1. Remdesivir

Ader, 2021

Type of study:

phase 3, open-label, adaptive, multicentre, randomised, controlled trial

Setting:

48 sites in Europe, Between March 22, 2020, and Jan 21, 2021

Country:

France, Belgium, Austria, Portugal, Luxembourg

Source of funding:

European Union’s

Horizon 2020 research and innovation programme (Europe); Austrian

Group Medical Tumor (Austria); Belgian Health Care Knowledge Centre

(Belgium); Fonds Erasme-COVID-Université Libre de Bruxelles (Belgium);

REACTing, a French multi-disciplinary collaborative network working on

emerging infectious diseases (France); Ministry of Health (France);

Domaine d’intérêt majeur One Health Île-de-France (France); European

Regional Development Fund (Luxembourg); Ministry of Health (Portugal);

Agency for Clinical Research and Biomedical Innovation (Portugal). We

thank all participants who consented to enrol in the trial, as well as all

study and site staff whose indispensable assistance made the conduct of

the DisCoVeRy trial possible (all listed in the appendix 2 pp 35–47).

Conflicts of interest:

DC reports grants and lecture fees from Janssen and lecture fees from

Gilead, outside the submitted work….

Please refer to full text for the full conflicts of interest.

Hospitalized patients with confirmed SARS-CoV-2

Inclusion criteria:

• age ≥ 18 years,
• clinical assessment (evidence of rales or crackles on examination)
•  oxygen saturation (SpO2) of 94% or less on room air;or
•  requirement of supplemental oxygen, high-flow oxygen devices, non-invasive ventilation, or mechanical ventilation

Exclusion criteria:

• liver enzymes (alanine aminotransferase or aspartate aminotransferase) more than five times the upper limit of normal
•  a stage 4 severe chronic kidney disease or requiring dialysis (estimated glomerular filtration rate less than 30 mL/min),
• if a transfer within 72 h to another hospital that was not a study site was anticipated.
• pregnant or breastfeeding,
•  contraindication to any study medication including allergy
•  treated with one of the evaluated antiviral drugs in the past 29 days
• used ribavirin either in the past 29 days or concomitantly to random assignment

N total at baseline:

Total:= 857

Intervention: = 429

Control: N = 428

ITT population:

I: 414

C: 418

Important characteristics:

Age, median (IQR):

I: 63 (55–73)

C: 64 (54–72)

Sex, n/N (%) male:

I: 291/414 (70%)

C: 288/418 (69%)

7-point ordinal scale at baseline:

3: hospitalised, not requiring

supplemental oxygen:

I:8 (2%) C: 8 (2%)

4: hospitalised, requiring supplemental oxygen

I: 241 (58%) C: 244 (58%)

5: hospitalised, on non-invasive ventilation or high flow oxygen devices

I: 90 (22%) C: 93 (22%)

6: hospitalised, on invasive mechanical ventilation or ECMO I: 75 (18%) C: 73 (18%)

Groups were comparable at baseline.

Remdesivir was administered intravenously at a loading

dose of 200 mg on day 1 followed by a 100 mg, 1-h

infusion once-daily for a total duration of 10 days

standards of care

Length of follow-up:

29 days

Loss-to-follow-up or incomplete data:

Intervention:

N = 0

Control:

N = 0

Clinical outcomes

Death within 28 days

I: 34 (8%)

C: 37 (9%)

OR 0·93

(95% CI: 0·57 to 1·52); p=0·77

7-point ordinal scale at day 15 (Primary Outcome)

OR 0·98 (95% CI: 0·77 to 1·25); p=0·85

7-point ordinal scale at day 29

OR 1·11 (95% CI: 0·87 to 1·42); p=0·39

Duration of hospitalisation

Days to hospital discharge within 29 days

I: 15 (10 to 29)

C: 13 (8 to 29)

HR 0·94 (95% CI: 0·80 to 1·11); p=0·49

New mechanical ventilation, ECMO, or death within 29 days*

I: 60/339 (18%)

C: 87/344 (25%)

HR 0·66 (95% CI: 0·47 to 0·91); p=0·010

Time to symptom resolution

Respiratory support

Oxygenation-free days until day 29

I: 17 (2 to 22)

C: 17 (0 to 23)

Least-square mean difference (LSMD) 0·35 (–0·90 to 1·60); p=0·59

Ventilator-free days until day 29

I: 29 (20 to 29)

C: 29 (16 to 29)

LSMD 1·08 (–0·15 to 2·30); p=0·080

Safety

Any Serious adverse events

I: 135 (33%)

C: 130 (31%)

OR 1·11 (0·83–1·50); p=0·48

Any adverse events

I: 241 (59%)

C: 236 (57%)

OR 1·14 (0·86–1·50); p=0·37

Virological outcomes

The median decrease in viral loads between baseline and day 3 was similar in the remdesivir and control groups (appendix 2 pp 12–13). There was no significant effect of remdesivir on the viral kinetics (figure 3; appendix 2 pp 14, 29).

Definitions:

WHO Master Protocol:(1) not hospitalised, no limitation on activities; (2) not hospitalised, limitation on activities; (3) hospitalised, not

requiring supplemental oxygen; (4) hospitalised, requiring supplemental oxygen; (5) hospitalised, on non-invasive

ventilation or high flow oxygen devices; (6) hospitalised, on invasive mechanical ventilation or ECMO; and (7) dead.

