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.

Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. 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 [0·95–2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early.

We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed 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 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation 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. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov

No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models.

Remdesivir (also GS-5734) is a monophosphoramidate prodrug of an adenosine analogue that has a broad antiviral spectrum including filoviruses, paramyxoviruses, pneumoviruses, and coronaviruses.In vitro, remdesivir inhibits all human and animal coronaviruses tested to date, including SARS-CoV-2,and has shown antiviral and clinical effects in animal models of SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV infections.In a lethal murine model of MERS, remdesivir was superior to a regimen of combined interferon beta and lopinavir–ritonavir.Remdesivir is a potent inhibitor of SARS-CoV-2 replication in human nasal and bronchial airway epithelial cells.In a non-lethal rhesus macaque model of SARS-CoV-2 infection, early remdesivir administration was shown to exert significant antiviral and clinical effects (reduced pulmonary infiltrates and virus titres in bronchoalveolar lavages vs vehicle only).Intravenous remdesivir was studied for treatment of Ebola virus disease, in which it was adequately tolerated but less effective than several monoclonal antibody therapeutics,and has been used on the basis of individual compassionate use over the past several months in patients with COVID-19 in some countries.Case studies have reported benefit in severely ill patients with COVID-19.However, the clinical and antiviral efficacy of remdesivir in COVID-19 remains to be established. Here, we report the results of a placebo-controlled randomised trial of remdesivir in patients with severe COVID-19.

No statistically significant benefits were observed for remdesivir treatment beyond those of standard of care treatment. Our trial did not attain the predetermined sample size because the outbreak of COVID-19 was brought under control in China. Future studies of remdesivir, including earlier treatment in patients with COVID-19 and higher-dose regimens or in combination with other antivirals or SARS-CoV-2 neutralising antibodies in those with severe COVID-19 are needed to better understand its potential effectiveness.

Our study is the first randomised, double-blind, placebo-controlled clinical trial assessing the effect of intravenous remdesivir in adults admitted to hospital with severe COVID-19. The study was terminated before attaining the prespecified sample size. In the intention-to-treat population, the primary endpoint of time to clinical improvement was not significantly different between groups, but was numerically shorter in the remdesivir group than the control group, particularly in those treated within 10 days of symptom onset. The duration of invasive mechanical ventilation, although also not significantly different between groups, was numerically shorter in remdesivir recipients than placebo recipients.

We searched PubMed, up to April 10, 2020, for published clinical trials assessing the effect of remdesivir among patients with laboratory-confirmed coronavirus disease 2019 (COVID-19). The search terms used were (“COVID-19” or “2019-nCoV” or “SARS-CoV-2”) AND “remdesivir” AND (“clinical trial” or “randomized controlled trial”). We identified no published clinical trials of the effect of remdesivir in patients with COVID-19.

Although several approved drugs and investigational agents have shown antiviral activity against SARS-CoV-2 in vitro,at present there are no antiviral therapies of proven effectiveness in treating severely ill patients with COVID-19. A multicentre, open-label, randomised controlled trial (RCT) of hydroxychloroquine involving 150 adults admitted to hospital for COVID-19 reported no significant effect of the drug on accelerating viral clearance.An RCT enrolling patients within 12 days of symptom onset found that favipiravir was superior to arbidol in terms of the clinical recovery rate at day 7 in patients with mild illness (62 [56%] of 111 with arbidol vs 70 [71%] of 98 with favipiravir), but not in those with critical illness (0 vs 1 [6%]).In severe illness, one uncontrolled study of five patients given convalescent plasma suggested a possible benefit, although the patients already had detectable anti-SARS-CoV-2 neutralising antibodies before receipt of the plasma.An open-label RCT of oral lopinavir–ritonavir found no significant effect on the primary outcome measure of time to clinical improvement and no evidence of reduction in viral RNA titres compared to control.However, per-protocol analyses suggested possible reductions in time to clinical improvement (difference of 1 day), particularly in those treated within 12 days of symptom onset. Further studies of lopinavir–ritonavir and other drugs are ongoing.

