Table 3 Patient Outcomes

Bosaeed et al. [40]

Favipiravir and Hydroxychloroquine Combination

Therapy in Patients with Moderate to Severe COVID-

19 (FACCT Trial): An Open-Label, Multicenter,

Randomized, Controlled Trial

•Time to clinical

•improvement

•Defined as the time from randomization to an improvement of two points on a seven-category ordinal scale or live discharge from the hospital, whichever came first

HCQ + FVP (n = 125)

•Time to clinical improvement, days: 9 (8, 12)

SoC (n = 129)

•Time to clinical improvement, days: 7 (6, 10)

HCQ + FVP (n = 125)

•Negative SARS-CoV-2 on (RT-PCR) by day 28: 25 (32.1%)

•Requirement of ICU admission: 33 (26.4%)

•Requirement of MV: 21 (16.8%)

•Duration of hospital stay, days: 9 (95% CI: 8, 12)

•28-day mortality: 9 (7.6%)

SoC (n = 129)

•Negative SARS-CoV-2 on (RT-PCR) by day 28: 23 (29.5%)

•Requirement of ICU admission: 26 (20.2%)

•Requirement of MV: 20 (15.5%)

•Duration of hospital stay, days: 8 (95% CI: 7, 10)

•28-day mortality: 13 (10.3%)

•Open-label design without a placebo group

•Only included

•hospitalized patients

•High number of follow-up SARS-CoV-2 (RT-

•PCR) tests were not obtained because of the limited resources and variable practices

•Premature termination could also have led to an

•increased data censoring related to the clinical

•outcome

•SoC group included patients treated with other antivirals

HCQ and FVP combination therapy plus

SoC did not achieve a higher efficacy than SoC alone in patients hospitalized with moderate-to-severe COVID-19. [9 (8, 12) vs. 7 (6, 10) p = 0.29]

Chen et al. [42]

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial

•Clinical recovery rate at 7 days from the beginning of treatment

•Clinical recovery was defined as continuous (> 72 h) recovery

FVP (n = 116)

•Clinical recovery rate

oD7: 71 (61.21%)

ARB (n = 120)

•Clinical recovery rate

oD7: 62 (51.67%)

FVP (n = 116)

•Incidence of AOT or NMV: 21 (18.1%)

•Respiratory failure: 1 (0.9%)

ARB (n = 120)

•Incidence of AOT or NMV: 27 (22.5%)

•Respiratory failure: 4 (3.3%)

•No clinically proven effective antiviral drug or placebo as the control arm

•Observation time frame was limited

•Did not require positive nucleic acid test in inclusion criteria

FVP did not improve clinical recovery but exhibited better symptom relief than ARB. [71 (61.21) vs. 62 (51.67) p = 0.1396]

Dabbous et al. [42]

Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study

•Mortality rate

•Need for MV

FVP (n = 44)

•Mortality: 1 (2.3%)

•Need for MV: 0 (0.0%)

CQ (n = 48)

•Mortality: 2 (4.2%)

•Need for MV: 4 (8.3%)

FVP (n = 44)

•Duration of hospital stay, days: 13.29 ± 5.86

•SpO₂:

o100-95%: 40 (90.9%)

o95-90%: 4 (9.1%)

o < 90%: 0 (0)

CQ (n = 48)

•Duration of hospital stay, days: 15.89 ± 4.75

•SpO₂:

o100-95%: 37 (77.1%)

o95-90%: 9 (18.8%)

o < 90%: 2 (4.2%)

•Not blinded

•No standard care control

•Did not examine need for ICU admission, mortality or the viremic response

•Included only COVID-19 patients who were mildly or moderately ill and therefore had a better prognosis than severely or critically ill patients

FVP is a promising drug for treatment of COVID-19 that might decrease the hospital stay and the need for MV

Mortality rate: [1 (2.3) vs. 2 (4.2) p = 1.00]

Doi et al. [48]

A Prospective, Randomized, Open-Label Trial of Early versus Late

Favipiravir Therapy in Hospitalized Patients with COVID-19

•Viral clearance by day 6

Early treatment FVP (n = 36)

•SARS-CoV-2 clearance by day 6: 66.7%

Late treatment FVP (n = 33)

•SARS-CoV-2 clearance by day 6: 56.1%

Early treatment FVP (n = 36)

•SARS-CoV-2 clearance by day 10: 86.1%

•50% logarithmic reduction in the SARS-CoV-2 viral load by day 6: 94.4%

•Median time until SARS-CoV-2 clearance by local RT-PCR: 12.8

•Disease progression or death (n = 44): 0.0

Late treatment FVP (n = 33)

•SARS-CoV-2 clearance by day 10: 83.1%

•50% logarithmic reduction in the SARS-CoV-2 viral load by day 6: 78.8%

•Median time until SARS-CoV-2 clearance by local RT-PCR: 17.8

•Disease progression or death (n = 44): 0.0

•Small sample size

•Unexpected high frequency of a negative RT-PCR at the time of enrollment likely underpowered the study

•Open-label study design

•Staggered treatment design where all patients eventually received FVP, adopted due to the unavailability of placebo at the time of study conception, made it difficult to interpret outcome differences beyond the sixth day

•Only recruited asymptomatic to mildly symptomatic COVID-19 patients

•Not known whether early treatment had any impact on replication-competent viruses

Administration of FVP did not significantly improve viral

clearance in the first 6 days, but there was a trend toward earlier viral clearance with

the agent. FVP was associated with numerical reduction in time to defervescence, and a significant improvement in fever was observed the day after starting therapy, compared with findings with no therapy. [66.7 (95% CI, 51.4 to 81.2) vs. 56.1 (95% CI, 0.764 to 2.623) HR = 1.416 (0.764–2.623)]

Lou et al. [30]

Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and

Favipiravir in COVID-19 Patients: An Exploratory Randomized,

Controlled Trial

•Viral negative rate at 14 days

•Viral negative was defined as two consecutive RT-PCR tests with undetectable viral RNA

