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MedRxiv (October 15) version
Repurposed antiviral drugs for COVID-19
–interim WHO SOLIDARITY trial results
WHO Solidarity trial consortium*
*A complete list of SOLIDARITY Trial investigators is
provided in the Supplementary Appendix.
Hongchao Pan, Ph.D., Richard Peto, F.R.S., Quarraisha Abdool Karim, Ph.D., Marissa Alejandria M.D., M.Sc., Ana Maria HenaoRestrepo, M.D., M.Sc., César Hernández García M.D., Ph.D., Marie-Paule Kieny Ph.D., Reza Malekzadeh M.D., Srinivas Murthy
M.D. C.M., Marie-Pierre Preziosi M.D., Ph.D., Srinath Reddy M.D., D.M., Mirta Roses Periago M. D., Vasee Sathiyamoorthy
B.M.B.Ch., Ph.D., John-Arne Røttingen M.D., Ph.D., and Soumya Swaminathan M.D. , as the members of the Writing Committee,
assume responsibility for the content and integrity of this article.
International Steering Committee *National PI; ‚NaWional CoordinaWor; ÁE[ecXWiYe GroXp;§Discovery add-on study.
Albania: University Hospital Centre, Tirana N Como*; National Agency for Medicines and Medical Devices N Sinani†. Argentina:
Fundación del Centro de Estudios Infectológicos G Lopardo*; National Academy of Sciences of Buenos Aires M Roses Periago†Á.
Austria:§. Belgium:§. Brazil: Oswaldo Cruz Foundation EP Nunes*, PPS Reges†. Canada: University of British Columbia S
Murthy*Á; Public Health Agency of Canada M Salvadori†. Colombia: National University of Colombia CA Alvarez- Moreno*;
Ministry of Health ML Mesa Rubio†. Egypt: National Hepatology and Tropical Medicine Research Institute M Hassany*; Ministry of
Health and population H Zaid†. Finland: Helsinki University Hospital and South Karelian Central Hospital, Lappeenranta KAO
Tikkinen*; Finnish Institute for Health and Welfare and University of Finland, Helsinki M Perola†. France: Hospices Civils de Lyon,
Lyon F Ader*§; Institut National de la Santé Et de la Recherche Médicale, Paris MP Kieny†Á§. Honduras: National Autonomous
University of Honduras MT Medina*; Secretaria de Salud de Honduras N Cerrato†. India: ICMR National AIDS Research Institute,
Pune S Godbole*†; Public Health Foundation of India KS ReddyÁ. Indonesia: National Institute of Health Research and
Development I Irmansyah*; RSUP Persahabatan, Jakarta MR Rasmin†. Iran (Islamic Republic of): Digestive Disease Research
Institute, Teheran University of Medical Sciences, Tehran R Malekzadeh*†Á. Ireland: HRB Clinical Research Facility, University
College, Cork J Eustace*; Department of Health T Maguire†. Italy: University of Verona E Tacconelli*; Italian Medicines Agency N
Magrini†. Kuwait: Infectious Diseases Hospital A Alhasawi*; Ministry of Health A Al-Bader†. Lebanon: Rafic Hariri University
Hospital P Abi Hanna*; Ministry of Public Health R Hamra†. Luxembourg:§. Lithuania: University Hospital Santaros klinikos,
Vilnius L Jancoriene*, L Griskevicius†. Malaysia: Penang Hospital TS Chow*; Hospital Sungai Buloh, Jalan Hospital S Kumar†.