Remarks:

It was open-label and

not placebo-controlled. Indeed, several treatments were

concomitantly evaluated at the beginning of the trial, and masking was thus impossible due to the different modes

of administration (intravenous, subcutaneous, or oral) of

the different treatment groups.

Authors conclusion:

In this randomised controlled trial, the use of remdesivir for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15 or day 29, nor with a reduction in mortality, nor with a reduction in SARS-CoV-2 RNA.

Barratt-Due, 2021

Type of study:

Independent, add-on RCT to WHO Solidarity trial, an open-label, adaptive RCT

Setting:

23 hospitals, between 28 March and 5 October 2020

Country:

Norway

Source of funding:

National Clinical Therapy Research, no role in RCT

Conflicts of interest:

JTA reports grant from South-Eastern Norway Regional Health Authority. ABD reports paid lecture by Allergan Norden AB and participation in advisory board meeting SANOFI-AVENTIS Norwy. SGD reports grant from Research Council of Norway. FLJ reports funding from Oslo University Hospital and Helse SørØst. MT reports participation in European advisory board for Eli Lilly and coordinator of National reference group on COVID-19 treatment in Norway.

Hospitalized patients with confirmed SARS-CoV-2 infection

Inclusion criteria:

• ≥18 years
• SARS-CoV-2 confirmed by PCR
• Hospitalized (ward or intensive care)

Exclusion criteria:

• Severe comorbid conditions with life expectancy <3 months
• Aspartate aminotransferase or alanine aminotransferase levels >5x normal upper limit
• Rate-corrected QT interval > 470 ms
• Pregnancy or breastfeeding
• Acute occurrence comorbid condition >7 days before inclusion
• Known intolerance to study drugs
• Participation confounding trial
• Concomitant medications interfering with study drugs

N total at baseline:

N = 181

Remdesivir: n=42

Hydroxychloroquine: n=52

Control remdesivir: n=57

Control HSQ: n=54

(some controls were in both groups)

Important characteristics:

Age, mean (SD): 59.8 (15.3)

R: 59.7 y (16.5)

CR: 58.1 y (15.7)

H: 60.3 y (13.3)

CH: 59.2 y (16.4)

Sex, n/N (%) male:

R: 29/42 (69%)

CR: 43/57 (75%)

H: 31/52 (60%)

CH: 34/54 (63%)

Disease severity, mean (SD):

Defined by Viral load (log₁₀ count/1000 cells)

R: 1.6 (1.6)

CR: 2.3 (1.8)

H: 2.3 (1.5)

CH: 2.0 (1.5)

Anti-SARS-CoV-2 antibodies, seroconverted (RDB ≥5) n/N (%)

R: 14/42 (42.4%)

CR: 18/57 (46.2%)

H: 15/52 (42.9%)

CH: 20/54 (54.1%)

Groups are not comparable on baseline regarding sex, comorbid conditions, ICU admission, P-F ratio less than 40 kPa, ACE and ARB medication, LDH level, D-dimer level, AST level, ALT, level.

R: standard of care plus 200 mg intravenous remdesivir on day 1, 100 mg daily up to day 9

H: standard of care plus 800 mg oral hydroxychloroquine 2x day on day 1, 400 mg 2x day up to day 9

All study treatment were discontinued at discharge.

Standard of care according to WHO guidelines recommending systemic steroids

Length of follow-up: 3 months

Loss-to-follow-up:

R: 9 (21%)

• n=1: no post-randomization data
• n=3: death
• n=3: loss to follow-up
• n=2: other

CR: 9 (16%)

• n=1: no post-randomization data
• n=1: voluntary discontinuation
• n=4: death
• n=1: loss to follow-up
• n=2: other

H: 13 (24%)

• n=2: no post-randomization data
• n=5: voluntary discontinuation
• n=4: death
• n=1: loss to follow-up
• n=1: other

CH: 8 (15%)

• n=1: voluntary discontinuation
• n=2: death
• n=1: loss to follow-up
• n=4: other

Incomplete outcome data:

Missing data due to discharge or participant withdrawal were imputed with best outcome. Not reported how many.

Clinical outcomes

Mortality (28 day)

R: 2.4 (0.1; 10.1)

CR: 5.2 (1.3-13.1)

RD: -2.9 (-10.3; 4.5)

H: 7.5 (2.4; 16.7)

CH: 1.8 (0.1; 7.6)

RD: 5.8 (-2.2; 13.7)

Mortality (60 day)

R: 7.1 (1.8; 17.5)

CR: 5.3 (1.3; 13.1)

RD: 1.9 (-7.8; 11.6)

H: 7.5 (2.4; 16.7)

CH: 1.8 (0.1; 7.6)

RD: 5.8 (-2.2; 13.7)

In-hospital mortality

R: 7.1 (1.8; 17.5)

CR: 7.0 (2.2; 15.6)

RR: 1.0 (0.2; 4.6)

H: 7.5 (2.4; 16.7)

CH: 3.6 (0.6; 10.6)

RR: 2.2 (0.4; 10.8)

Duration of hospitalization

Not reported

Admission to ICU during hospitalization

R: 19.0 (9.2; 32.6)

CR: 19.3 (10.5; 30.8)