•Time from randomization to clinical improvement

•Improvement was defined as either increase by two points on NEWS2 or discharge from the hospital

Total (n = 29)

•Viral negative, n (%)

oD7: 15 (51.7%)

oD14: 24 (82.8%)

B/M (n = 10)

•Viral negative, n (%)

oD7: 6 (60.0%)

oD14: 7 (70.0%)

FVP (n = 9)

•Viral negative, n (%)

oD7: 4 (44.4%)

oD14: 7 (77.8%)

Control (n = 10)

•Viral negative, n (%)

oD7: 5 (50.0%)

oD14: 10 (100.0%)

Total (n = 29)

•Incidence of MV: 1 (3%)

B/M (n = 10)

•Incidence of MV: 0

FVP (n = 9)

•Incidence of MV: 0

Control (n = 10)

•Incidence of MV: 1 (10)

•Small sample size

•Subjects were all under treatment with other medication

•The poor correlation could be due to the delay between infection and treatment initiation

•Patients in FVP group showed oldest average age and shortest time from symptom onset to randomization, even though, the clinical performance of FVP group was not inferior to the other two groups

•Not blinded

No extra benefit to COVID-19 treatment was observed when adding B/M or FVP to standard care

Viral negative rate at 14 days: [7 (70) vs. 7 (77) vs. 10 (100)]

Time from randomization to clinical improvement: [14 (6–49) vs. 14 (6–38) vs. 15 (6–24)]

Shinkai et al. [52]

Efficacy and Safety of Favipiravir in Moderate COVID-

19 Pneumonia Patients without Oxygen Therapy:

A Randomized, Phase III Clinical Trial

•Composite outcome defined as the time to

•improvement in temperature, SpO₂, and findings on chest imaging, and recovery to SARS-CoV-2-negative

FVP (n = 107)

•Number of patients who improved: 81

•Median time to improvement: 11.9

Placebo (n = 49)

•Number of patients who improved: 28

•Median time to improvement: 14.7

FVP (n = 107)

•Number of patients who improved:

•Temperature: 70

•SpO₂: 48

•Chest imaging: 95

•Median time to improvement:

•Temperature: 2.0

•SpO₂: 2.9

•Chest imaging: 4.8

•Number of patients with undetectable SARS-CoV-2: 87

•Median time to recovery, SARS-CoV-2: 11.0

Placebo (n = 49)

•Number of patients who improved:

•Temperature: 30

•SpO₂: 26

•Chest imaging: 35

•Median time to improvement:

•Temperature: 2.1

•SpO₂: 2.7

•Chest imaging: 5.7

•Number of patients with undetectable SARS-CoV-2: 31

•Median time to recovery, SARS-CoV-2: 12.1

•Single-blind design

•Virological

•investigations were measured solely by

•nasopharyngeal swabs, despite targeting COVID-19 patients with pneumonia

•Difficulty in recruiting only suitable patients of early-onset for evaluating antiviral drug efficacy

•Only COVID-19 patients with moderate pneumonia

•(SpO₂ ≥ 94%)

•Primary endpoint based on COVID-19 patient discharge criterion at that time and cannot be directly

•applied to the current criterion

FVP may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia,

should be carefully considered. (11.9 vs. 14.7 p = 0.0136)

Solaymani-Dodaran et al. [44]

Safety and efficacy of Favipiravir in moderate to severe

SARS-CoV-2 pneumonia

•Number of admissions to the intensive

•care unit

FVP (n = 190)

•ICU admission: 31 (16.3%)

LPV/r (n = 183)

•ICU admission: 25 (13.7%)

FVP (n = 190)

•In-hospital mortality: 26 (13.7%)

•Intubation: 27 (14.2%)

•Length of hospital stay, days (n = 153): 7 (4, 9)

•Survival time till clinical recovery, days (n = 185): 6 (4, 10)

LPV/r (n = 183)

•In-hospital mortality: 21 (11.5%)

•Intubation: 17 (9.3%)

•Length of hospital stay, days (n = 150): 6 (4, 10)

•Survival time till clinical recovery, days (n = 182): 6 (4, 10)

•Not blinded

•No control group without antivirals

No clinical

benefit from a treatment regimen based on FVP in moderate to

severe cases of SARS-CoV-2 over a treatment regimen based on LPV/r. [31 (16.3) vs. 25 (13.7) p = 0.47]

Udwadia et al. [35]

Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial

•Time from randomization to the cessation of oral shedding of the SARS-Cov-2 virus

•28 days maximum

•Defined as a negative RT-PCR result for both oropharyngeal and nasopharyngeal swabs

FVP (n = 72)

•Time to cessation of SARS-CoV-2 oral shedding:

oNumber of events: 70 (97.2%)

oTime to event, median days: 5.0

Control (n = 75)

•Time to cessation of SARS-CoV-2 oral shedding:

oNumber of events: 68 (90.7%)

oTime to event, median days: 7.0

FVP (n = 72)

•Time to clinical cure:

oNumber of events: 51/53 (96.2%)

oTime to event, median days: 3.0

•Time to hospital discharge:

oNumber of events: 70/72 (97.2%)

oTime to event, median days: 9.0

Control (n = 75)

•Time to clinical cure:

oNumber of events: 46/49 (93.9%)

oTime to event, median days: 5.0

•Time to hospital discharge:

oNumber of events: 68/75 (90.7%)

oTime to event, median days: 10.0

•Primary endpoint was confounded by interpretation issues with RT-PCR positivity and its lack of correlation with clinical cure

•Impact of RT-PCR assay variables such as cycle time was not evaluated

•Hazard ratios observed much smaller than previously reported

•Open-label design

Despite failure to achieve statistical significance on the primary endpoint of time to RT-PCR negativity, early administration of oral FVP may reduce the duration of clinical signs and symptoms in patients with mild-to-moderate COVID-19, as demonstrated by the significantly decreased time to clinical cure. [5 (95% CI: 4–7) vs. 7 (95% CI 5–8) p = 0.129]