North Macedonia: University Clinic of Infectious Diseases and Febrile Conditions M Stevanovikj*; Ministry of Health S
Manevska†. Norway: Oslo University Hospital P Aukrust*, A Barratt-Due†; Research Council of Norway JA RøttingenÁ. Pakistan:
Shaukat Khanum Memorial Cancer Hospital and Research Centre M Hassan*†. Peru: Universidad Peruana Cayetano Heredia PJ
García*, E Gotuzzo†. Philippines: National Institutes of Health, University of the Philippines, Manila MM Alejandria*†Á. Saudi
Arabia: Ministry for Preventive Health AO Athari Alotaibi*, A Asiri†. South Africa: University of the Witwatersrand J Nel*; Wits
Reproductive Health and HIV Institute H Rees†; Centre for the AIDS Programme of Research In South Africa Q Abdool KarimÁ.
Spain: Hospital Clinico San Carlos, UCM, IdISSC, Madrid A Portoles*; Agency of Medicine and Medical Devices C HernándezGarcia†Á. Switzerland: Lausanne University Hospital O Manuel*†.
Writing committee affiliations: Nuffield Department of Population Health, University of Oxford, Oxford (H.P. and R.P.); Centre for
the AIDS Programme of Research In South Africa (CAPRISA), Durban, South Africa (Q.A.K.); National Institutes of Health, Manila,
University of the Philippines, Manila (M.M.A.); Agency of Medicine and Medical Devices, Madrid, Spain (C.H.G); Institut National
de la Santé Et de la Recherche Médicale (INSERM), Paris, France (M.P.K.); Ministry of Health and Medical Education, Tehran, Iran
(R.M.); University of British Columbia, Vancouver, Canada (S.M); Public Health Foundation of India, New Delhi, India (K.S.R.);
National Academy of Sciences of Buenos Aires, Buenos Aires, Argentina (M.R.P.); Research Council of Norway, Oslo, Norway (JA.R.); World Health Organization, Geneva, Switzerland (A-M.H-R., M-P.P., V.S.M., S.S.).
Address correspondence and reprint requests to WHO R&D Blueprint at 20 Avenue Appia, 1211 Geneva,
Switzerland or rdblueprint@who.int
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ABSTRACT
BACKGROUND
WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral
drugs.
METHODS
Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and
Interferon-ȕ1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were
randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4
active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4
pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without
that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are
stratified for age and ventilation at entry.
RESULTS
In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954
Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study
drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at
median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization,
10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were:
Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19
(0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and
Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in
unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation
duration.
CONCLUSIONS
These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect
on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital
stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are
consistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151,
NCT04315948)
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INTRODUCTION
A WHO COVID-19 research forum in February 2020 recommended evaluation of treatments in large
randomized trials,1 and other WHO expert groups identified 4 re-purposed anti-viral drugs that might have at
least a moderate effect on mortality: Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon-ȕ1a.2 In
March 2020, WHO began a large, simple, multi-country, open-label randomized trial among hospital inpatients
of the effects of these 4 drugs on in-hospital mortality. The trial was adaptive; unpromising drugs could be
dropped and others added. Hydroxychloroquine and Lopinavir were eventually dropped, but others, such as
monoclonal antibodies, will be added. We report interim mortality results for the original 4 drugs.
METHODS
The protocol3 was designed to involve hundreds of potentially over-stressed hospitals in dozens of countries.
Hence, no form-filling was required, and trial procedures were minimal but rigorous. Online randomization of
consented patients (via a cloud-based GCP-compliant clinical data management system) took just a few
minutes, as did online reporting of death in hospital or discharge alive (plus brief details of respiratory support
in hospital and use of study drugs and certain non-study drugs). No other reporting was required unless doctors
suspected an unexpected serious adverse reaction (SUSAR). National and global monitors resolved queries and
checked progress and data completeness. Eligible patients were age ≥18 years, hospitalized with a diagnosis of
COVID-19, not known to have received any study drug, without anticipated transfer elsewhere within 72 hours,
and, in the physician¶s view, with no contra-indication to any study drug. Participants were randomized in equal
proportions between control and whichever other study drugs were locally available (up to 5 options: these
drugs, and local standard-of-care). Placebos were not used. Study drugs were Remdesivir, Hydroxychloroquine,
Lopinavir-Ritonavir and Interferon (given with Lopinavir, until July 4). Hydroxychloroquine and Lopinavir
were discontinued for futility on June 18 and July 4, 2020, respectively; Interferon is ceasing on October 16.