RD: -0.3 (-15.9; 15.4)

H: 22.6 (12.8; 35.0)

CH: 16.1 (8.1; 27.1)

RD: 6.6 (-8.2; 21.4)

Time to symptom resolution

Not reported

Respiratory support

Mechanical ventilation

R: 9.5 (3.1; 20.8)

CR: 7.0 (2.2; 15.6)

RD: 2.5 (-8.6; 13.6)

H: 15.1 (7.2; 26.3)

CH: 10.7 (4.4; 20.5)

RD: 4.4 (-8.2; 17.0)

Time to receipt mechanical ventilation

RR R vs CR: 1.4 (0.4; 5.8)

RR H vs CH: 2.1 (0.7; 6.2)

Duration of mechanical ventilation

Reported in appendix figure 1

Safety

Adverse events n/N (%)

R: 34/42 (81%)

H: 26/52 (50%)

C: 33/87 (n=38%)

Serious adverse events n/N (%)

R: 13/42 (31%)

H: 12/52 (23%)

C: 20/87 (n=23%)

Virological outcomes

Viral clearance

Not reported

Viral load

Reported in a figure 2 and appendix figure 2

Subgroup analysis based on symptom duration before hospitalization, the presence of ARS-CoV-2 antibodies, high or low viral load at hospital admission, degree of inflammation, and age were performed.

Definitions: not applicable

Remarks:

• Randomization to remdesivir started on 7 April 2020. Hydroxychloroquine was removed on 8 June 2020. The trial was stopped on 5 October because of low mortality, potential adverse events and little effect of remdesivir.
• 185 were randomly assigned, 4 excluded due of absence of post-randomization information
• The groups are not well balanced, see table 1
• No blinding was performed
• Some participants receiving SoC act as controls for both active treatment groups, whereas some act in one or the other, giving a partial overlap of the 2 control groups.

Authors conclusion:

The overall lack of effect of remdesivir and HCQ on the clinical course of patients hospitalized for COVID-19 was accompanied by a paucity of effect on SARS-CoV-2 viral clearance in the oropharynx. Our findings question the antiviral potential of these drugs in hospitalized patients with COVID-19.

Mahajan, 2021

Type of study:

RCT; not blinded

Setting:

June to December

2020;

Country:

India

Source of funding:

“Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.”

Hospitalized COVID-19 patients with moderate-to-severe disease

Inclusion criteria:

• Hospitalised
• 18-60 years of age
• SARS-CoV-2 infection confirmed by PCR within the last 4 days
• radiographic evidence of pneumonia,
• respiratory rate >24/min
• oxygen saturation ≤ 94%
• creatinine clearance above 40 ml per minute

Exclusion criteria:

• receiving mechanical ventilation
• multi organ failure
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 3x normal upper limit

N total at baseline:

N = 82

Randomized:

 Intervention: 41

 Control: 41

Included in analysis:

 Intervention: 34 (incl. 1 cross

 over)

 Control: 36

Important characteristics:

Age, mean (SD):

I: 58.08±12.1

C: 57.41±14.1

Sex, n/N (%) male:

I: 13 (38.3)

C: 9 (25.0)

Duration of symptoms before involvement in trial (days); mean±SD

I: 6.26±2.49

C: 7.38±0.99

Receiving low flow supplemental oxygen

I: 27 (79.4)

C: 26 (72.2)

Receiving non‑invasive ventilation or high‑flow oxygen I: 7 (20.6)

C: 10 (27.8)

Receiving invasive mechanical ventilation

I: 0 (0)

C: 0 (0)

Groups comparable at baseline? No, time from symptoms to enrolment longer in the control group, less patient in intervention group received non-invasive ventilation or high-flow oxygen in stead of low flow oxygen compared to the control group.

Remdesivir + standard of care

IV 200 mg remdesivir on day 1, followed by 100 mg of remdesivir once daily for the subsequent

four days

Standard of care

supportive

therapy throughout the duration of the study. Other drugs used for COVID treatment (off-label use and in the absence of written policy) were not allowed to be

administered to the patients in the study period. Drugs

like corticosteroids and heparin were given as per standard of care

protocol.

Length of follow up:

12 days, or until discharge of death

Loss to follow-up:

I: 8/41 (19.5%)

Reasons: 2 patients discharged, 1 patient died, 2 witheld treatment, 3 remdesivir

C: 5/41 (12.2%)

Reasons: 2 patients discharged, 2 patients died, 1 requested remdesivir treatment

Clinical outcomes

Mortality

Reported as ‘death’, score 6, on ordinal scale. Unclear at which moment in time (1 result for 12 to 24 days):

Death

I: 5 (14.7)

C: 3 (8.3)

Duration of hospitalization

No data reported

Symptom resolution

Nausea, vomiting

I:

 Baseline: 7

 After treatment: 3

C:

 Baseline: 9

 After treatment: 2

Need for respiratory support

Clinical status from day 12 to 24

Did not require hospitalisation*

I: 2 (5.9)

C: 3 (8.3)

Hospitalised, but did not require supplemental oxygen

I: 0 (0)

C: 0 (0)

Hospitalised, required supplemental oxygen

I: 4 (11.8)

C: 6 (16.7)

Required high‑flow oxygen or non‑invasive ventilation

I: 19 (55.9)