The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has led to more than 4 692 797 cases and 195 920 deaths globally as of April 25, 2020.Although most infections are self-limited, about 15% of infected adults develop severe pneumonia that requires treatment with supplemental oxygen and an additional 5% progress to critical illness with hypoxaemic respiratory failure, acute respiratory distress syndrome, and multiorgan failure that necessitates ventilatory support, often for several weeks.At least half of patients with coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation have died in hospital,and the associated burden on health-care systems, especially intensive care units, has been overwhelming in several affected countries.

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.

The primary efficacy analysis was done on an intention-to-treat (ITT) basis with all randomly assigned patients. Time to clinical improvement was assessed after all patients had reached day 28; no clinical improvement at day 28 or death before day 28 were considered as right censored at day 28. Time to clinical improvement was portrayed by Kaplan-Meier plot and compared with a log-rank test. The HR and 95% CI for clinical improvement and HR with 95% CI for clinical deterioration were calculated by Cox proportional hazards model. Other analyses include subgroup analyses for those receiving treatment 10 days or less vs more than 10 days after symptom onset, time to clinical deterioration (defined as one category increase or death), and for viral RNA load at entry. The differences in continuous variables between the groups was calculated using Hodges-Lehmann estimation. We present adverse event data on the patients' actual treatment exposure, coded using Medical Dictionary for Regulatory Activities. Statistical analyses were done using SAS software, version 9.4. This trial is registered with ClinicalTrials.gov

One interim analysis using triangular boundariesand a 2:1 allocation ratio between remdesivir and placebo had been accounted for in the original design. Assuming an 80% event rate within 28 days across both groups and a dropout rate of 10% implies that about 453 patients should be recruited for this trial (151 on placebo and 302 on remdesivir). The possibility for an interim analysis after enrolment of about 240 patients was included in the design if requested by the independent data safety and monitoring board.

The original design required a total of 325 events across both groups, which would provide 80% power under a one-sided type I error of 2·5% if the hazard ratio (HR) comparing remdesivir to placebo is 1·4, corresponding to a change in time to clinical improvement of 6 days assuming that time to clinical improvement is 21 days on placebo.

Secondary outcomes were the proportions of patients in each category of the six-point scale at day 7, 14, and 28 after randomisation; all-cause mortality at day 28; frequency of invasive mechanical ventilation; duration of oxygen therapy; duration of hospital admission; and proportion of patients with nosocomial infection. Virological measures included the proportions of patients with viral RNA detected and viral RNA load (measured by quantitative RT-PCR). Safety outcomes included treatment-emergent adverse events, serious adverse events, and premature discontinuations of study drug.

The primary clinical endpoint was time to clinical improvement within 28 days after randomisation. Clinical improvement was defined as a two-point reduction in patients' admission status on a six-point ordinal scale, or live discharge from the hospital, whichever came first. The six-point scale was as follows: death=6; hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5; hospital admission for non-invasive ventilation or high-flow oxygen therapy=4; hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3; hospital admission but not requiring oxygen therapy=2; and 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. The six-point scale was modified from the seven-point scale used in our previous COVID-19 lopinavir–ritonavir RCTby combining the two outpatient strata into one.

The trial was monitored by a contract research organisation ( Hangzhou Tigermed Consulting ). Virological testing was done at the Teddy Clinical Research Laboratory (Tigermed–DI'AN, Hangzhou, China) using quantitative real-time RT-PCR. RNA was extracted from clinical samples with the MagNA Pure 96 system (Roche, Rotkreuz, Switzerland), detected and quantified by Cobas z480 qPCR (Roche), using LightMix Modular SARS-CoV-2 assays (TIB MOBIOL, Berlin, Germany). At baseline, the upper (nasopharyngeal or oropharyngeal swabs) and lower respiratory tract specimens were tested for detection of E-gene, RNA-dependent RNA polymerase gene, and N-gene, then samples on the subsequent visits were quantitatively and qualitative assessed for E-gene.