Daily doses were those already used for other diseases, but to maximize any efficacy without undue cardiac risk
Hydroxychloroquine dosage was based on that for amoebic liver abscess, rather than the lower dosage for
malaria.4 (Hydroxychloroquine slightly prolongs QT, and unduly high or rapid dosage might cause arrhythmias
or hypotension.) All treatments were stopped at discharge; otherwise, regimens were:
Remdesivir (intravenous): Day 0, 200mg; days 1-9, 100mg.
Hydroxychloroquine (oral): Hour 0, four tablets; Hour 6, four tablets; Hour 12, begin two tablets twice daily
for 10 days. Each tablet contained 200mg Hydroxychloroquine sulphate (155mg base/tablet; a little-used
alternative involved 155mg chloroquine base/tablet).
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Lopinavir (oral): Two tablets twice daily for 14 days. Each tablet contained 200mg Lopinavir (plus 50mg
Ritonavir, to slow hepatic clearance of Lopinavir). Other formulations were not provided, so ventilated patients
received no study Lopinavir while unable to swallow.
Interferon (mainly subcutaneous): Three doses over six days of 44µg subcutaneous Interferon-ß1a; where
intravenous interferon was available, patients on high-flow oxygen, ventilators or ECMO were instead to be
given 10µg intravenously once daily for six days.
ENDPOINTS
The protocol-specified primary objective was to assess effects on in-hospital mortality (ie, mortality during the
original episode of hospitalization; follow-up ceased at discharge) not only in all patients but also in those with
moderate COVID and in those with severe COVID (subsequently defined as ventilated when randomized).
The protocol-specified secondary outcomes were initiation of ventilation and hospitalization duration. Although
no placebos were used, appropriate analyses of these non-fatal outcomes can still be reliably informative. The
CATCO add-on study in Canada and the Discovery add-on study in Europe (mostly France) recorded additional
outcomes that will be reported elsewhere.
SAMPLE SIZE
The protocol stated ³The larger the number entered the more accurate the results will be, but numbers entered
will depend on how the epidemic develops… it may be possible to enter several thousand hospitalised patients
with relatively mild disease and a few thousand with severe disease, but realistic, appropriate sample sizes could
not be estimated at the start of the trial.´ The Executive Group, blind to any findings, decided the timing of
release of interim results.
STATISTICAL ANALYSES
The four main sets of analyses involve the evenly randomized pairwise comparisons of each study drug vs its
controls. The controls for those randomly allocated one particular drug were those patients who could by chance
have been randomly allocated that drug (at that moment, in that hospital), but instead got allocated standard of
care. If, for a particular study entrant, more than one study drug was available, allocation to standard of care
would put that patient into the control group for each of them. Hence, there is partial overlap between the four
control groups. Each comparison between a study drug and its controls, however, is evenly randomized (50/50)
and unbiased, as both groups are affected equally by any differences between countries or hospitals and by any
time trends in patient characteristics or standard of care.
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All analyses relate mortality to allocated treatment (ie, they are intent-to-treat analyses). The overall mortality
analyses were of all randomised patients (drug vs its control), and the only protocol-specified subgroup analyses
are those considering separately patients with moderate and with severe COVID (ie, already ventilated; the type
of ventilation was not recorded at study entry.)