C: 22 (61.1)

Required or received mechanical ventilation

I: 4 (11.8)

C: 2 (5.6)

Death

I: 5 (14.7)

C: 3 (8.3)

Also reported:

AST levels, ALT levels and creatinine levels at baseline and after treatment

Safety

Adverse events

Virological outcomes

Viral clearance

not reported

Definitions:

Clinical status day 1 – 12; assessed on 4-point ordinal scale:

1), receiving low-flow

oxygen supplementation;

2), receiving non-invasive

ventilation or high-flow oxygen;

3), not receiving

supplemental oxygen but requiring medical care;

4), receiving invasive mechanical ventilation

Clinical status day 12 – 24; assessed on 6-point ordinal scale:

1), Do not require hospitalisation,

2), hospitalised, but not requiring supplemental oxygen,

3), hospitalised, requiring supplemental oxygen;

4), Patients requiring high-flow oxygen or non-invasive ventilation;

5), Requiring or receiving mechanical ventilation;

6), Death

Remarks:

• Concerns about study quality / risk of bias
• High drop-out rate; 1 patient crossed-over to treatment group upon request
• Unclear how results of clinical status are reported (1 result for ordinal status from day 12 to 24)

Authors conclusion:

Remdesivir therapy for five days did not produce improvement in clinical outcomes in moderate to severe COVID‑19 cases.

Pan, 2020

Type of study:

RCT (open-label, non-blinded)

Setting & country:

405 hospitals in 30 countries; WHO Solidarity Trial

Source of funding:

Funded by the World Health Organization;

ISRCTN Registry nr, ISRCTN83971151; ClinicalTrials.gov nr, NCT04315948.)

N total at baseline:

N = 11,330

Remdesivir arm

I: 2743

C: 2708

Important characteristics:

Age, n/N (%):

I:

 <50y: 961/2743 (35%)

 50-69y: 1282/2743 (47%)

 ≥70y: 500/2743 (18%)

C:

 <50y: 952/2708 (35%)

 50-69y: 1287/2708 (48%)

 ≥70y: 469/2708 (17%)

Sex, n/N (%) male:

I: 1706/2743 (62%)

C: 1725/2708 (64%)

Respiratory support

I:

 No suppl. Oxygen at entry:

 661/2743 (24%)

 Suppl. Oxygen at entry

 1828/2743 (67%)

 Already receiving ventilation

 254/2743 (9%)

C:

 No suppl. Oxygen at entry:

 664/2708 (25%)

 Suppl. Oxygen at entry

 1811/2708 (67%)

 Already receiving ventilation

 233/2708 (9%)

Previous days in hospital

I:

 0 days: 724/2743 (26%)

 1 day: 917/2743 (33%)

 ≥2 days: 1102/2743 (40%)

C:

 0 days: 712/2708 (26%)

 1 day: 938/2708 (35%)

 ≥2 days: 1058/2708 (39%)

Remdesivir

Intravenous; 200 mg on day 0 and 100 mg on days 1 through

9.

Taking trial drug midway through scheduled duration*:

I: 96%

C: 2%

Use of non-study drug, n/N (%):

Corticosteroids

 I: 1310 (47.8%)

 C: 1288 (47.6%)

Convalescent plasma

 I: 52 (1.9%)

 C: 58 (2.1%)

Anti-IL-6 drug

 I: 133 (4.9%)

 C: 143 (5.3%)

Non-trial interferon

 I: 3 (0.1%)

 C: 25 (0.9%)

Non-trial antiviral

 I: 65 (2.4%)

 C: 152 (5.6%)

Standard of care

Length of follow up:

28 days, or up to discharge

Loss to follow-up:

I: 7/2750 (0.3%)

Reasons: no or unknown consent

C: 17/2725 (0.6%)

Reasons: no or unknown consent

Clinical outcomes

All-cause in-hospital mortality, regardless of whether death occurred before or after day 28:

I: 301/2743 (12.5%)

C: 303/2708 (12.7%)

RR 0.98 (95% CI 0.84 to 1.14)

HR=0.95 (95% CI 0.81-1.11)

Adjusted** HR=0.95 (95% CI 0.81-1.11)

All-cause in-hospital mortality, stratified by ventilation at randomization:

Ventilated: HR 1.20 (95% CI 0.89-1.64)

Not ventilated: HR 0.86 (95% CI 0.72-1.04)

Initiation of mechanical ventilation, in those not receiving ventilation at baseline:

I: 295/2489 (11.6%)

C: 284/2475 (11.5%)

RR 1.03 (95% CI 0.89 to 1.20)

Composite death or initiation ventilation:

I: 479/2743 (18.5%)

C: 479/2708 (18.9%)

RR 0.99 (95% CI 0.88 to 1.11)

Publication: RR 0.97 [0.85-1.10]

Hospitalized, not discharged:

Percentage of patients (rather than number of patients) ever reported as discharged who were still in the hospital:

Day 7, %

  I: 69%

 C: 59%

Day 14

  I: 22%

 C: 19%

Day 21

  I: 9%

 C: 8%

Definitions/information:

*Taking trial drug midway through scheduled duration, %, calculated only among patients who died or were discharged alive, % patients who were taking the trial drug midway through its

scheduled duration (or midway through the time from entry to death or discharge, if this was shorter).