Zhao et al. [45]

Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: A multicenter, open-label, randomized trial

•Time to achieve consecutive twice (intervals of more than 24 h) negative RT-PCR result for SARS-CoV-2 RNA in nasopharyngeal swab and sputum sample

FVP (n = 36)

•SPD (SARS-CoV-2 RNA positive duration) (days): 28.3 ± 16.6

•Proportion of RNA PCR turning negative: 80.6% (29/36)

Control (n = 19)

•SPD (SARS-CoV-2 RNA positive duration) (days): 27.8 ± 11.3

•Proportion of RNA PCR turning negative: 52.6% (10/19)

FVP (n = 36)

•Mortality: 0 (0)

•CRP change from baseline: 4.0 ± 9.1 mg/L to 1.5 ± 2.1 mg/L

•CD3 + Lymphocyte (count/μL):

•D0: 1192.8 ± 444.6

•D15: 1074.4 ± 229.6

•D30: 1094.3 ± 298.9

•CD4 + Lymphocyte (count/μL):

•D0: 719.1 ± 226.6

•D15: 484.1 ± 177.4

•D30: 571.8 ± 108.9

•CD8 + Lymphocyte (count/μL):

•D0: 473.7 ± 218.5

•D15: 361.9 ± 192.2

•D30: 538 ± 213.7

Control (n = 19)

•Mortality: 0 (0)

•CRP change from baseline: 2.0 ± 2.8 mg/L to 1.8 ± 2.7 mg/L

•CD3 + Lymphocyte (count/μL):

•D0: 1159.2 ± 280.7

•D15: 1046.6 ± 275.5

•D30: 778 ± 173.5

•CD4 + Lymphocyte (count/μL):

•D0: 672.5 ± 120.2

•D15: 624.7 ± 185.7

•D30: 505.8 ± 151.4

•CD8 + Lymphocyte (count/μL):

•D0: 402.2 ± 168.8

•D15: 323.1 ± 93.1

•D30: 334.5 ± 115.6

•Small sample size

•Trial was not blinded

•Followed up all the patients for only 30 days, and it is not clear whether these patients will return to positive again

•Not been able to obtain the Ct value of the dynamic changes of SARS-CoV-2 RNA in patients

•Presence of few symptomatic patients in this study, and only mild symptoms, prevents from demonstrating a clear clinical benefit of FVP

•Hospital admission is mandatory in PCR positive patients in China, and discharge is not allowed meanwhile PCR is still positive, but these measures are not followed worldwide, so the benefits of treatment may not be widespread in other settings

FVP was safe and superior to control in shortening the duration of viral shedding in SARS-CoV-2 RNA recurrent positive after discharge. [27.8 vs. 28.3 HR = 2.1 (95% CI 1.1–4.0) p = 0.038]

Ader et al. [37]

An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/

ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with

COVID-19

•Clinical status at day 15, measured by the WHO 7-point ordinal scale

•7-point ordinal scale:

o1. Not hospitalized/no

olimitations on activities

o2. Not hospitalized, limitation

oon activities

o3. Hospitalized, not requiring

osupplemental oxygen

o4. Hospitalized, requiring

osupplemental oxygen

o5. Hospitalized, on non-invasive ventilation or high flow oxygen device

o6. Hospitalized, on IMV or ECMO

o7. Death

LPV/r + standard of care(n = 145), moderate (n = 94)/severe (n = 51):

•1: 21 (22.3%)/

1 (2.0%)

•2: 36 (38.3%)/

2 (3.9%)

•3: 16 (17.0%)/

5 (9.8%)

•4: 9 (9.6%)/

9 (17.6%)

•5: 2 (2.1%)/

1 (2.0%)

•6: 7 (7.4%)/

29 (56.9%)

•7: 3 (3.2%)/

4 (7.8%)

LPV/r + IFN + standard of care (n = 145), moderate (n = 91)/severe (n = 54):

•1: 20 (22.0%)/

0 (0.0%)

•2: 35 (38.5%)/

1 (1.9%)

•3: 13 (14.3%)/

5 (9.3%)

•4: 9 (9.9%)/

6 (11.1%)

•5: 2 (2.2%)/

4 (7.4%)

•6: 9 (9.9%)/

28 (51.9%)

•7: 3 (3.3%)/

10 (18.5%)

HCQ + standard of care (n = 145), moderate (n = 93)/severe (n = 52):

•1: 20 (21.5%)/

1 (1.9%)

•2: 34 (36.6%)/

7 (13.5%)

•3: 18 (19.4%)/

7 (13.5%)

•4: 11 (11.8%)/

6 (11.5%)

•5: 1 (1.1%)/

3 (5.8%)

•6: 5 (5.4%)/

25 (48.1%)

•7: 4 (4.3%)/

3 (5.8%)

Control (n = 148), moderate (n = 94)/severe (n = 54):

•1: 23 (24.5%)/

1 (1.9%)

•2: 41 (43.6%)/

6 (11.1%)

•3: 7 (7.4%)/

5 (9.3%)

•4: 12 (12.8%)/

10 (18.5%)

•5: 1 (1.1%)/

2 (3.7%)

•6: 6 (6.4%)/

24 (44.4%)

•7: 4 (4.3%)/

6 (11.1%)

LPV/r + standard of care(n = 145), moderate (n = 94)/severe (n = 51):

•Death within 28 days: 4 (4.3%)/

10 (19.6%)

LPV/r + IFN + standard of care (n = 145), moderate (n = 91)/severe (n = 54):

•Death within 28 days: 4 (4.4%)/

13 (24.1%)

HCQ + standard of care (n = 145), moderate (n = 93)/severe (n = 52):

•Death within 28 days: 6 (6.5%)/

5 (9.6%)

Control (n = 148), moderate (n = 94)/severe (n = 54):

•Death within 28 days: 5 (5.3%)/

7 (13.0%)

