Piis0140673620310229 PDF
Piis0140673620310229 PDF
Piis0140673620310229 PDF
Summary
Background No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus Lancet 2020; 395: 1569–78
disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic Published Online
animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, April 29, 2020
https://doi.org/10.1016/
and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal
S0140-6736(20)31022-9
models.
This online publication has been
corrected. The corrected version
Methods We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. first appeared at thelancet.com
Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, on May 28, 2020
with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air See Comment page 1525
or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically *Contributed equally
confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 Department of Pulmonary and
followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days. Critical Care Medicine, Center
of Respiratory Medicine,
Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary
National Clinical Research
endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the Center for Respiratory Diseases
point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or (Ye Wang MD, F Zhou MD,
discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) Z Liu MD, L Shang MD,
Y Zhang MD, Prof B Cao MD,
population and safety analysis was done in all patients who started their assigned treatment. This trial is registered
Prof C Wang MD) and Institute
with ClinicalTrials.gov, NCT04257656. of Clinical Medical Sciences
(G Fan MS, X Gu PhD), China-
Findings Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment Japan Friendship Hospital,
Beijing, China; Department of
group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was Respiratory Medicine, Capital
not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical Medical University, Beijing,
improvement (hazard ratio 1·23 [95% CI 0·87–1·75]). Although not statistically significant, patients receiving China (Ye Wang, Prof B Cao);
remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with Jin Yin-tan Hospital, Wuhan,
Hubei, China (D Zhang MD,
symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]). Adverse events were reported in 102 (66%) of H Li MD, S Wang MS, S Ruan MS);
155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse Institute of Materia Medica,
events in 18 (12%) patients versus four (5%) patients who stopped placebo early. Chinese Academy of Medical
Sciences and Peking Union
Medical College, Beijing, China
Interpretation In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated (Prof G Du PhD,
with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in Prof K Wang PhD, Prof Y Lu PhD);
those treated earlier requires confirmation in larger studies. Wuhan Lung Hospital, Wuhan,
China (Prof R Du MD, C Yang MD,
C Mei MD); Tongji Hospital
Funding Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and (Prof J Zhao MD, Yi Wang MD,
Development Program of China, the Beijing Science and Technology Project. D Ding MD) and Union Hospital
(Prof Y Jin MD, F Wu MD,
Copyright © 2020 Elsevier Ltd. All rights reserved. X Tang MD), Tongji Medical
College of Huazhong University
of Science and Technology,
Introduction ventilatory support, often for several weeks.2–4 At least half Wuhan, China; Wuhan Third
The ongoing pandemic of severe acute respiratory of patients with coronavirus disease 2019 (COVID-19) Hospital, Wuhan, China
(Prof S Fu MD, X Ye MD); Renmin
syndrome coronavirus 2 (SARS-CoV-2) infections has led requiring invasive mechanical ventilation have died in
Hospital of Wuhan University,
to more than 4 692 797 cases and 195 920 deaths globally as hospital,4,5 and the associated burden on health-care Wuhan, China (Prof L Gao MD,
of April 25, 2020.1 Although most infections are self- systems, especially intensive care units, has been over Y Ye MD); Zhongnan Hospital of
limited, about 15% of infected adults develop severe whelming in several affected countries. Wuhan University, Wuhan,
China (Prof Z Cheng MD,
pneumonia that requires treatment with supplemental Although several approved drugs and investigational
B Liu MD); Wuhan Fourth
oxygen and an additional 5% progress to critical illness agents have shown antiviral activity against SARS-CoV-2 Hospital, Wuhan, China
with hypoxaemic respiratory failure, acute respiratory in vitro,6,7 at present there are no antiviral therapies of (Prof Q Lu MD, J Yang MD);
distress syndrome, and multiorgan failure that necessitates proven effectiveness in treating severely ill patients with The Central Hospital of Wuhan,
confirmed by chest imaging, had oxygen saturation of expectorated sputa as available, and faecal or anal swab
94% or lower on room air or a ratio of arterial oxy specimens were collected on days 1, 3, 5, 7, 10, 14, 21,
gen partial pressure to fractional inspired oxygen of and 28 for viral RNA detection and quantification.