Patients received either intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for a total of 10 days (both provided by Gilead Sciences, Foster City, CA, USA). Patients were assessed once daily by trained nurses using diary cards that captured data on a six-category ordinal scale and safety from day 0 to 28 or death. Other clinical data were recorded using the WHO–International Severe Acute Respiratory and Emerging Infections Consortium ( ISARIC ) case record form. The safety assessment included daily monitoring for adverse events, clinical laboratory testing (days 1, 3, 7, and 10), 12-lead electrocardiogram (days 1 and 14), and daily vital signs measurements. Clinical data were recorded on paper case record forms and then double entered into an electronic database and validated by trial staff. Nasopharyngeal or oropharyngeal swabs, expectorated sputa as available, and faecal or anal swab specimens were collected on days 1, 3, 5, 7, 10, 14, 21, and 28 for viral RNA detection and quantification.

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. Eligible patients were allocated to receive medication in individually numbered packs, according to the sequential order of the randomisation centre (Jin Yin-tan Hospital central pharmacy). Envelopes were prepared for emergency unmasking.

Eligible patients were men and non-pregnant women with COVID-19 who were aged at least 18 years and were 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, and were 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 included 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 m 2 ) or receipt of continuous renal replacement therapy, haemodialysis, or peritoneal dialysis; possibility of transfer to a non-study hospital within 72 h; and enrolment into an investigational treatment study for COVID-19 in the 30 days before screening. The use of other treatments, including lopinavir–ritonavir, was permitted.

Ethical approval was obtained from the institutional review boards of each participating hospital. Written informed consent was obtained from all patients, or their legal representative if they were unable to provide consent. The trial was done in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization–Good Clinical Practice guidelines. The protocol is available online

This was an investigator-initiated, individually randomised, placebo-controlled, double-blind trial to assess the effectiveness and safety of intravenous remdesivir in adults (aged ≥18 years) admitted to hospital with severe COVID-19. The trial was done at ten hospitals in Wuhan, Hubei, China).

Results

Figure 1 Trial profile Between Feb 6, 2020, and March 12, 2020, 255 patients were screened, of whom 237 were eligible ( figure 1 ). 158 patients were assigned to receive remdesivir and 79 to receive placebo; one patient in the placebo group withdrew their previously written informed consent after randomisation, so 158 and 78 patients were included in the ITT population. No patients were enrolled after March 12, because of the control of the outbreak in Wuhan and on the basis of the termination criteria specified in the protocol, the data safety and monitoring board recommended that the study be terminated and data analysed on March 29. 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%.