•Open-labelled design

•Did not target patients at the early phase of the disease

•Did not include arms testing anti-inflammatory agents that could be used as part of the standard of care arm

•Standard of care

•underwent substantial changes over time

In patients admitted to hospital with COVID-19, LVP/r, LVP/r plus IFN-β-1a and HCQ were not associated with clinical improvement at day 15 and day 29, nor reduction in viral shedding. [aOR 0.83 (95% CI 0.55–1.26 p = 0.39) vs. aOR 0.69 (95% CI 0.45–1.04 p = 0.08) vs. aOR 0.93 (95% CI 0.62–1.41 p = 0.75)]

Alavi Darazam et al. [47]

Umifenovir in hospitalized moderate to severe COVID-19 patients: A

randomized clinical trial

•Time clinical improvement evaluated based on improvement of two points of the seven-category ordinal scale (recommended by the World Health Organization) or discharge from the hospital,

•whichever came first

LPV/r + HCQ + IFN-β-1a + ARB (n = 51)

•Time to clinical

•improvement: 9 (5–11)

Control (n = 50)

•Time to clinical

•improvement, median: 7 (4–10)

LPV/r + HCQ + IFN-β-1a + ARB (n = 51)

•Mortality at D

•21: 17 (33.3%)

•ICU adm: 51 (100.0%)

•IMV: 17 (33.3%)

Control (n = 50)

•Mortality at D

•21: 19 (38.0%)

•ICU adm: 50 (100.0%)

•IMV: 14 (28.0%)

•Not blinded

•38 patients unable to complete treatment course of administration because of liver enzyme elevation

•The trial was

•conducted on hospitalized patients with moderate-severe COVID-19 and the effectiveness of umifenovir in patients with mild Covid-19 not

•evaluated

Additive ARB was not effective in

shortening the duration of SARS-CoV-2 in severe patients and improving

the prognosis in non-ICU patients. [9 (5–11) vs. 7 (4–10) p = 0.22]

Arabi et al. [38]

Lopinavir-ritonavir and hydroxychloroquine

for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial

•Ordinal scale of organ support-free days

LPV/r (n = 225)

•Organ support-free days: 4 (− 1, 15)

HCQ (n = 50)

•Organ support-free days: 0 (− 1, 9)

Combination therapy (n = 27)

•Organ support-free days: − 1 (− 1, 7)

Control (n = 362)

•Organ support-free days: 6 (− 1, 16)

LPV/r (n = 225)

•90-day survival, adjusted HR: 0.83 (95% CI: 0.65, 1.07)

•Respiratory support-free days: 3 (− 1, 15)

•Time to hospital discharge, adjusted HR: 0.83 (95% CI: 0.68, 0.99)

•Progression to IMV, ECMO or death: 89/176 (50.6%)

HCQ (n = 50)

•90-day survival, adjusted HR: 0.71 (95% CI: 0.45, 0.97)

•Respiratory support-free days: 0 (− 1, 9)

•Time to hospital discharge, adjusted HR: 0.76 (95% CI: 0.56, 0.97)

•Progression to IMV, ECMO or death: 17/24 (70.8%)

Combination therapy (n = 27)

•90-day survival, adjusted HR: 0.58 (95% CI: 0.36, 0.92)

•Respiratory support-free days: −1 (− 1, 7)

•Time to hospital discharge, adjusted HR: 0.63 (95% CI: 0.42, 0.89)

•Progression to IMV, ECMO or death: 11/14 (78.6%)

Control (n = 362)

•90-day survival, adjusted HR: 1

•Respiratory support-free days: 5 (− 1, 16)

•Time to hospital discharge, adjusted HR: 1

•Progression to IMV, ECMO or death: 107/239 (44.8%)

•Data on the bioavailability of dissolved or crushed

•LPV/r tablets in critically ill patients are limited

•Open-label design

Among critically ill patients with

COVID-19, treatment with LPV/r, HCQ, or combination therapy resulted in worse outcomes compared to no antiviral therapy. [4 (-1, 15) vs. 0 (-1, 9) vs. -1 (-1, 7) vs. 6 (-1, 16)]

Cao et al. [24]

A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19

•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

LPV/r (n = 99)

•Time to clinical improvement, days: 16.0 (13.0, 17.0)

Control (n = 100)

•Time to clinical improvement, days: 16.0 (15.0, 18.0)

LPV/r (n = 99)

•28-day mortality: 19 (19.2%)

•Clinical improvement:

•D7: 6 (6.1%)

•D14: 45 (45.5%)

•D28: 78 (78.8%)

•Hospital stay (days): 14 (12, 17)

•Duration of IMV: 4 (3, 7)

Control (n = 100)

•28-day mortality: 25 (25.0%)

•Clinical improvement:

•D7: 2 (2.0%)

•D14: 30 (30.0%)

•D28: 70 (70.0%)

•Hospital stay (days): 16 (13, 18)

•Duration of IMV: 5 (3, 9)

•Not blinded

•Characteristics of the patients at baseline were generally balanced across the two groups, but the somewhat higher throat viral loads in the LPV/r group raise the possibility that this group had more viral replication

•Do not have data on the LPV exposure levels in patients

In hospitalized patients with severe COVID-19, LPV/r showed no benefit compared to standard care. [16 vs. 16 HR = 1.31, 95% CI (0.95–1.85), p = 0.09]

Li et al. [29]

Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderateCOVID-19: an exploratory randomized controlled trial

•Rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid

LPV/r (n = 34)

•Positive-to-negative conversion of SARS-CoV-2 nucleic acid by pharyngeal swab

•D7: 12 (35.3%)

ARB (n = 35)

•Positive-to-negative conversion of SARS-CoV-2 nucleic acid by pharyngeal swab

•D7: 13 (37.1%)

Control (n = 17)

•Positive-to-negative conversion of SARS-CoV-2 nucleic acid by pharyngeal swab

•D7: 7 (41.2%)

LPV/r (n = 34)