Unstratified Kaplan-Meier methods plot 28-day risk. Death rate ratios (RRs) and p-values are from log-rank
analyses, stratified for 3×2=6 strata of age and ventilation at entry. If the stratified log-rank Observed minus
Expected number of deaths is O-E with variance V, logeRR is calculated as (O-E)/V with variance 1/V and a
Normal distribution.8 The few currently uncertain death times were taken as day 7. Analyses censored patients
with outcome not yet reported at day 0, and censored the few inter-hospital transfers at transfer. They did not
censor patients discharged alive, as analyses were of mortality during the initial hospitalisation. Forest plots
(with 95% CIs only for overall results, otherwise 99% CIs) and chi-squared statistics (sum of [O-E]2/V, with no
p-value given) help interpret any apparent heterogeneity of treatment RRs between subgroups. Analyses used
SASv9.4 and Rv4.02.
The Discussion includes meta-analyses of the major trial results, based on the inverse-variance-weighted
average of b=logeRR from each stratum of each trial, using odds ratios where hazard or death rate ratios were
unavailable. (This weighted average is derived from the sums of [O-E] and of V over strata.8) In general, the
more deaths in a stratum the larger V is and, correspondingly, the smaller is the variance of logeRR, so the more
weight that stratum gets. The variance attributed to the result in each stratum and to the overall weighted
average reflects only the play of chance at randomization. Homogeneity of different RRs is not needed for this
weighted average to be informative.
OVERSIGHT AND FUNDING
The trial is registered (ISRCTN83971151, NCT04315948), with protocol approved by local and WHO ethics
committees. Study conduct accorded with Helsinki Declaration and Good Clinical Practice principles, and
national trial regulations. Consent forms were signed and retained by patients, but noted for records. Consent
was generally prospective but could (where locally approved) be retrospective. The only exclusions were
patients without clear consent to follow-up. All other randomized patients were included (³intent-to-treat
analyses´). WHO is global co-sponsor and governments national co-sponsors, with trial governance by the
International Steering Committee¶s Executive Group (EG). External statistical analyses for the independent
Data and Safety Monitoring Committee (DSMC) were unseen by the EG or WHO, with two exceptions. After
outside evidence of Hydroxychloroquine and Lopinavir futility, the EG requested unblinded analyses of them.
Second, after deciding blindly to report all interim results, the EG revised this manuscript, drafted by the WHO
trial team and external statisticians.
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Participating countries covered almost all local costs and WHO covered all other study costs, receiving no extra
funding. Collaborators, committee members, data analysts and data management systems charged no costs, and
drugs were donated. No donor unduly (see end-material) influenced analyses, manuscript preparation, or
submission. The Writing Group vouch for protocol fidelity and data accuracy and completeness.
RESULTS
From March 22 to October 4, 2020, 11,330 patients were entered from 405 hospitals in 30 countries in all 6
WHO regions. Of these, 64 (0.6%) had no, or uncertain, consent to follow-up, leaving 11,266 for intent-to-treat
analyses: 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 only Lopinavir-ritonavir, 2063 Interferon,
and 4088 no study drug (Figure 1; reporting is 97% complete for those entered >1 month earlier, and 99.7%
complete for those entered >3 months earlier). All 3 patients with COVID refuted are included, and survived.
Table 1 shows patient characteristics: 9120 (81%) age <70 years, 6985 (62%) male, 2768 (25%) with diabetes,
916 (8%) already ventilated, and 7002 (62%) randomized on days 0-1. For each drug, patient characteristics
were well balanced by the unstratified 50/50 randomization between it and its controls. Deaths were at median
day 8 (IQR 4-14) and discharges at median day 8 (IQR 5-13). With 1253 deaths, the Kaplan-Meier estimate of
28-day mortality was 11.8%. This risk depended on several factors, particularly age (20% if ≥70 years, 6% if
<50 years) and ventilation (39% if ventilated, otherwise 10%).
Table 1 also describes compliance. For Remdesivir the scheduled treatment period was 10 days (or to prior
death or discharge). Of those allocated Remdesivir, 98.5% began treatment. Midway through this period 96%
were still taking it (as against only 2% of the Remdesivir controls). Likewise, for other drugs compliance
midway was high (94-95%) and crossover low (2-6%). Study treatments ceased on schedule. Absolute
treatment vs control differences in use of corticosteroids and other non-study treatments were small (Table S2).