Table 1 Baseline patient characteristics Remdesivir group (n=158) Placebo group (n=78) Age, years 66·0 (57·0–73·0) 64·0 (53·0–70·0) Sex Men 89 (56%) 51 (65%) Women 69 (44%) 27 (35%) Any comorbidities 112 (71%) 55 (71%) Hypertension 72 (46%) 30 (38%) Diabetes 40 (25%) 16 (21%) Coronary heart disease 15 (9%) 2 (3%) Body temperature, °C 36·8 (36·5–37·2) 36·8 (36·5–37·2) Fever 56 (35%) 31 (40%) Respiratory rate >24 breaths per min 36 (23%) 11 (14%) White blood cell count, × 109 per L Median 6·2 (4·4–8·3) 6·4 (4·5–8·3) 4–10 108/155 (70%) 58 (74%) <4 27/155 (17%) 12 (15%) >10 20/155 (13%) 8 (10%) Lymphocyte count, × 109 per L 0·8 (0·6–1·1) 0·7 (0·6–1·2) ≥1·0 49/155 (32%) 23 (29%) <1·0 106/155 (68%) 55 (71%) Platelet count, × 109 per L 183·0 (144·0–235·0) 194·5 (141·0–266·0) ≥100 148/155 (95%) 75 (96%) <100 7/155 (5%) 3 (4%) Serum creatinine, μmol/L 68·0 (56·0–82·0) 71·3 (56·0–88·7) ≤133 151/154 (98%) 76 (97%) >133 3/154 (2%) 2 (3%) Aspartate aminotransferase, U/L 31·0 (22·0–44·0) 33·0 (24·0–48·0) ≤40 109/155 (70%) 49 (63%) >40 46/155 (30%) 29 (37%) Alanine aminotransferase, U/L 26·0 (18·0–42·0) 26·0 (20·0–43·0) ≤50 130/155 (84%) 66 (85%) >50 25/155 (16%) 12 (15%) Lactate dehydrogenase, U/L 339·0 (247·0–441·5) 329·0 (249·0–411·0) ≤245 36/148 (24%) 17/75 (23%) >245 112/148 (76%) 58/75 (77%) Creatine kinase, U/L 75·9 (47·0–131·1) 75·0 (47·0–158·0) ≤185 118/141 (84%) 54/67 (81%) >185 23/141 (16%) 13/67 (19%) National Early Warning Score 2 level at day 1 5·0 (3·0–7·0) 4·0 (3·0–6·0) Six-category scale at day 1 2—hospital admission, not requiring supplemental oxygen 0 3 (4%) 3—hospital admission, requiring supplemental oxygen 129 (82%) 65 (83%) 4—hospital admission, requiring high-flow nasal cannula or non-invasive mechanical ventilation 28 (18%) 9 (12%) 5—hospital admission, requiring extracorporeal membrane oxygenation or invasive mechanical ventilation 0 1 (1%) 6—death 1 (1%) 0 Baseline viral load of nasopharyngeal and oropharyngeal swabs, log 10 copies per mL 4·7 (0·3) 4·7 (0·4) Receiving interferon alfa-2b at baseline 29 (18%) 15 (19%) Receiving lopinavir–ritonavir at baseline 27 (17%) 15 (19%) Antibiotic treatment at baseline 121 (77%) 63 (81%) Corticosteroids therapy at baseline 60 (38%) 31 (40%) Data are median (IQR), n (%), n/N (%), or mean (SE). Three patients in the remdesivir group did not start their assigned treatment so were not included in safety analyses ( figure 1 ). The median age of study patients was 65 years (IQR 56–71); sex distribution was 89 (56%) men versus 69 (44%) women in the remdesivir group and 51 (65%) versus 27 (35%) in the placebo group ( table 1 ). The most common comorbidity was hypertension, followed by diabetes and coronary heart disease. Lopinavir–ritonavir was co-administered in 42 (18%) patients at baseline. Most patients were in category 3 of the six-point ordinal scale of clinical status at baseline. Some imbalances existed at enrolment between the groups, including 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.

Table 2 Treatments received before and after enrolment Remdesivir group (n=158) Placebo group (n=78) Time from symptom onset to starting study treatment, days * * Three patients did not start treatment so are not included in time from symptom onset to start of study treatment subgroup analyses. 11 (9–12) 10 (9–12) Early (≤10 days from symptom onset) 71/155 (46%) 47 (60%) Late (>10 days from symptom onset) 84/155 (54%) 31 (40%) Receiving injection of interferon alfa-2b 46 (29%) 30 (38%) Receiving lopinavir–ritonavir 44 (28%) 23 (29%) Vasopressors 25 (16%) 13 (17%) Renal replacement therapy 3 (2%) 3 (4%) Highest oxygen therapy support Non-invasive mechanical ventilation 14 (9%) 3 (4%) Invasive mechanical ventilation 11 (7%) 10 (13%) Extracorporeal membrane oxygenation or mechanical ventilation 2 (1%) 0 Antibiotic 142 (90%) 73 (94%) Corticosteroids therapy 102 (65%) 53 (68%) Time from symptom onset to corticosteroids therapy, days 9 (7–11) 8 (6–10) Duration of corticosteroids therapy, days 9 (5–15) 10 (6–16) Data are median (IQR) or n (%). Median time from symptom onset to starting study treatment was 10 days (IQR 9–12). No important differences were apparent between the groups in other treatments received (including lopinavir–ritonavir or corticosteroids; table 2 ). During their hospital stay, 155 (66%) patients received corticosteroids, with a median time from symptom onset to corticosteroids therapy of 8·0 days (6·0–11·0); 91 (39%) patients received corticosteroids before enrolment.