•Positive-to-negative conversion of SARS-CoV-2 nucleic acid by pharyngeal swab

•D14: 29 (85.3%)

•Time of positive-to-negative conversion of SARS-CoV-2 nucleic acid in pharyngeal swab (days): 9.0 ± 5.0

•Conversion rate from moderate to severe/critical clinical status: 8 (23.5%)

ARB (n = 35)

•Positive-to-negative conversion of SARS-CoV-2 nucleic acid by pharyngeal swab

•D14: 32 (91.4%)

•Time of positive-to-negative conversion of SARS-CoV-2 nucleic acid in pharyngeal swab, days: 9.1 ± 4.4

•Conversion rate from moderate to severe/critical clinical status: 3 (8.6%)

Control (n = 17)

•Positive-to-negative conversion of SARS-CoV-2 nucleic acid by pharyngeal swab

oD14: 13 (76.5%)

•Time of positive-to-negative conversion of SARS-CoV-2 nucleic acid in pharyngeal swab, days: 9.3 ± 5.2

•Conversion rate from moderate to severe/critical clinical status: 2 (11.8%)

•Small sample size

•Did not include severely or critically ill patients or patients at increased risk of poor outcomes with many comorbidities

•Not completely blinded

LPV/r and ARB therapy show little benefit for improving clinical outcome in hospitalized patients with mild to moderate COVID-19 compared to supportive care. [35.3 vs. 37.1 vs. 41.2 p = 0.966]

Nojomi et al. [31]

Effect of Arbidol (Umifenovir) on COVID-19:

a randomized controlled trial

•Duration of hospitalization

•Time to clinical improvement

LPV/r (n = 50)

•Duration of hospitalization, days: 9.6 ± 5.2

•Time to clinical improvement: 3.1 ± 1.4

ARB (n = 50)

•Duration of hospitalization, days: 7.2 ± 4.7

•Time to clinical improvement: 2.7 ± 1.1

LPV/r (n = 50)

•30-day mortality: 2 (4.0%)

•IMV: 2 (4.0%)

ARB (n = 50)

•30-day mortality: 1 (2.0%)

•IMV: 3 (6.0%)

•Not blinded

•Treatments were given in combination with HCQ

•Small sample sizes for disease severity subgroups

ARB significantly shortens duration of hospitalization compared to LPV/r in patients with COVID-19

Duration of hospitalization: (7.2 vs. 9.6 p = 0.02)

Time to clinical improvement: (2.7 vs. 3.1)

RECOVERY collaborative group [26]

Lopinavir–ritonavir in patients admitted to hospital with COVID-19

(RECOVERY): a randomised, controlled, open-label, platform trial

•28-day all-cause mortality

LPV/r (n = 1616)

•28-day mortality: 374 (23%)

Standard care (n = 3424)

•28-day mortality: 767 (22%)

LPV/r (n = 1616)

•Discharged from hospital within 28 days: 1113 (69%)

•IMV: 152/1556 (10%)

•Death: 350/1556 (22%)

Standard care (n = 3424)

•Discharged from hospital within 28 days: 2382 (70%)

•IMV: 279/3280 (9%)

•Death: 712/3280 (22%)

•Not blinded

•Did not collect detailed information on non-serious adverse reactions or reasons for stopping treatment

•Did not collect information on physiological, laboratory, or virological parameters

•Very few intubated patients with COVID-19 were enrolled in this study as there were difficulties in administering treatment to patients who could not swallow

LPV/r was not associated with reduction in 28-day mortality, duration of hospital stay, or risk of progression to IMV or death. [23 vs. 22, 95% CI (0.91–1.17) p = 0.60]

Reis et al. [27]

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir

on Risk of Hospitalization Among Patients With COVID-19

The TOGETHER Randomized Clinical Trial

•COVID-19-associated

•hospitalization and death 90 days after randomization

HCQ (n = 214)

•COVID-19 hospitalization: 8 (3.7%)

•Death: 0 (0.0%)

LPV/r (n = 244)

•COVID-19 hospitalization: 14 (5.7%)

•Death: 2 (0.8%)

Placebo (n = 227)

•COVID-19 hospitalization: 11 (4.8%)

•Death: 1 (0.4%)

HCQ (n = 214)

•All-cause hospitalization: 11 (5.1%)

•Time to viral clearance (n = 185): 97 (52.4%)

LPV/r (n = 244)

•All-cause hospitalization: 16 (6.6%)

•Time to viral clearance (n = 201): 125 (62.2%)

Placebo (n = 227)

•All-cause hospitalization: 12 (5.3%)

•Time to viral clearance (n = 195): 112 (57.4%)

•Found a low rate of hospitalizations, even though the population had risk factors for developing serious COVID-19 and median (range) age of 53 (18–94) years

No clinical benefit to support the use of either

HCQ or LPV/r in an outpatient population

Hospitalization: [8 (3.7) vs. 14 (5.7) vs. 11 (4.8)]

Death: [0 (0) vs. 2 (0.8) vs. 1 (0.4)]

Barratt-Due et al. [39]

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19: A Randomized Trial

•All-cause, in-

•hospital mortality

RDV (n = 42)

•Mortality during

•hospitalization: 7.1% (95% CI: 1.8 to 17.5)

RDV control (n = 57)

•Mortality during

•hospitalization: 7.0% (95% CI: 2.2 to 15.6)

HCQ (n = 52)

•Mortality during

•hospitalization: 7.5% (95% CI: 2.4 to 16.7)

HCQ control (n = 54)

•Mortality during

•hospitalization: 3.6% (95% CI: 0.6 to 10.6)

RDV (n = 42)

•Admission to ICU during

•hospitalization: 19.0% (95% CI: 9.2 to 32.6)

•MV

•during hospitalization: 9.5% (95% CI: 3.1 to 20.8)

RDV control (n = 57)

•Admission to ICU during

•hospitalization: 19.3% (95% CI: 10.5 to 30.8)