For each pairwise drug comparison, Figure 2 gives unstratified Kaplan-Meier analyses of 28-day in-hospital
mortality (listing below the x-axis numbers at risk and dying in each week, and numbers dying after day 28),
along with death rate ratios (RRs) stratified for age and ventilation. Figure 3 gives RRs in subgroups of age
stratified by ventilation and of ventilation stratified by age, and overall RRs stratified by both.
Taking Figures 2 and 3 together, no study drug had any definite effect on mortality, either overall (each p>0.10)
or in any subgroup defined by age or ventilation at entry (or other entry characteristics, or geographic region, or
corticosteroid use: Figures S6-S9). Death rate ratios (with 95% CIs, and drug vs control numbers of deaths thus
far reported) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 vs 303/2708), Hydroxychloroquine
RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs
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146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). Unstratified comparisons
yielded similarly null findings (Figure 2), as did analyses excluding corticosteroid users and multivariate
sensitivity analyses estimating simultaneously the effects of all 4 study drugs (Table S3).
If ventilation prevents oral administration of Lopinavir or other study drugs then this could reduce any effects
on mortality of allocation to those drugs, but the pre-planned analyses of mortality in patients not already
ventilated at entry also indicated no definite protective effect of any study drug (Figure 3).
The pre-planned study outcomes were death, ventilation and time to discharge. No study drug appreciably
reduced initiation of ventilation in those not already ventilated. The numbers, study drug vs control, with
ventilation initiated after randomization were: Remdesivir 295v284, Hydroxychloroquine 75v66, Lopinavir
124v119, Interferon 209v210 (Table S1).
In this open-label trial, patients who would be considered fit for discharge might be kept in somewhat longer
just because they were being given a study drug, but this difficulty can be circumvented. Each of the 3 study
treatments scheduled to last >7 days increased the percentages remaining in hospital at day 7. If one of these 3
drugs had accelerated recovery then the sizes of these increases should have differed, but they did not: the
increases were strikingly similar. The proportions still hospitalized at day 7, study drug vs control, were
Remdesivir 69%v59%, Hydroxychloroquine 64%v54%, Lopinavir 68%v59% (Table 1). The medically
informative result is the lack of any material difference between these 3 increases.
Supplementary analyses by treatment allocation (Tables S2-S3, Figures S2-S9) tabulate co-medication (finding
only small absolute differences), provide a multi-variable Cox regression fitting all 4 treatment effects
simultaneously (yielding mortality RRs like those in Figure 3), subdivide 28-day mortality graphs (like those in
Figure 2) by ventilation at entry, and give subgroup analyses of mortality RRs by many patient characteristics
and by corticosteroid use (identifying no noteworthy subgroup-specific or geographic variation).
All active treatment ended within ≤14 days, and the numbers of deaths during this 14-day period with any
cardiac cause mentioned on the electronic death record was Remdesivir 7v8, Hydroxychloroquine 4v2,
Lopinavir 6v3, and Interferon 6v8 (Figure S11). Although many COVID deaths involved multi-organ failure,
no study drug death was attributed to renal or hepatic disease.
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DISCUSSION
The main outcomes of mortality, initiation of ventilation and hospitalization duration were not clearly reduced
by any study drug. The mortality findings cannot have been appreciably biased by the open-label design without
placebos, or by variation in patient characteristics or local care. The effects on ventilation initiation are unlikely
to have been materially biased, and although allocation to 10 days of medication can delay discharge while
medication is being given, the striking similarity of this delay with 3 different daily medications is evidence that
none had a pharmacological effect that appreciably reduced time to recovery. Although ACTT-1, with placebo
control, reported Remdesivir moderately reduced time to recovery, in the present study there were no material
effects on ventilation initiation or time to discharge.