300 mm Hg or less, and were within 12 days of symptom The trial was monitored by a contract research orga
onset. Eligible patients of child-bearing age (men and nisation (Hangzhou Tigermed Consulting). Virological For more on Tigermed see
women) agreed to take effective contraceptive measures testing was done at the Teddy Clinical Research Laboratory https://tigermedgrp.com/
(including hormonal contraception, barrier methods, or (Tigermed–DI’AN, Hangzhou, China) using quantitative
abstinence) during the study period and for at least real-time RT-PCR. RNA was extracted from clinical
7 days after the last study drug administration. Exclusion samples with the MagNA Pure 96 system (Roche,
criteria included pregnancy or breast feeding; hepatic Rotkreuz, Switzerland), detected and quantified by Cobas
cirrhosis; alanine aminotransferase or aspartate amino z480 qPCR (Roche), using LightMix Modular SARS-CoV-2
transferase more than five times the upper limit of assays (TIB MOBIOL, Berlin, Germany). At baseline,
normal; known severe renal impairment (estimated the upper (nasopharyngeal or oropharyngeal swabs) and
glomerular filtration rate <30 mL/min per 1·73 m²) lower respiratory tract specimens were tested for detec
or receipt of continuous renal replacement therapy, tion of E-gene, RNA-dependent RNA polymerase gene,
haemodialysis, or peritoneal dialysis; possibility of and N-gene, then samples on the subsequent visits were
transfer to a non-study hospital within 72 h; and quantitatively and qualitative assessed for E-gene.
enrolment into an investigational treatment study for
COVID-19 in the 30 days before screening. The use of Outcomes
other treatments, including lopinavir–ritonavir, was The primary clinical endpoint was time to clinical
permitted. improvement within 28 days after randomisation. Clinical
improvement was defined as a two-point reduction in
Randomisation and masking patients’ admission status on a six-point ordinal scale, or For ISARIC resources see
Eligible patients were randomly assigned (2:1) to either live discharge from the hospital, whichever came first. https://isaric.tghn.org/
the remdesivir group or the placebo group. Random
isation was stratified according to the level of respiratory
support as follows: (1) no oxygen support or oxygen 255 participants screened
support with nasal duct or mask; or (2) high-flow
oxygen, non-invasive ventilation, invasive ventilation, or
18 excluded
extracorporeal membrane oxygenation. The permuted 14 did not meet eligibility criteria
block (30 patients per block) randomisation sequence, 4 withdrew
including stratification, was prepared by a statistician not
involved in the trial using SAS software, version 9.4. 237 were enrolled
Eligible patients were allocated to receive medication
in individually numbered packs, according to the sequen
tial order of the randomisation centre (Jin Yin-tan
Hospital central pharmacy). Envelopes were prepared for 158 assigned to the remdesivir group 79 assigned to the placebo group
emergency unmasking.
1 withdrew consent
Procedures
Patients received either intravenous remdesivir (200 mg
158 in the intention-to-treat population 78 in the intention-to-treat population
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, 3 did not start study
Foster City, CA, USA). Patients were assessed once daily treatment
by trained nurses using diary cards that captured data
on a six-category ordinal scale and safety from day 0 155 started study treatment 78 started study treatment
to 28 or death. Other clinical data were recorded using
the WHO–International Severe Acute Respiratory and
Emerging Infections Consortium (ISARIC) case record 5 received remdesivir <5 days 2 received placebo <5 days
form. The safety assessment included daily monitoring
for adverse events, clinical laboratory testing (days 1, 3, 150 included in the per-protocol population 76 included in the per-protocol population
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 155 included in the safety population 78 included in the safety population
entered into an electronic database and validated
by trial staff. Nasopharyngeal or oropharyngeal swabs, Figure 1: Trial profile
The six-point scale was as follows: death=6; hospital pital admission for oxygen therapy (but not requiring
admission for extracorporeal membrane oxygenation or high-flow or non-invasive ventilation)=3; hospital admis
mechanical ventilation=5; hospital admission for non- sion but not requiring oxygen therapy=2; and discharged
invasive ventilation or high-flow oxygen therapy=4; hos or having reached discharge criteria (defined as clinical
recovery—ie, normalisation of pyrexia, respiratory rate
Remdesivir group (n=158) Placebo group (n=78) <24 breaths per minute, saturation of peripheral oxygen
Age, years 66·0 (57·0–73·0) 64·0 (53·0–70·0)
>94% on room air, and relief of cough, all maintained for
at least 72 h)=1. The six-point scale was modified from the
Sex
seven-point scale used in our previous COVID-19
Men 89 (56%) 51 (65%)
lopinavir–ritonavir RCT11 by combining the two outpatient
Women 69 (44%) 27 (35%)
strata into one.