•MV

•during hospitalization: 7.0% (95% CI: 2.2 to 15.6)

HCQ (n = 52)

•Admission to ICU during

•hospitalization: 22.6% (95% CI: 12.8 to 35)

•MV

•during hospitalization: 15.1% (95% CI: 7.2 to 26.3)

HCQ control (n = 54)

•Admission to ICU during

•hospitalization: 16.1% (95% CI: 8.1 to 27.1)

•MV

•during hospitalization: 10.7% (95% CI: 4.4 to 20.5)

•Not blinded

•Relatively few

•patients were included, and CIs were wide enough to include moderate effects

•Not all data were available from all patients at all

•time points

•Most of the patients did not receive the full treatment length

•of the tested medication due to hospital discharge

Neither RDV nor HCQ affected viral clearance in hospitalized patients with COVID-19

[7.1 vs. 7.0 vs. 7.5 vs. 3.6]

Beigel et al. [23]

Remdesivir for the Treatment of Covid-19—Final Report

•Time to recovery

•Defined by either discharge from the hospital or hospitalization for infection-control purposes only

RDV (n = 541)

•Time to recovery: 10 (9, 11)

Control (n = 521)

•Time to recovery: 15 (13, 18)

RDV (n = 541)

•Recovery: 399 (73.8%)

•29-day mortality: 59 (10.9%)

•Time to clinical improvement, one category on ordinal scale, days 7.0 (6.0, 8.0)

•Duration of initial hospitalization, days: 12 (6, 28)

•New use of MV or ECMO: 52/402 (12.9%)

Control (n = 521)

•Recovery: 352 (67.6%)

•29-day mortality: 77 (14.8%)

•Time to clinical improvement, one category on ordinal scale, days: 9.0 (8.0, 11.0)

•Duration of initial hospitalization, days: 17 (8, 28)

•New use of MV or ECMO: 82/364 (22.5%)

•Training, site initiation visits, and monitoring visits often were performed remotely due to restricted travel and hospital restriction of entrance of nonessential personnel

•Research staff were often assigned other clinical duties and staff illnesses strained research resources

•Many sites did not have adequate supplies of personal protective equipment and trial-related supplies, such as swabs

RDV shortens time to recovery in hospitalized COVID-19 patients with evidence of infection in the lower respiratory tract

[10 days vs. 15 days, p < 0.001]

Goldman et al. [53]

Remdesivir for 5 or 10 Days in Patients

with Severe Covid-19

•Clinical status assessed on D14 on a 7-point ordinal scale

o1. death

o2. hospitalized, receiving IMV or ECMO

o3. hospitalized, receiving noninvasive ventilation or high-flow oxygen devices

o4. hospitalized, requiring low-flow supplemental oxygen

o5. hospitalized, not requiring supplemental oxygen but receiving ongoing medica care (related or not related to Covid-19);

o6. hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for RDV administration)

o7. not hospitalized

5-day RDV (n = 200)

•Clinical status at day 14 on the 7-point ordinal scale:

•1: 16 (8.0%)

•2: 16 (8.0%)

•3: 9 (4.5%)

•4: 19 (9.5%)

•5: 11 (5.5%)

•6: 9 (4.5%)

•7: 120 (60.0%)

10-day RDV (n = 197)

•Clinical status at day 14 on the 7-point ordinal scale:

•1: 21 (10.5%)

•2: 33 (16.5%)

•3: 10 (5.0%)

•4: 14 (7.0%)

•5: 13 (6.5%)

•6: 3 (1.5%)

•7: 103 (51.5%)

5-day RDV (n = 200)

•Time to clinical improvement (median day of 50% cumulative incidence): 10

•Time to recovery (median day of 50% cumulative incidence): 10

10-day RDV (n = 197)

•Time to clinical improvement (median day of 50% cumulative incidence): 11

•Time to recovery (median day of 50% cumulative incidence): 11

•Not blinded

•Did not have SARS-CoV-2 viral-load results during and after treatment, owing to the variability in local access to testing and practices across the global sites

No significant difference was found between a 5-day course and a 10-day course of RDV in patients with severe Covid-19 not requiring MV

[65.2 vs. 57.1, 95% CI (1.16–1.90) p = 0.002]

Mahajan et al. [51]

Clinical outcomes of using remdesivir in patients with moderate to severe COVID-19: A prospective randomised study

•Improvement in clinical outcomes

RDV + standard of care (n = 34)

•Did not require hospitalization: 2 (5.9%)

Standard of care (n = 36)

•Did not require hospitalization: 3 (8.3%)

RDV + standard of care (n = 34)

•Hospitalized, but did not require supplemental oxygen: 0 (0.0%)

•Hospitalized, required supplemental oxygen: 4 (11.8%)

•Required high-flow oxygen or non-invasive ventilation: 19 (55.9%)

•Required or received MV: 4 (11.8%)

•Death: 5 (14.7%)

Standard of care (n = 36)

•Hospitalized, but did not require supplemental oxygen: 0 (0.0%)

•Hospitalized, required supplemental oxygen: 6 (16.7%)

•Required high-flow oxygen or non-invasive ventilation: 22 (61.1%)

•Required or received MV: 2 (5.6%)

•Death: 3 (8.3%)

•All study cases were of moderate to severe disease category

•Did not grade the adverse events

•Did not give placebo injection in the no-RDV group

•Not blinded

•Small sample size

RDV therapy for five days did not produce improvement in clinical outcomes in moderate to severe COVID-19 cases

[2 (5.9) vs. 3 (8.3) p = 0.749]

Spinner et al. [34]

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19 A Randomized Clinical Trial

•Difference in clinical status distribution

10-day RDV (n = 193)

•Difference in clinical status distribution vs standard care: p = 0.18

5-day RDV (n = 191)

•Difference in clinical status distribution vs standard care: OR 1.65 (95% CI: 1.09, 2.48), p = 0.02

10-day RDV (n = 193)

•D11 clinical status

oDeath: 2 (1.0%)

oNot hospitalized: 125 (64.8%)