**Adjusted model all-cause mortality: some overlap between the 4 control groups; an exploratory sensitivity analysis used multivariate Cox regression to fit all 4 treatment effects simultaneously; adjusted for several prognostic factors (age, sex, diabetes, bilateral

lung lesions at entry (no, yes, not imaged at entry), and respiratory support at entry (no oxygen, oxygen but no ventilation, ventilation).

Authors conclusion:

These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little

or no effect on hospitalized patients with Covid-19, as indicated by overall mortality,

initiation of ventilation, and duration of hospital stay.

Beigel, 2020

Type of study:

Double-blind, randomized placebo-controlled trial

Setting + Country:

There were

60 trial sites and 13 subsites in the United States

(45 sites), Denmark (8), the United Kingdom (5),

Greece (4), Germany (3), Korea (2), Mexico (2),

Spain (2), Japan (1), and Singapore (1).

Source of funding:

Funded by the National Institute of Allergy and Infectious Diseases and others;

ACCT-1 ClinicalTrials.gov number, NCT04280705

Inclusion criteria:

• Male / non-pregnant female
• Age ≥18y
• Diagnostic specimen positive for SARS-CoV-2 on RT-PCR

[more detailed information can be found in the supplementary file]

Exclusion criteria:

• Allergy to product
• Anticipated discharge from the hospital or transfer to another hospital within 72 hours of enrolment.

[more detailed information can be found in the supplementary file]

N total at baseline:

N = 1062

Intervention: 541

Control: 521

Important characteristics:

Intervention group:

Age (mean (SD)):

58.6 (14.6)

Male: 352 (65.1%)

Control group:

Age (mean (SD)):

59.2 (15.4)

Male: 332 (63.3%)

Groups comparable at baseline. 

Remdesivir:
intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on

days 2 through 10 or until hospital discharge or

death

Placebo:

Matching placebo was administered

according to the same schedule and in the same

volume as the active drug.

28 days

Remdesivir versus control

Median recovery time:

Remdesivir:

10 days (95% CI 9 – 11)

Placebo:

15 days (95% CI 13 – 18)

Recovery

HR for recovery: 1.29; 95% CI, 1.12 to 1.49; P<0.001).

Mortality by 14 days

Remdesivir: 6.7%

Placebo 11.9%

HR for death: 0.55; 95% CI, 0.36 to 0.83)

Serious adverse events

Remdesivir: 24.6%
Placebo: 31.6%

Comments:

Authors conclusion:

Remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.

Spinner,

2020

Type of study:

Randomized open-label multicentre clinical trial

Setting:

105 hospitals

Country:

US, Europe and Asia

Source of funding:

Gilead Sciences, which designed and conducted the study in consultation with the FDA and the investigators.

Inclusion criteria:

Willing and able to provide written informed consent; aged ≥ 18 years (at all sites), or aged ≥ 12 and < 18 years of age weighing ≥ 40 kg; SARS-CoV-2 infection confirmed by PCR ≤ 4 days before randomization; currently hospitalized; SpO2 > 94% on room air at screening; radiographic pulmonary infiltrates; men and women of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified

method(s) of contraception.

Exclusion criteria:

Participation in any other clinical trial of an experimental agent treatment for COVID-19; concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 < 24

hours prior to study drug dosing; Requiring mechanical ventilation at screening; ALT or AST > 5 x ULN; creatinine clearance < 50 mL/min, pregnant or breastfeeding

woman; known hypersensitivity to the study drug, the metabolites, or formulation excipient.

N total at baseline:

N = 596

Intervention1: 197*

Intervention2: 199*

Control: 200*

Of which respectively 193 (I1), 191 (I2) and 200 (C) patients were included in primary analysis.

Important characteristics:

Age, median (IQR):

I1: 56 (45-66)

I2: 58 (48-66)

C: 57 (45-66)

P=not reported

Sex, n/N (%) male:

I1: 118/193 (61)

I2: 114/191 (60)

C: 125/200 (63)

P=not reported

Groups comparable at baseline?

Patients in standard care group were more commonly prescribed with other COVID-19 agents.

I1: Remdesivir for 10 days. 73 (38%) patients completed the assigned treatment duration; the median number of doses for the group was 6 (range, 1-10). Reasons were hospital discharge (n=98), withdrawal (n=8) or adverse events (n=6).

I2: Remdesivir for 5 days. 145 (76%) patients completed the assigned treatment duration (median, 5 doses;

range, 1-5). Reasons were hospital discharge (n=35), withdrawal (n=5) or adverse events (n=4).

Remdesivir was dosed intravenously (30-60 minutes) at 200 mg on day 1 followed by 100 mg/d.

Remdesivir treatment was to

be discontinued in any patient experiencing severe elevations in liver enzymes or decreases in estimated creatinine

clearance to less than 30 mL/min.

Standard care (not specified)

28 days (in person for hospitalized patients or by phone for discharged patients)

Difference in clinical status distribution versus standard care (OR (95%CI)

I1: not reported *

P=0.18

I2: 1.65 (1.09 to 2.48)

P=0.02

*The proportional odds assumption was not met.