The chief aim was to help determine whether any of 4 re-purposed antivirals could at least moderately affect inhospital mortality, and whether any effects differed between moderate and severe disease. The results should be
considered in the context of all the evidence on mortality from properly randomized trials, but for Remdesivir
and for Interferon this study provides more than three-quarters of that evidence.
There are 4 trials of Remdesivir vs the same management without it: Solidarity (604 deaths in about 5000
randomized), ACTT-1 (136 deaths in about 1000) and two smaller trials (41 deaths).5-7 Figure 4 gives mortality
results from each trial, subdivided by initial respiratory support. (These like-vs-like comparisons allow for the
proportion already on high-flow oxygen or ventilation at entry into ACTT-1 having been, by chance, somewhat
lower with Remdesivir than with placebo.) Combining data appropriately from all 4 trials,8 the Remdesivir vs
control death rate ratio (RR) is 0.91 (95% CI 0.79-1.05).
Interpretation should chiefly reflect not the p-value (p=0.21) or point estimate (RR=0.91) but the confidence
interval (0.79-1.05), which shows the range of death rate ratios comfortably compatible with the weighted
average of the findings from all trials. This absolutely excludes the suggestion that Remdesivir can prevent a
substantial fraction of all deaths. The confidence interval is comfortably compatible with prevention of a small
fraction of all deaths, but is also comfortably compatible with prevention of no deaths (which would be
consistent with the apparent lack of any reduction by Remdesivir in the initiation of ventilation or the duration
of hospitalization in Solidarity).
The statistical uncertainties are much greater if attention is restricted to particular subgroups or time periods.9 If
Remdesivir has no effect on mortality then chance could still produce somewhat favourable findings in a
subgroup of the results for all trials, with more striking findings in a selected subgroup of a particular trial (as in
the one subgroup of ACTT-1 where the death rate ratio appeared to be 0.30: Figure 4). Although both ACTT-1
and Solidarity envisaged the possibility of different degrees of benefit in lower- and higher-risk patients, the
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particular lower-risk/higher-risk subdivision of the ACTT-1 findings in Figure 4 was unplanned. (The ACTT-1
protocol specified separate analyses of those not requiring any oxygen, with only 3/75 vs 3/63 deaths in ACTT-
1, 11/661 vs 13/664 in Solidarity, and 5/384 vs 4/200 in SIMPLE; overall RR=0.82, but with wide confidence
interval 0.43-1.55.) Thus, although the all-trials subtotals in Figure 4 suggest some benefit in low-risk patients
and some hazard in high-risk inpatients (with the absolute benefit in low-risk appearing somewhat smaller than
the absolute hazard in high-risk), neither subtotal should be considered in isolation from the other subtotal, or
from the CI for the total.
For Hydroxychloroquine and Lopinavir, Solidarity found no definite evidence of benefit or of hazard in any
subgroup. The only other substantial trial of these two drugs is Recovery,10,11 which for these drugs is larger
than Solidarity. Combination of log-rank analyses from these two relatively large trials (by the meta-analysis
methods used in Figure 4) consolidate the findings of both.
For Hydroxychloroquine, the joint mortality RR (combining 2 trials) was 1.11, 95% CI 0.99-1.24, with no
apparent benefit whether ventilated or not. This CI excludes any material benefit from this Hydroxychloroquine
regimen in hospitalized COVID. It is compatible with some hazard, but does not demonstrate hazard. Despite
concerns that the loading dose could be temporarily cardiotoxic, in neither trial was there any excess mortality
during the first few days, when blood levels were highest. Neither trial recorded dosage/kg, obesity, or cardiac
parameters, and cardiac deaths were too few to be reliably informative. A recent meta-analysis identified 27
small randomized Hydroxychloroquine trials (total 167 deaths, RR=1.00, 0.71-1.42);12 combining all 29 trials,
RR=1.10, 0.99-1.22, again excluding any material benefit.