Table 3 Outcomes in the intention-to-treat population Remdesivir group (n=158) Placebo group (n=78) Difference * * Differences are expressed as rate differences or Hodges-Lehmann estimator and 95% CI. Time to clinical improvement 21·0 (13·0 to 28·0) 23·0 (15·0 to 28·0) 1·23 (0·87 to 1·75) † † Hazard ratio and 95% CI estimated by Cox proportional risk model. Day 28 mortality 22 (14%) 10 (13%) 1·1% (−8·1 to 10·3) Early (≤10 days of symptom onset) 8/71 (11%) 7/47 (15%) −3·6% (−16·2 to 8·9) Late (>10 days of symptom onset) 12/84 (14%) 3/31 (10%) 4·6% (−8·2 to 17·4) Clinical improvement rates Day 7 4 (3%) 2 (3%) 0·0% (−4·3 to 4·2) Day 14 42 (27%) 18 (23%) 3·5% (−8·1 to 15·1) Day 28 103 (65%) 45 (58%) 7·5% (−5·7 to 20·7) Duration of invasive mechanical ventilation, days 7·0 (4·0 to 16·0) 15·5 (6·0 to 21·0) −4·0 (−14·0 to 2·0) Duration of invasive mechanical ventilation in survivors, days ‡ ‡ Three patients in each group were survivors and ten patients in the remdesivir group and seven patients in the placebo group were non-survivors. 19·0 (5·0 to 42·0) 42·0 (17·0 to 46·0) −12·0 (−41·0 to 25·0) Duration of invasive mechanical ventilation in non-survivors, days ‡ ‡ Three patients in each group were survivors and ten patients in the remdesivir group and seven patients in the placebo group were non-survivors. 7·0 (2·0 to 11·0) 8·0 (5·0 to 16·0) −2·5 (−11·0 to 3·0) Duration of oxygen support, days 19·0 (11·0 to 30·0) 21·0 (14·0 to 30·5) −2·0 (−6·0 to 1·0) Duration of hospital stay, days 25·0 (16·0 to 38·0) 24·0 (18·0 to 36·0) 0·0 (−4·0 to 4·0) Time from random group assignment to discharge, days 21·0 (12·0 to 31·0) 21·0 (13·5 to 28·5) 0·0 (−3·0 to 3·0) Time from random group assignment to death, days 9·5 (6·0 to 18·5) 11·0 (7·0 to 18·0) −1·0 (−7·0 to 5·0) Six-category scale at day 7 1—discharge (alive) 4/154 (3%) 2/77 (3%) OR 0·69 (0·41 to 1·17) § § Calculated by ordinal logistic regression model. 2—hospital admission, not requiring supplemental oxygen 21/154 (14%) 16/77 (21%) .. 3—hospital admission, requiring supplemental oxygen 87/154 (56%) 43/77 (56%) .. 4—hospital admission, requiring high-flow nasal cannula or non-invasive mechanical ventilation 26/154 (17%) 8/77 (10%) .. 5—hospital admission, requiring extracorporeal membrane oxygenation or invasive mechanical ventilation 6/154 (4%) 4/77 (5%) .. 6—death 10/154 (6%) 4/77 (5%) .. Six-category scale at day 14 1—discharge (alive) 39/153 (25%) 18/78 (23%) OR 1·25 (0·76 to 2·04) § § Calculated by ordinal logistic regression model. 2—hospital admission, not requiring supplemental oxygen 21/153 (14%) 10/78 (13%) .. 3—hospital admission, requiring supplemental oxygen 61/153 (40%) 28/78 (36%) .. 4—hospital admission, requiring high-flow nasal cannula or non-invasive mechanical ventilation 13/153 (8%) 8/78 (10%) .. 5—hospital admission, requiring extracorporeal membrane oxygenation or invasive mechanical ventilation 4/153 (3%) 7/78 (9%) .. 6—death 15/153 (10%) 7/78 (9%) .. Six-category scale at day 28 1—discharge (alive) 92/150 (61%) 45/77 (58%) OR 1·15 (0·67 to 1·96) § § Calculated by ordinal logistic regression model. 2—hospital admission, not requiring supplemental oxygen 14/150 (9%) 4/77 (5%) .. 3—hospital admission, requiring supplemental oxygen 18/150 (12%) 13/77 (17%) .. 4—hospital admission, requiring high-flow nasal cannula or non-invasive mechanical ventilation 2/150 (1%) 2/77 (3%) .. 5—hospital admission, requiring extracorporeal membrane oxygenation or invasive mechanical ventilation 2/150 (1%) 3/77 (4%) .. 6—death 22/150 (15%) 10/77 (13%) .. Data are median (IQR), n (%), or n/N (%). Clinical improvement (the event) was defined as a decline of two categories on the modified six-category ordinal scale of clinical status, or hospital discharge. OR=odds ratio. Figure 2 Time to clinical improvement in the intention-to-treat population Show full caption Adjusted hazard ratio for randomisation stratification was 1·25 (95% CI 0·88–1·78). *Including deaths before day 28 as right censored at day 28, the number of patients without clinical improvement was still included in the number at risk. Final follow-up was on April 10, 2020. In the ITT population, the time to clinical improvement in the remdesivir group was not significantly different to that of the control group (median 21·0 days [IQR 13·0–28·0] in the remdesivir group vs 23·0 days [15·0–28·0]; HR 1·23 [95% CI 0·87–1·75]; table 3 figure 2 ).