5-day RDV (n = 191)

•D11 clinical status

oDeath: 0 (0.0%)

oNot hospitalized: 134 (70.2%)

Standard care (n = 200)

•D11 clinical status

oDeath: 4 (2.0%)

oNot hospitalized: 120 (60.0%)

•Original protocol written when clinical understanding of disease was limited, so primary end point changed on first day of study enrollment

•Open-label design

•Virological outcomes (SARS-CoV-2 viral load) not assessed

•Other lab parameters that may have aided in identifying predictors of outcomes not collected

5-day course of RDV improved clinical status of moderate COVID-19 patients, but the magnitude of treatment was of questionable clinical relevance

[1.65 (1.09–2.48) vs. 1 p = 0.02]

Wang et al. [36]

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

•Time to clinical improvement up to day 28

•Defined as the time 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

RDV (n = 158)

•Time to clinical improvement: 21.0 (13.0, 28.0)

Control (n = 78)

•Time to clinical improvement: 23.0 (15.0, 28.0)

RDV (n = 158)

•Clinical improvement rates

oD7: 4 (2.5%)

oD14: 42 (26.6%)

oD28: 103 (65.2%)

•D28 mortality: 22 (13.9%)

•Duration of IMV, days: 7.0 (4.0, 16.0)

•Duration of hospital stay, days: 25.0 (16.0, 38.0)

Control (n = 78)

•Clinical improvement rates

oD7: 2 (2.6%)

oD14: 18 (23.1%)

oD28: 45 (57.7%)

•D28 mortality: 10 (12.8%)

•Duration of IMV, days: 15.5 (6.0, 21.0)

•Duration of hospital stay, days: 24.0 (18.0, 36.0)

•Insufficient power to detect assumed differences in clinical outcomes

•Initiation of treatment late after symptom onset

•Frequent use of corticosteroids patients may have promoted viral replication

•No answer to whether longer treatment course and higher dose of RDV would be beneficial in patients with severe COVID-19

No benefits were observed with RDV above and beyond that observed with standard therapies in severe COVID-19 patients

[21.0 (13.0, 28.0) vs. 23.0 (15.0, 28.0), 95% CI 1.23 (0.87–1.75)]

Abbaspour-Kasgari et al. [22]

Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial

•Length of hospital stay

SOF/DCV + ribavirin (n = 24)

•Duration of hospitalization, days: 6 (5, 7)

Standard care (n = 24)

•Duration of hospitalization, days: 6 (5.5, 7.5)

SOF, DCV, ribavirin (n = 24)

•Recovery: 24 (100.0%)

•Death: 0 (0.0%)

•Time to recovery, days: 6 (5, 7)

•ICU admission: 0 (0.0%)

•ICU duration, days: N/A

•IMV: 0 (0.0%)

•IMV duration, days: N/A

Standard care (n = 24)

•Recovery: 21 (87.5%)

•Death: 3 (12.5%)

•Time to recovery, days: 6 (6, 8)

•ICU admission: 4 (16.7%)

•ICU duration, days: 2.5 (1.5, 7)

•IMV: 4 (16.7%)

•IMV duration, days: 2.5 (1.5, 7)

•Median age was higher in the control arm

•More patients with diabetes in the control arm

•Number of patients not high enough to identify probable beneficial effects on survival

•Excluded elderly subject

•Not blinded

•Not able to analyze biological markers of improvement

There were signs of improved recovery and death rates in the with SOF/DCV + ribavirin, but the sample size was too small to see conclusive differences

[6 (5–7) vs. 6 (5.5–7.5) p = 0.398]

Abbass et al. [46]

Efficacy and safety of sofosbuvir plus daclatasvir or ravidasvir

in patients with COVID‐19: A randomized controlled trial

•Sum of the counted symptoms at D7 and D10 compared to D3

•Mean change in SpO₂ from D1 to D10

SOF/DCV + SoC (n = 40)

•D7 change in counts of

•clinical symptoms, value (SE) (p versus SoC: 0.041): − 0.12647 (0.13953)

•D10 change in counts of

•clinical symptoms, value (SE) (p versus SoC: 0.0399): − 0.031655 (0.174262)

SOF/ravidasvir + SoC (n = 40)

•D7 change in counts of

•clinical symptoms, value (SE) (p versus SoC: 0.491): − 0.09579 (0.13895)

•D10 change in counts of

•clinical symptoms, value (SE) (p versus SoC: 0.66969): + 0.071006 (0.166456)

SOF/DCV + SoC (n = 40)

•D1 SpO₂: 88.7 ± 4.2

•D10 SpO₂: 95.8 ± 2.7

SOF/ravidasvir + SoC (n = 40)

•D1 SpO₂: 87.5 ± 6.25

•D10 SpO₂: 94.52 ± 4.58

SoC (n = 40)

•D1 SpO₂: 87.9 ± 5.8

•D10 SpO₂: 93.4 ± 3.7

•Small sample size

•Open‐label design

•Lack of a placebo group

SOF/DCV + SoC was found to improve

clinical symptoms, oxygen saturation, and decrease ICU admission. SOF/ravidasvir had no effect relative to SoC alone

El-Bendary et al. [49]

Efficacy of combined Sofosbuvir and Daclatasvir

in the treatment of COVID-19 patients with pneumonia: a multicenter Egyptian study

•Rate of clinical/ virological cure

SOF/DCV (n = 96)

•Negative PCR D7: 12/24 (50.0%)

•Negative PCR D14: 81/96 (84.4%)

Control (n = 78)

•Negative PCR D7: 9/25 (36.0%)

•Negative PCR D14: 37/78 (47.4%)

SOF/DCV (n = 96)

•Adm to hospital: 79 (82.3%)

•ICU adm: 19 (19.8%)

•Duration inside hospital, median (IQR): 8 (9%)

•Follow up of WHO assessment scale, improved: 76 (79.2%)

Control (n = 78)

