivir group, but this difference was not statistically significant.
Wang et al. 2020 [18]	Adults (aged ≥18 years) admitted to hospital with laboratory-confirmed severe SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less, and radiologically confirmed pneumonia.	RCT	Remdesivir (Antiviral)	Time to clinical improvement up to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1 = discharged to 6 = death) or discharged alive from hospital, whichever came first.	Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1.23 [95% CI 0.87–1.75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1.52 [95% CI 0.95–2.43]).		Insufficient power.
							Initiation of treatment late in COVID-19.
					Mortality at day 28 was not significantly different between the groups.		Absence of data on infectious virus recovery or on possible emergence of reduced susceptibility to remdesivir.
							Some patients concomitantly treated with other pharmacologic agents.
Goldman et al. 2020 [19]	Hospitalized patients with confirmed SARS-CoV-2 infection, O2 saturation ≤ 94% on ambient air, and radiologic evidence of pneumonia.	RCT	Remdesivir (Antiviral)	Clinical status on day 14 measured on a 7-point ordinal scale.	Clinical improvement of 2 points or more occurred in 65% of patients in the 5-day group and 54% of patients in the 10-day group. After correction of imbalance of baseline clinical status, clinical status at day 14 was similar between the 5-day and 10-day groups (p = .14).		The patients in the 10-day group had a significantly worse clinical status than those in the 5-day group (p = .02).
							No placebo control.
							Open label design.
Hung et al. 2020 [20]	Age at least 18 years, a national early warning score 2 (NEWS2) of at least 1, and symptom duration of 14 days or less upon recruitment.	RCT	IFN beta-1b (Anti-inflammatory), lopinavir-ritonavir and ribavirin (Antivirals)	Time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR.	The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [[8], [9], [10], [11], [12], [13], [14], [15]]; hazard ratio 4.37 [95% CI 1.86–10.24], p = .0010).		Open label trial.
							Absence of placebo group.
							Confounded by subgroup omitting of interferon beta-1b within the combination group, depending on time from symptom onset.
							Absence of critically ill patients.
Cao et al. 2020 [21]	Male and non-pregnant female patients 18 years of age or older with diagnostic specimen that was positive on RT-PCR, had pneumonia confirmed by chest imaging, and had an oxygen saturation of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen at or below 300 mg Hg.	RCT	Lopinavir-ritonavir (Antiviral)	Time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.	Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement 1.24 (95% CI 0.90–1.72)). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI −17.3-5.7).		Non-blinded.
							Higher throat viral loads in the lopinavir–ritonavir group on baseline.
							Absence of data on lopinavir exposure levels in severe and critically ill patients.
Li et al. 2020 [22]	Patients with mild/moderate COVID-19.	RCT	Lopinavir/ritonavir vs. Umifenovir (Antivirals)	Rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid.	No significant difference in the rate of positive-to-negative conversion between the lopinavir/ritonavir, arbidol, and control groups (p > .05).		Small sample size.
					No significant differences between the groups for the rates of antipyresis, cough alleviation, or improvement of CT findings at day 7 or 14 (p > .05).		Limited to patients with mild/moderate COVID-19.
					The lopinavir/ritonavir and arbidol groups experienced adverse effects, whereas the control group did not.		Single center.
							Not blinded to clinicians who recruited patients and research staff.
Cao et al. 2020 [23]	Patients with severe COVID-19, between 18 and 75 years of age.	RCT	Ruxolitinib (JAK inhibitor)	Time to clinical improvement (time from randomization to an improvement of 2 points on a 7-category ordinal scale or live discharge from the hospital).	Ruxolitinib plus standard-of-care was associated with a non-statistically significant decrease in median time clinical improvement (12 [IQR, 10–19] days vs. 15 [IQR, 10–18] days).		Small sample size.
					90% of ruxolitinib patients had significant CT improvement at day 14 compared to 61.9% of control patients (p = .0495).		Use of an ordinal scale to assess primary end points.
					Levels of 7 cytokines (including IL-6, IL-12 and VEGF) were significantly decreased in the experimental group.		Some patients concomitantly treated with other pharmacologic agents.