Results for time to clinical improvement were similar in the per-protocol population (median 21·0 days [IQR 13·0–28·0] in the remdesivir group vs 23·0 days [15·0–28·0] in the placebo group HR 1·27 [95% CI 0·89–1·80]; appendix pp 2–3, 5 ). Although not statistically significant, in patients receiving remdesivir or placebo within 10 days of symptom onset in the ITT population, those receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo (median 18·0 days [IQR 12·0–28·0] vs 23·0 days [15·0–28·0]; HR 1·52 [0·95–2·43]; appendix p 6 ). If clinical improvement was defined as a one, instead of two, category decline, the HR was 1·34 with a 95% CI of 0·96–1·86 ( appendix p 7 ). For time to clinical deterioration, defined as a one-category increase or death, the HR was 0·95 with a 95% CI of 0·55–1·64 ( appendix p 8 ).

28-day mortality was similar between the two groups (22 [14%] died in the remdesivir group vs 10 (13%) in the placebo group; difference 1·1% [95% CI −8·1 to 10·3]). In patients with use of remdesivir within 10 days after symptom onset, 28-day mortality was not significantly different between the groups, although numerically higher in the placebo group; by contrast, in the group of patients with late use, remdesivir patients had numerically higher 28-day mortality, although there was no significant difference. Clinical improvement rates at days 14 and day 28 were also not significantly different between the groups, but numerically higher in the remdesivir group than the placebo group. For patients assigned to the remdesivir group, duration of invasive mechanical ventilation was not significantly different, but numerically shorter than in those assigned to the control group; however, the number of patients with invasive mechanical ventilation was small. No significant differences were observed between the two groups in length of oxygen support, hospital length of stay, days from randomisation to discharge, days from randomisation to death and distribution of six-category scale at day 7, day 14, and day 28 ( table 3 appendix p 9 ).

10 copies per mL (SE 0·3) in the remdesivir group and 4·7 log 10 copies per mL (0·4) in the control group ( Figure 3 Viral load by quantitative PCR on the upper respiratory tract specimens (A) and lower respiratory tract specimens (B) Show full caption Data are mean (SE). Results less than the lower limit of quantification of the PCR assay and greater than the limit of qualitative detection are imputed with half of actual value; results of patients with viral-negative RNA are imputed with 0 log 10 copies per mL. Of 236 patients (158 in the remdesivir group and 78 in the placebo group) who were RT-PCR positive at enrolment, 37 (19%) of the 196 with data available had undetectable viral RNA on the nasopharyngeal and oropharyngeal swab taken at baseline. The mean baseline viral load of nasopharyngeal and oropharyngeal swabs was 4·7 logcopies per mL (SE 0·3) in the remdesivir group and 4·7 logcopies per mL (0·4) in the control group ( table 1 ). Viral load decreased over time similarly in both groups ( figure 3A ). No differences in viral load were observed when stratified by interval from symptom onset to start of study treatment ( appendix p 10 ). In the subset of patients from whom expectorated sputa could be obtained (103 patients), the mean viral RNA load at enrolment was nearly 1-log higher in the remdesivir group than the placebo group at enrolment ( figure 3B ). 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 ( appendix p 4 ).