Clinical improvement day 11 (n/N, %)**

I1: 126/193 (65)

I2: 134/191 (70)

C: 121/200 (61)

Difference I1-C (95%CI): 4.8 (−5.0 to 14.4)

Difference I2-C (95%CI): 9.7 (0.1 to 19.1)

Clinical improvement day 28 (n/N, %)**

I1: 174/193 (90)

I2: 171/191 (90)

C: 166/200 (83)

Difference I1-C: not reported

Difference I2-C: not reported

**Defined as ≥2-point

improvement from baseline on the 7-point ordinal scale.

Recovery at day 11 (n/N, %)***

I1: 132 (68)

I2: 141 (74)

C: 128 (64)

Difference I1-C (95%CI): 4.4 (−5.0 to 13.8)

Difference I2-C (95%CI): 9.8 (0.3 to 19.0)

Recovery at day 28 (n/N, %)***

I1: 178 (92)

I2: 175 (92)

C: 170 (85)

Difference I1-C: not reported

Difference I2-C: not reported

***Defined as improvement from a baseline score of 2-5 to a score of 6 or 7 or from a baseline score of 6 to a score of 7, on the 7-point ordinal scale.

All-cause mortality at day 28 (n/N, %)

I1: 3/193 (2)

I2: 2/191 (1)

C: 4/200 (2)

HR (95%CI) I1 vs C: 0.76 (0.17 to 3.40)

HR (95%CII I1 vs C: 0.51 (0.09 to 2.80)

Adverse events (n/N, %)

Any adverse event

I1: 113/193 (59)

I2: 98/191 (51)

C: 93/200 (47)

Any serious adverse event

I1: 10/193 (5)

I2: 9/191 (5)

C: 18/200 (9)

There were no significant differences between the remdesivir and standard care groups in duration of oxygen therapy or hospitalization (data not reported).

Remarks:

Patients who had sufficiently

improved in the judgment of the investigator could be discharged from the hospital before finishing their assigned course of treatment.

Data on clinical improvement and recovery are also reported for other days. Furthermore, data on other exploratory outcome measures and details on adverse events were reported, but data is not shown here.

Peaks in discharge rates were observed in the remdesivir groups following the end of their assigned duration of treatment (i.e., there were increased rates of discharge on day 6 in

the 5-day remdesivir group and on day 11 in the 10-day group), suggesting that discharges were delayed for some patients to allow them to complete full courses of assigned remdesivir treatment.

Original protocol was amended on the basis of emerging understanding of the clinical presentation and assessment of COVID-19.

Authors conclusion:

Among patients with moderate COVID-19, those randomized

to a 10-day course of remdesivir did not have a statistically significant

difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant

difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.

Wang, 2020a

Type of study:

Randomised, double-blind, placebo-controlled, multicentre trial

Setting:

10 hospitals in Wuhan, Hubei, between Feb 6 and March 12, 2020

Country:

China

Source of funding:

Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and

Development Program of China, the Beijing Science and Technology Project

Conflicts of interest:

One author has served as non-compensated consultant to Gilead Sciences on its respiratory antiviral program, outside the submitted work. All other authors declare no competing interests.

Inclusion criteria:

• Men and non-pregnant women with COVID-19
• Aged at least 18 years
• RT-PCR positive for SARS-CoV-2, had pneumonia confirmed by chest imaging, had oxygen saturation of 94% or lower on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less
• within 12 days of symptom onset

Eligible patients of child-bearing age (men and women) agreed to take effective contraceptive measures (including hormonal contraception, barrier methods, or abstinence) during the study period and for at least 7 days after the last study drug administration

Exclusion criteria:

• pregnancy or breast feeding;
• hepatic cirrhosis;
• alanine aminotransferase or aspartate aminotransferase more than five times the upper limit of normal;
• known severe renal impairment (estimated glomerular filtration rate <30 mL/min per 1·73 m²) or receipt of continuous renal replacement therapy, haemodialysis, or peritoneal dialysis;
• possibility of transfer to a non-study hospital within 72 h;
• enrolment into an investigational treatment study for COVID-19 in the 30 days before screening

N total at baseline:

N = 237

Intervention: 158

Control: 79

Important characteristics:

Age, median (IQR)

I: 66 (57–73)

C: 64 (53–70)

Sex, n/N (%) male:

I: 89/158 (56%)

C: 51/78 (65%)

Time from symptom onset to starting study treatment, n/N (%) of ≤10 days

I: 71/155 (46%)
C: 47/78 (60%)

Groups comparable at baseline?

More patients with

hypertension, diabetes, or coronary artery disease in the

remdesivir group than the placebo group.

More patients

in the control group than in the remdesivir group had been symptomatic for 10 days or less at the time of starting remdesivir or placebo treatment, and a higher

proportion of remdesivir recipients had a respiratory

rate of more than 24 breaths per min. No other major

differences in symptoms, signs, laboratory results,

disease severity, or treatments were observed between

groups at baseline.

Remdesivir

Treatment regimens

Intravenous remdesivir (200 mg

on day 1 followed by 100 mg on days 2–10 in single daily

infusions) for

a total of 10 days (both provided by Gilead Sciences,

Foster City, CA, USA).