Any comorbidities 112 (71%) 55 (71%)
Secondary outcomes were the proportions of patients
Hypertension 72 (46%) 30 (38%)
in each category of the six-point scale at day 7, 14, and
Diabetes 40 (25%) 16 (21%)
28 after randomisation; all-cause mortality at day 28;
Coronary heart disease 15 (9%) 2 (3%)
frequency of invasive mechanical ventilation; duration
Body temperature, °C 36·8 (36·5–37·2) 36·8 (36·5–37·2)
of oxygen therapy; duration of hospital admis sion;
Fever 56 (35%) 31 (40%)
and proportion of patients with nosocomial infection.
Respiratory rate >24 breaths per min 36 (23%) 11 (14%)
Virological measures included the proportions of
White blood cell count, × 10⁹ per L patients with viral RNA detected and viral RNA load
Median 6·2 (4·4–8·3) 6·4 (4·5–8·3) (measured by quantitative RT-PCR). Safety outcomes
4–10 108/155 (70%) 58 (74%) included treatment-emergent adverse events, serious
<4 27/155 (17%) 12 (15%) adverse events, and premature discontinuations of study
>10 20/155 (13%) 8 (10%) drug.
Lymphocyte count, × 10⁹ per L 0·8 (0·6–1·1) 0·7 (0·6–1·2)
≥1·0 49/155 (32%) 23 (29%) Statistical analysis
<1·0 106/155 (68%) 55 (71%) The original design required a total of 325 events across
Platelet count, × 10⁹ per L 183·0 (144·0–235·0) 194·5 (141·0–266·0) both groups, which would provide 80% power under a
≥100 148/155 (95%) 75 (96%) one-sided type I error of 2·5% if the hazard ratio (HR)
<100 7/155 (5%) 3 (4%) comparing remdesivir to placebo is 1·4, corresponding to a
Serum creatinine, μmol/L 68·0 (56·0–82·0) 71·3 (56·0–88·7) change in time to clinical improvement of 6 days assuming
≤133 151/154 (98%) 76 (97%) that time to clinical improvement is 21 days on placebo.
>133 3/154 (2%) 2 (3%) One interim analysis using triangular boundaries23 and
Aspartate aminotransferase, U/L 31·0 (22·0–44·0) 33·0 (24·0–48·0) a 2:1 allocation ratio between remdesivir and placebo had
≤40 109/155 (70%) 49 (63%) been accounted for in the original design. Assuming an
>40 46/155 (30%) 29 (37%) 80% event rate within 28 days across both groups and a
Alanine aminotransferase, U/L 26·0 (18·0–42·0) 26·0 (20·0–43·0) dropout rate of 10% implies that about 453 patients
≤50 130/155 (84%) 66 (85%) should be recruited for this trial (151 on placebo and
>50 25/155 (16%) 12 (15%) 302 on remdesivir). The possibility for an interim
Lactate dehydrogenase, U/L 339·0 (247·0–441·5) 329·0 (249·0–411·0) analysis after enrolment of about 240 patients was
≤245 36/148 (24%) 17/75 (23%) included in the design if requested by the independent
>245 112/148 (76%) 58/75 (77%) data safety and monitoring board.
Creatine kinase, U/L 75·9 (47·0–131·1) 75·0 (47·0–158·0) The primary efficacy analysis was done on an intention-
≤185 118/141 (84%) 54/67 (81%) to-treat (ITT) basis with all randomly assigned patients.
>185 23/141 (16%) 13/67 (19%)
Time to clinical improvement was assessed after all
National Early Warning Score 2 level at day 1 5·0 (3·0–7·0) 4·0 (3·0–6·0)
patients had reached day 28; no clinical improvement at
Six-category scale at day 1
day 28 or death before day 28 were considered as right
2—hospital admission, not requiring 0 3 (4%)
censored at day 28. Time to clinical improvement was
supplemental oxygen portrayed by Kaplan-Meier plot and compared with a log-
3—hospital admission, requiring 129 (82%) 65 (83%) rank test. The HR and 95% CI for clinical improvement
supplemental oxygen and HR with 95% CI for clinical deterioration were
4—hospital admission, requiring high-flow 28 (18%) 9 (12%) calculated by Cox proportional hazards model. Other
nasal cannula or non-invasive mechanical analyses include subgroup analyses for those receiving
ventilation
treatment 10 days or less vs more than 10 days after
5—hospital admission, requiring 0 1 (1%)
extracorporeal membrane oxygenation or
symptom onset, time to clinical deterioration (defined as
invasive mechanical ventilation one category increase or death), and for viral RNA load at
(Table 1 continues on next page) entry. The differences in continuous variables between
the groups was calculated using Hodges-Lehmann
Between Feb 6, 2020, and March 12, 2020, 255 patients Receiving lopinavir–ritonavir at baseline 27 (17%) 15 (19%)
were screened, of whom 237 were eligible (figure 1). Antibiotic treatment at baseline 121 (77%) 63 (81%)
158 patients were assigned to receive remdesivir and Corticosteroids therapy at baseline 60 (38%) 31 (40%)
79 to receive placebo; one patient in the placebo group Data are median (IQR), n (%), n/N (%), or mean (SE).