•Adm to hospital: 49 (62.8%)

•ICU adm: 24 (30.8%)

•Duration inside hospital, median (IQR): 10 (12%)

•Follow up of WHO assessment scale, improved: 57 (73.1%)

•Not blinded

SOF/DCV was effective as a treatment for COVID-19 and was associated with reduced hospital stay, a larger proportion of virological clearance at Day 14 and a trend toward lower mortality

[84.4 vs. 47.4 p < 0.01]

Khalili et al. [28]

Efficacy and safety of sofosbuvir/ ledipasvir in treatment of

patients with COVID-19; A randomized clinical trial

•Clinical response

•Time to clinical

•response

•Clinical response

•was defined as one order decline in disease category

•in the five category ordinal scale

SOF/LDP (n = 42)

•Clinical response: 38 (90.5%)

•Time to clinical response, days: 2 (1, 3.75)

Control (n = 40)

•Clinical response: 37 (92.5%)

•Time to clinical response, days: 4 (2, 5)

SOF/LDP (n = 42)

•Duration of hospital stay, days: 4 (2, 9.5)

•Duration of ICU stay, days: 6 (4, 11)

•14-day mortality: 3 (8.8%)

Control (n = 40)

•Duration of hospital stay, days: 5 (3.25, 7)

•Duration of ICU stay, days: 9 (6, 12)

•14-day mortality: 3 (7.5%)

•Not blinded

•Follow-up RT-PCR and chest imaging were not possible

•Small sample size

SOF/LDP accelerated time to

the clinical response, but did not have a significant effect on duration of hospital stay or mortality

Clinical Response: [38 (90.48) vs. 37 (92.5) p = 0.65]

Time to clinical response (days): [2 (1–3.75) vs. 4 (2.5) p = 0.02]

Roozbeh et al. [32]

Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial

•Symptom alleviation after 7 days of follow-up

SOF/DCV + standard care (n = 27)

•Any symptoms:

•D1: 27 (100.0%)

•D3: 16 (59.3%)

•D5: 12 (44.4%)

•D7: 7 (25.9%)

Standard care (n = 28)

•Any symptoms:

•D1: 26 (92.9%)

•D3: 15 (53.6%)

•D5: 12 (42.9%)

•D7: 7 (25.0%)

SOF/DCV + standard care (n = 27)

•Hospital admission: 1 (3.7%)

•Fatigue D30: 2 (7.4%)

•Anosmia D30: 0 (0.0%)

•Dyspnea D30: 4 (14.8%)

Standard care (n = 28)

•Hospital admission: 4 (14.3%)

•Fatigue D30: 16/26 (61.5%)

•Anosmia D30: 3/26 (11.5%)

•Dyspnea D30: 11/26 (42.3%)

•Assessment of symptom outcomes not carried out using an objective grading system

•Small sample size

SOF/DCV did not significantly reduce symptoms at 7 days compared to control. However, the intervention significantly reduced the number of patients with fatigue and dyspnea at 1 month

[7 (26) vs. 7 (28) p = 1.00]

Sadeghi et al. [33]

Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial

•Clinical recovery within 14 days of treatment

SOF/DCV + standard care (n = 33)

•Clinical recovery ≤ 14 days: 29 (87.9%)

Standard care (n = 33)

•Clinical recovery ≤ 14 days: 22 (66.7%)

SOF/DCV + standard care (n = 33)

•Duration of hospitalization, days: 6 (4, 8)

•Time to clinical recovery, days: 6 (4, 10)

•IMV: 3 (9.1%)

•Death: 3 (9.1%)

Standard care (n = 33)

•Duration of hospitalization, days): 8 (5, 13)

•Time to clinical recovery, days: 11 (6, 17)

•IMV: 7 (21.2%)

•Death: 5 (15.2%)

•Not blinded

•Fewer patients in the treatment arm received LVP/r

•Small sample size

SOF/DCV significantly reduced the duration of hospital stay

[29 (88) vs. 22 (67) p = 0.076]

Sayad et al. [43]

Efficacy and safety of sofosbuvir/velpatasvir versus the standard of

care in adults hospitalized with COVID-19: a single-centre, randomized

controlled trial

•28-day mortality

SOF/VEL (n = 40)

•All-cause mortality: 3 (7.5%)

Control (n = 40)

•All-cause mortality: 3 (7.5%)

SOF/VEL (n = 40)

•Time to clinical improvement, days: 6 (4, 8)

•Duration of hospital stay, days: 6 (5, 8.5)

•Time from randomization to death, days: 6 (2, 9)

•Need for MV: 1 (2.4%)

•Duration of MV—days: 3 (3, 3)

•RT-PCR conversion (positive to negative): 6 (15.0%)

Control (N = 40)

•Time to clinical improvement, days: 7 (4–11)

•Duration of hospital stay, days: 7 (5–13)

•Time from randomization to death, days: 7 (7, 30)

•Need for MV: 3 (8.1%)

•Duration of MV, days: 1 (1, 1)

•RT-PCR conversion (positive to negative): 4 (10.0%)

•Did not assess viral load

•Small sample size

•Open-label design

SOF/VEL + SoC did not improve the clinical status or reduce mortality in patients with moderate to severe

COVID-19

[3 (7.5) vs. 3 (7.5) p = 1.00]

Holubovska et al. [50]

Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial

•Time-to-recovery

•Defined as improvement in the Severity Rating (SR) baseline status by 2 SR score values (e.g., a change from SR 4 to SR 6)

Enisamium (n =  ~ 186)

•Mean time-to-

•recovery, days: 11.1

Placebo (n =  ~ 186)

•Mean time-to-

•recovery, days: 13.9 days

Enisamium (n =  ~ 186)

•Maximum time-to-recovery, days: 21

Placebo (n =  ~ 186)

•Maximum time-to-recovery, days: not reported

•Patient baseline characteristics not reported

•Group sizes not directly reported

Enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen

[13.9 vs. 11.1 p = 0.0259]