Placebo

Treatment regimens

The same volume of placebo infusions for a total of 10 days (provided by Gilead Sciences, Foster City, CA, USA)

Follow-up period:

28 days

Primary clinical endpoint

Clinical improvement

Defined as a 2-point reduction in patients’ admission status on a 6-point ordinal scale, or live discharge from the hospital, whichever came first.

n/N (%)

Day 7:

I: 4/158 (3%)

C: 2/78 (3%)

Day 14:

I: 42/158 (11%)

C: 18/78 (23%)

Day 28:

I: 103/158 (65%)

C: 45/78 (58%)

Time to clinical improvement

Median (IQR) days

I: 21 (13–28)

C: 23 (15–28)

HR 1.23 (95% CI: 0.87 to 1.75)

Subgroup analysis ≤10 days from symptom onset:

I: 18 (12–28)

C: 23 (15–28)

HR 1.52 (95% CI: 0.95 to 2.43)

Secondary outcomes

Proportion of patients in each category of the 6-point scale

Day 7

OR: 0.69 (0.41─1.17)

Day 14

OR: 1.25 (0.76─2.04)

Day 28

OR 1.15 (0.67─1.96)

All-cause mortality at day 28, n/N (%)

I: 22/158 (14%)

C: 10/78 (13%)

Difference: 1.1% (95% CI: -8.1 to 10.3)

Duration of invasive mechanical ventilation, median (IQR) days

I: 7·0 (4·0 to 16·0)

C: 15·5 (6·0 to 21·0)

Difference: –4·0 (–14·0 to 2·0)

Duration

of oxygen support, median (IQR) days

I: 19·0 (11·0 to 30·0)

C: 21·0 (14·0 to 30·5)

Difference: –2·0 (–6·0 to 1·0)

Duration of hospital admission, median (IQR) days

I: 25·0 (16·0 to 38·0)

C: 24·0 (18·0 to 36·0)

Difference: 0·0 (–4·0 to 4·0)

Virological measures Proportions of

patients with viral RNA detected and viral RNA load

Measured by quantitative RT-PCR

Viral load decreased over time similarly in both groups. When adjusted for baseline sputum viral load at enrolment, the remdesivir group showed no significant difference at day 5 from placebo, but a slightly more rapid decline in load (p=0.0672). The cumulative rate of undetectable viral RNA of nasopharyngeal and oropharyngeal swabs by day 28 was 153 (78%) of 196 patients, and the negative proportion

was similar among patients receiving remdesivir and those receiving placebo.

Safety outcomes

Treatment-emergent adverse events

I: 102/155 (66%)

C: 50/78 (64%)

Serious

adverse events,

I: 28/155 (18%)

C: 20/78 (26%)

Premature discontinuations of study drug

I: 18/155 (12%)

C: 4/78 (5%)

Remarks:

- number of patients needed according to power calculation was not reached, because no patients were enrolled after

March 12, because of the control of the outbreak in Wuhan. Based on the termination criteria

specified in the protocol, the data safety and monitoring

board recommended that the study be terminated.

- At this stage, the interim analysis was abandoned. When all the other assumptions

stayed the same, with the actual enrolment of 236 participants, the statistical power was reduced from 80% to 58%.

Authors conclusion:

Our trial found that intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of virus in patients with serious COVID-19 compared with placebo. We found that this dose regimen of intravenous remdesivir was adequately tolerated but did not provide significant clinical or antiviral effects in seriously ill patients with COVID-19. However, we could not exclude clinically meaningful differences and saw numerical reductions in some clinical parameters.

In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.

[See also the study by Shih, 2020: Remdesivir is Effective for Moderately Severe Patients: A Re-Analysis of the First Double-Blind,

Placebo-Controlled, Randomized Trial on Remdesivir

for Treatment of Severe COVID-19 Patients Conducted in Wuhan City]

Note: 6-point ordinal scale:

6 = death;

5 = hospital

admission for extracorporeal membrane oxygenation or

mechanical ventilation;

4 = hospital admission for non-invasive

ventilation or high-flow oxygen therapy;

3 = hospital

admission for oxygen therapy (but not requiring

high-flow or non-invasive ventilation);

2 = hospital admission

but not requiring oxygen therapy;

1 = discharged

or having reached discharge criteria (defined as clinical

recovery—ie, normalisation of pyrexia, respiratory rate

<24 breaths per minute, saturation of peripheral oxygen

>94% on room air, and relief of cough, all maintained for

at least 72 h)

1. Remdesivir

Ader et al., 2021

Computerized block randomization

Participants were randomly assigned 1:1:1:1:1 when

five groups were initially implemented, and were then

assigned 1:1 to receive either standard of care or standard of care plus remdesivir, once the other three treatment groups had been stopped for futility.

Randomisation was done in the electronic case report

form to ensure appropriate allocation concealment and

used computer-generated blocks of various sizes; it was

stratified on severity of disease at inclusion and on European administrative region.

Likely

Participants allocated to standard of care alone or in combination with remdesivir were recruited contemporaneously.

Allocated treatment was not masked

to participants nor study investigator.

Likely

Open-label trial

Likely

Open-label trial

Likely

Open-label trial

Unlikely

All outcome measures described in the methods are reported in the results.

Unlikely

No lost to follow up.

Unlikely

Participants included in the analysis are not significantly different from those who were randomized into the trial.

Barratt-Due et al., 2021

Computerized.