withdrew their previously written informed consent after
Table 1: Baseline patient characteristics
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 Remdesivir group (n=158) Placebo group (n=78)
Wuhan and on the basis of the termination criteria
Time from symptom onset to starting study 11 (9–12) 10 (9–12)
specified in the protocol, the data safety and monitoring treatment, days*
board recommended that the study be terminated and Early (≤10 days from symptom onset) 71/155 (46%) 47 (60%)
data analysed on March 29. At this stage, the interim Late (>10 days from symptom onset) 84/155 (54%) 31 (40%)
analysis was abandoned. When all the other assump
Receiving injection of interferon alfa-2b 46 (29%) 30 (38%)
tions stayed the same, with the actual enrolment of
Receiving lopinavir–ritonavir 44 (28%) 23 (29%)
236 participants, the statistical power was reduced from
Vasopressors 25 (16%) 13 (17%)
80% to 58%.
Renal replacement therapy 3 (2%) 3 (4%)
Three patients in the remdesivir group did not start
Highest oxygen therapy support
their assigned treatment so were not included in safety
Non-invasive mechanical ventilation 14 (9%) 3 (4%)
analyses (figure 1). The median age of study patients
Invasive mechanical ventilation 11 (7%) 10 (13%)
was 65 years (IQR 56–71); sex distribution was 89 (56%)
Extracorporeal membrane oxygenation or 2 (1%) 0
men versus 69 (44%) women in the remdesivir group mechanical ventilation
and 51 (65%) versus 27 (35%) in the placebo group Antibiotic 142 (90%) 73 (94%)
(table 1). The most common comorbidity was hyper
Corticosteroids therapy 102 (65%) 53 (68%)
tension, followed by diabetes and coronary heart
Time from symptom onset to corticosteroids 9 (7–11) 8 (6–10)
disease. Lopinavir–ritonavir was co-administered in therapy, days
42 (18%) patients at baseline. Most patients were in Duration of corticosteroids therapy, days 9 (5–15) 10 (6–16)
category 3 of the six-point ordinal scale of clinical status
Data are median (IQR) or n (%). *Three patients did not start treatment so are not included in time from symptom
at baseline. Some imbalances existed at enrolment onset to start of study treatment subgroup analyses.
between the groups, including more patients with
hypertension, diabetes, or coronary artery disease in the Table 2: Treatments received before and after enrolment
death, the HR was 0·95 with a 95% CI of 0·55–1·64 different between the groups, although numerically
(appendix p 8). higher in the placebo group; by contrast, in the group
28-day mortality was similar between the two groups of patients with late use, remdesivir patients had
(22 [14%] died in the remdesivir group vs 10 (13%) in the numerically higher 28-day mortality, although there
placebo group; difference 1·1% [95% CI –8·1 to 10·3]). was no significant difference. Clinical improvement
In patients with use of remdesivir within 10 days after rates at days 14 and day 28 were also not significantly
symptom onset, 28-day mortality was not significantly different between the groups, but numerically higher in
the remdesivir group than the placebo group. For 1·0 Remdesivir
patients assigned to the remdesivir group, duration of 0·9 Control
were treated within 10 days of symptom onset, recipients than placebo recipients. However, a higher
remdesivir was not a significant factor but was associated proportion of remdesivir recipients than placebo
with a numerical reduction of 5 days in median time to recipients had dosing prematurely stopped by the
clinical improvement. Ongoing controlled clinical trials investigators because of adverse events including gastro
are expected to confirm or refute our findings. In intestinal symptoms (anorexia, nausea, and vomiting),
one murine model of SARS, remdesivir treatment aminotransferase or bilirubin increases, and worsened
starting at 2 days after infection, after virus replication cardiopulmonary status.