					The 28-day overall mortality was 0% in the experimental group and 14.3% in the control group.		Critically ill patients and patients with invasive ventilator dependence were not included.
The RECOVERY Collaborative Group 2020 [24]	Hospitalized patients with clinically suspected or laboratory confirmed SARS-CoV-2 infection, including those under 18 and pregnant or breastfeeding women.	RCT	Dexamethasone (Corticosteroid)	28-day mortality	Mortality at day 28 was significantly lower in the experimental group. 22.9% of patients treated with dexamethasone died within 28 days, compared to 25.7% of patients treated with standard care (age-adjusted rate ratio 0.83, 95% CI 0.75–0.93).		Preliminary data.
					Compared to the standard of care group, the incidence of death lower in dexamethasone patients receiving mechanical ventilation (rate ratio 0.64, 95% CI 0.51–0.81) and in those receiving oxygen without mechanical ventilation (rate ratio 0.82, 95% CI 0.72–0.94), but not in those receiving no respiratory support (rate ratio 1.19, 95% CI 0.91–1.55).		Open label design.
					Patients treated with dexamethasone also had a shorter duration of hospitalization (median 12 days vs. 13 days).
Zhu et al. 2020 [25]	Healthy, HIV-negative adults ≥18 years old who were not previously infected with SARS-CoV-2.	RCT	Ad5-vectored COVID-19 vaccine (vaccine)	Immunogenicity as measured by the geometric mean titers (GMT) of RBD-specific ELISA antibody responses and neutralizing antibody responses against live virus or pseudovirus at day 28 post-vaccination.	Participants who received either a low or high viral particles dose had a significant increase in RBD-specific ELISA antibodies, seroconversion rates and neutralizing antibody responses compared to the placebo group.		52% of participants had high pre-existing immunity, and 48% of the participants had low pre-existing immunity.
					Placebo group showed no antibody increase from baseline.
					No IFNγ-ELISpot responses in placebo group.
				Immunogenicity as measured by RBD-specific ELISA antibody responses at day 14, and specific T-cell responses at day 28 post-vaccination.	High dose (1 × 1011 viral particles)	Low dose (5 × 1010 viral particles)	Did not calculate sample size based on study power in advance.
				Seroconversion of the humoral response.	• RBD-specific ELISA antibodies peaked at 656.5 (95% CI 575.2–749.2).	• RBD-specific ELISA antibodies peaked at 571.0 (95% CI 476.6–697.3).	Only reported data within 28 days of vaccination.
					• GMTs were 19.5 (95% CI 16.8–22.7).	• GMTs were 18.3 (95% CI 14.4–23.3).
					• Seroconversion rates were 96% (95% CI 93–98).	• Seroconversion rates were 97% (95% CI 92–99).
					• Specific interferon γ enzyme-linked immunospot assay responses observed in 90% (95% CI 85–93).	• Specific interferon γ enzyme-linked immunospot assay responses observed in 88% (95% CI 81–92).
					• Severe adverse reactions in 9%.	• Severe adverse reactions in 1%.
Li et at. 2020 [26]	Patients with severe (respiratory distress and/or hypoxemia) or life threatening (shock, organ failure, mechanical ventilation) COVD-19.	RCT	Convalescent plasma (Immunotherapy)	Time to clinical improvement within 28 days, as defined by a reduction of 2 points on a 6-point disease severity scale, or discharge.	Clinical improvement within 28 days occurred in 51.9% of patients in the convalescent plasma group compared to 43.1% in the control group (8.8% difference, 95% CI −10.4–28.0%, p = .26). Clinical improvement occurred at a higher rate in those with severe disease compared to those with life threatening disease (91.3% vs 68.2%).		Small sample size.
					There was no significant difference in 28-day mortality (OR 0.65, 95% CI 0.29–1.46) or time to discharge (HR 1.61, 95% CI 0.88–2.93).		Study terminated early. Open-label design.
					Use of convalescent plasma resulted in an 87.2% negative conversion rate of viral PCR at 72 h compared to 37.5% in the control group.		Possibly underpowered study.