Eligible patients were allocated in an equal ratio using computer randomization procedures. There were 2 separate allocation lists. The first was the global list, in which the allocation sequence was prepared by an independent statistician appointed by the international trial steering group. A secondary national list was additionally prepared as a backup if allocation according to the global list was not available. The randomization procedure ensured that a patient could be allocated only to an available treatment. The randomization lists were not stratified or blocked; thus, the randomization can be regarded as simple.

Unlikely

The first was the global list, in which the allocation sequence was prepared by an independent statistician appointed by the international trial steering group. A secondary national list was additionally prepared as a backup if allocation according to the global list was not available.

Likely

Open label

Likely

Open label

Unclear

Despite being a randomized controlled trial with blinded analyses of all relevant data, it did not include a placebo group.

Unlikely

All outcomes were reported in main article of appendix

ClinicalTrials.gov: NCT04321616

Likely

15 to 24% of participants in study groups were lost to follow-up.

Missing data on outcomes due to discharge or participant withdrawal were imputed with best outcome.

Unlikely

Each pairwise intention-to-treat analysis was between the remdesivir or HCQ group and its respective SoC. Some participants receiving SoC act as controls for both active treatment groups, whereas some act in one or the other, giving a partial overlap of the 2 control groups.

Mahajan, 2021

Computerized (Excel)

“For administering

intervention, random number was generated in Excel to follow simple random sampling technique.”

Unclear

Not described at what time the random number was generated and who had knowledge of it

Likely

“We did not give placebo injection in the no-remdesivir group and did not do

blinding.”

Likely

“We did not give placebo injection in the no-remdesivir group and did not do

blinding.”

Likely

“We did not give placebo injection in the no-remdesivir group and did not do

blinding.”

Unclear

Trial not registered; some results described without data presented

Likely

Relatively small sample size and multiple drop outs (I: 19.5%; C: 12.2%)

Likely

Analysis not performed according to intention-to-treat protocol; drop outs and 1 cross over in relatively small study groups

Pan, 2020

(WHO Solidarity Trial Consortium)

Computerized

Once a hospital has obtained approval, electronic entry of patients who have given informed consent takes only a few minutes. At the end of it, the randomly allocated treatment is displayed on the screen and confirmed by electronic messaging.

Unlikely

Allocation displayed on screen after entry of patient in the system

Likely

Unblinded trial

(mortality: unlikely)

Likely

Unblinded trial

(mortality: unlikely)

Likely

Unblinded trial

(mortality: unlikely)

Unlikely

Protocol published

https://www.who.int/publications/m/item/an-international-randomised-trial-of-additional-treatments-for-covid-19-in-hospitalised-patients-who-are-all-receiving-the-local-standard-of-care

Unlikely

Low rate of lost-to follow-up and reasons comparable between groups

Unlikely

analyses performed according to intention-to-treat protocol

Beigel, 2020

Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir or placebo. Randomization was stratified by study site and disease severity at enrollment

Unlikely

Adequate procedure

Unlikely

No bias expected

Unlikely

No bias expected

Unlikely

At the time of the data and safety monitoring board report, which was based on data cutoff date of April 22, 2020, a total of 482 recoveries (exceeding the estimated number of recoveries needed for the trial) and 81 deaths had been entered in the database. At that time, the data and safety monitoring board recommended that the preliminary primary analysis report and mortality data from the closed safety report be provided to trial team members from the National Institute of Allergy and Infectious Diseases (NIAID).

Unlikely

Primary endpoints relevant and described.
The protocol is available online.

Unlikely

Unlikely

Intention-to-treat analysis performed

Spinner, 2020

The randomization list was created and validated by the interactive web response system (IWRS) vendor. A dummy randomization

list was provided to the biostatistician

employed by the study sponsor for review. A

separate list of sequential patient numbers within each treatment group was generated by the IWRS vendor.

Unclear

Patients were not stratified by site at enrolment, which may have led to imbalances in patient

care and discharge practices.

Unclear

It was an open label study.

Likely

It was an open label study, which might have led to differences in patient care.

Unclear

It was an open label study, which might have led to differences in reporting the results.

Unlikely

Outcome measures reported in the method section are also reported.

Unlikely

One patient was lost to follow up (I2 group) and was therefore not included in the primary analysis.

Unlikely

Not all randomized patients were included in analysis, but intention to treat analysis did not reveal different results.

Wang, 2020

Eligible patients were randomly assigned (2:1) to either the remdesivir group or the placebo group. Randomisation

was stratified according to the level of respiratory support as follows: (1) no oxygen support or oxygen

support with nasal duct or mask; or (2) high-flow oxygen, non-invasive ventilation, invasive ventilation, or

extracorporeal membrane oxygenation. The permuted block (30 patients per block) randomisation sequence, including stratification, was prepared by a statistician not involved in the trial using SAS software, version 9.4.

Unlikely

Eligible patients were allocated to receive medication in individually numbered packs, according to the sequential order of the randomisation centre. Envelopes were prepared for emergency unmasking.

Unclear

Double-blind, but method of blinding was not described.

Unclear

Double-blind, but method of blinding was not described.

Unclear

It was not described whether assessors were blinded.

Unlikely

The protocol is available online. This trial is registered with ClinicalTrials.gov, before the start of recruitment

Unlikely

Numbers lost to follow-up were not reported.

Unlikely

All allocated patients were included in the intention-to-treat analysis.