and lung airway epithelial damage had already peaked, Limitations of our study include insufficient power to
significantly reduced SARS-CoV-1 lung titres but did detect assumed differences in clinical outcomes, initiation
not decrease disease severity or mortality.13 A need for of treatment quite late in COVID-19, and the absence of
early treatment has been found in non-human primate data on infectious virus recovery or on possible emer
models of SARS and MERS in which virus replication is gence of reduced susceptibility to remdesivir. Of note, in
very short-lived and lung pathology appears to develop non-human primates, the inhibitory effects of remdesivir
more rapidly than in human infections.17,19 Such findings on infectious SARS-CoV-2 recovery in bronchoalveolar
argue for testing of remdesivir earlier in COVID-19. lavages were much greater than in controls, but viral
Remdesivir did not result in significant reductions RNA detection in upper and lower respiratory tract
in SARS-CoV-2 RNA loads or detectability in upper specimens were not consistently de creased versus
respiratory tract or sputum specimens in this study controls.19 Coronaviruses partially resistant to inhibition
despite showing strong antiviral effects in preclinical by remdesivir (about six-times increased EC50) have been
models of infection with coronaviruses. In African green obtained after serial in vitro passage, but these viruses
monkey kidney Vero E6 cells, remdesivir inhibited remain susceptible to higher remdesivir concentrations
SARS-CoV-2 with a 50% effective concentration (EC50) of and show impaired fitness.26 The frequent use of
0·46 µg/mL and an EC90 of 1·06 µg/mL.6 In human corticosteroids in our patient group might have promoted
nasal and bronchial airway epithelial cells, a fixed 20 µM viral replication, as observed in SARS27 and MERS,28
(12·1 µg/mL) concentration reduced estimated intra although these studies only reported prolongation of the
cellular viral titres over 7·0 log10 50% tissue culture detection of viral RNA, not infectious virus. Furthermore,
infective dose per mL at 48 h.18 In human airway we have no answer to whether longer treatment course
epithelial cells, the EC50 for remdesivir was 0·042 µg/mL and higher dose of remdesivir would be beneficial in
for SARS-CoV and 0·045 µg/mL for MERS-CoV.13 In a patients with severe COVID-19.
murine model of MERS, subcutaneous remdesivir In summary, we found that this dose regimen of
showed significant antiviral and clinical effects with a intravenous remdesivir was adequately tolerated but did
dose regimen that maintained plasma concentrations not provide significant clinical or antiviral effects in
greater than 1 µM (0·60 µg/mL) throughout the dosing seriously ill patients with COVID-19. However, we could
interval.13 In rhesus macaques, a 5 mg/kg dose, reported not exclude clinically meaningful differences and saw
to be roughly equivalent to 100-mg daily dosing in numerical reductions in some clinical parameters.
humans, was effective for treatment of MERS-CoV Ongoing studies with larger sample sizes will continue to
infection and reduced pulmonary virus replication inform our understanding of the effect of remdesivir on
when started at 12 h after infection.18 Healthy adult COVID-19. Furthermore, strategies to enhance the
volunteers receiving doses similar to our trial (200 mg antiviral potency of remdesivir (eg, higher-dose regimens,
on day 1, 100 mg on days 2–4) had mean peak plasma combination with other antivirals, or SARS-CoV-2 neu
concentrations of 5·4 µg/mL (percentage coefficient of tralising antibodies) and to mitigate immunopathological
variation 20·3) on day 1 and 2·6 µg/mL (12·7) on day 5.24 host responses contributing to COVID-19 severity (eg,
Doses of 150 mg/day for 14 days have been adequately inhibitors of IL-6, IL-1, or TNFα) require rigorous study
tolerated in healthy adults, and a daily dose regimen of in patients with severe COVID-19.
150 mg for 3 days followed by 225 mg for 11 days Contributors
appeared to be generally well tolerated in one patient BC, CW, and YeW had full access to all of the data in the study and
with Ebola meningoencephalitis.25 However, the phar take responsibility for the integrity of the data and the accuracy of
the data analysis. CW and BC decided to publish the paper. BC, CW,
macokinetics of remdesivir in severely ill patients, and YeW, PWH, TJ, and FGH provided input on the trial design. BC, CW,
particularly the concentrations of the active nucleotide YeW, FGH, and PWH were responsible for acquisition, analysis,
metabolite (GS-441524) triphosphate in respiratory and interpretation of data. YeW, FGH, PWH, and GF drafted the
tract cells of treated patients, are unknown. Studies of manuscript. BC, CW, PWH, FGH, GF, TJ, and XG critically revised
the manuscript. YeW contributed to statistical analysis. GF gave
higher-dose regimens for which there are safety data valuable suggestions for data analysis. All authors contributed to
(eg, 150–200 mg daily doses) warrant consideration in conducting the trial.
severe COVID-19. Our study found that remdesivir Declaration of interests
was adequately tolerated and no new safety concerns FGH has served as non-compensated consultant to Gilead Sciences on
were identified. The overall proportion of patients with its respiratory antiviral programme, outside the submitted work.
serious adverse events tended to be lower in remdesivir All other authors declare no competing interests.
Data sharing 9 Chen C, Huang J, Cheng Z, et al. Favipiravir versus arbidol for
After approval from the Human Genetic Resources Administration of COVID-19: a randomized clinical trial. medRxiv 2020; published
China, this trial data can be shared with qualifying researchers who online April 15. DOI:10.1101/2020.03.17.20037432 (preprint).
submit a proposal with a valuable research question. A contract should 10 Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients
be signed. with COVID-19 with convalescent plasma. JAMA 2020; published
online March 27. DOI:10.1001/jama.2020.4783.
Acknowledgments 11 Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults
We thank Gilead Sciences for providing the study drugs and Huyen Cao hospitalized with severe Covid-19. N Engl J Med 2020; published
and Anu Osinusi for advice regarding safe use of remdesivir. We thank online March 18. DOI:10.1056/NEJMoa2001282.
Joe Yao and Ella Lin for statistical consultation. We also thank members of 12 Lo MK, Jordan R, Arvey A, et al. GS-5734 and its parent nucleoside
the international data safety monitoring board (Jieming Qu [chair], analog inhibit filo-, pneumo-, and paramyxoviruses. Sci Rep 2017;
Weichung Joe Shih, Robert Fowler, Rory Collins, and Chen Yao), 7: 43395.
independent statisticians (Xiaoyan Yan and Bin Shan), academic 13 Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral
secretaries (Lingling Gao and Junkai Lai), and eDMC system providers GS-5734 inhibits both epidemic and zoonotic coronaviruses.
(Tai Xie, Rong Ran, Peng Zhang, and Emily Wang) for their services. Sci Transl Med 2017; 9: eaal3653.
Roche Diagnostics (Shanghai) provided instruments and SARS-CoV-2 14 Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small
assay detection; SMO assistance was provided by Shanghai MedKey molecule GS-5734 against Ebola virus in rhesus monkeys. Nature
Med-Tech Development, Clinplus, Hangzhou SIMO, and MEDPISON. 2016; 531: 381–85.
This work was supported by the Chinese Academy of Medical Sciences 15 Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral
Emergency Project of COVID-19 (2020HY320001); Major Projects of remdesivir inhibits human endemic and zoonotic deltacoronaviruses
National Science and Technology on New Drug Creation and with a highly divergent RNA dependent RNA polymerase.
Development (2020ZX09201012); the National Key Research and Antiviral Res 2019; 169: 104541.
Development Program of China (2018YFC1200102); and the Beijing 16 Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic
Science and Technology Project (Z19110700660000). This work was also efficacy of remdesivir and combination lopinavir, ritonavir,
and interferon beta against MERS-CoV. Nat Commun 2020; 11: 222.
supported by the China Evergrande Group, Jack Ma Foundation, Sino
Biopharmaceutical Limited, Ping An Insurance (Group), and New 17 de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic
remdesivir (GS-5734) treatment in the rhesus macaque model of
Sunshine Charity Foundation. TJ is funded by a National Institutes of
MERS-CoV infection. Proc Natl Acad Sci USA 2020; 117: 6771–76.
Health Research (NIHR) Senior Research Fellowship (2015-08-001). PH is
18 Pizzorno A, Padey B, Julien T, et al. Characterization and treatment of
funded by the Wellcome Trust and the UK Department for International
SARS-CoV-2 in nasal and bronchial human airway epithelia. bioRxiv
Development [215091/Z/18/Z], the Bill & Melinda Gates Foundation 2020; published online April 2. DOI:10.1101/2020.03.31.017889
[OPP1209135], and NIHR [200907]. (preprint).
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