For Lopinavir (always co-administered with Ritonavir), the joint mortality RR (combining Solidarity, Recovery
and the only informative smaller trial13) was 1.02, 95% CI 0.91-1.14. Although Lopinavir tablets could not be
swallowed by ventilated patients, there was no apparent benefit in analyses restricted to those not already being
ventilated at entry. This CI indicates no material effect on mortality, and excludes a 10% proportional reduction.
An add-on study within Solidarity, Discovery, recorded many clinical parameters, identifying an unexpected
increase in creatinine (perhaps because blood levels are higher than in similarly-dosed HIV patients14,15), but
Solidarity and Recovery recorded no renal or hepatic deaths with Lopinavir.
For Interferon-ȕ1a no large mortality trials have been reported. Based on about 4000 patients, the mortality RR
in Solidarity was 1.16, 0.96-1.39; p=0.11 (or 1.12, 0.83-1.51, without Lopinavir co-administration: Figure S9).
This does not demonstrate hazard, but the lower confidence limit does exclude a moderate mortality reduction
in these circumstances. About half the interferon-allocated patients (and half their controls) received
corticosteroids,16 but the interferon vs control mortality RR seemed unaffected by corticosteroids. Most
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interferon was subcutaneous, and subcutaneous and intravenous interferon have different pharmacokinetics,17
but the clinical relevance of this is unclear. Randomization to Interferon is ceasing in Solidarity on October 16,
but other evidence will emerge: a report that nebulized Interferon-ȕ1a might be highly effective involved only
about 100 COVID patients (NCT04385095), but the ongoing placebo-controlled ACTT-3 trial of subcutaneous
Interferon-ȕ1a aims to involve 1000 (NCT04492475).
For each of these 4 repurposed non-specific antivirals, several thousand patients have now been randomized in
various trials. The unpromising overall findings from the regimens tested suffice to refute early hopes, based on
smaller or non-randomized studies, that any will substantially reduce inpatient mortality, initiation of ventilation
or hospitalisation duration. Narrower confidence intervals would be helpful (particularly for Remdesivir), but
the main need is for better treatments. Solidarity is still recruiting about 2000 patients per month, and efficient
factorial designs will allow it to assess further treatments, such as immune-modulators and specific anti-SARSCov-2 monoclonal antibodies.
The chief acknowledgement is to the thousands of patients and their families who participated in this trial, and the
hundreds of medical staff who randomized and cared for the patients. The Ministries of Health of the participating
Member States and their national institutions provided critical implementation support. The views expressed are those of
the Writing Group, not necessarily those of WHO. NJ White et al4 provided unpublished Hydroxychloroquine
pharmacokinetic data, the Recovery trial10,11 shared log-rank statistics, the ACTT-1 trial5 shared subgroup hazard ratios,
and Bin Cao shared Wuhan trial6 details.
MS preparation, revision and submission was controlled by the WHO trial team and the writing committee. There were no
funders for the main Solidarity trial, but the Discovery add-on study received EU Horizon 2020 research and innovation
program grant 101015736. Participating countries covered almost all local costs and WHO covered all other study costs,
receiving no extra funding. Collaborators, committee members, data analysts and data management systems charged no
costs, and drugs were donated. Castor EDC donated and managed their cloud-based clinical data capture and management
system, blind to study findings. Anonymized data handling and analysis was by the Universities of Berne, Bristol and
Oxford. Remdesivir was donated by Gilead Sciences, Hydroxychloroquine by Mylan, Lopinavir by Abbvie, Cipla and
Mylan, and Interferon ȕ1a by Merck KGaA (subcutaneous) and Faron (intravenous).
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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11
REFERENCES
1. World Health Organization, R&D Blueprint. A coordinated global research roadmap: 2019 novel
coronavirus. Geneva, Switzerland March 2020 https://www.who.int/docs/defaultsource/coronaviruse/coordinated-global-research-roadmap.pdf?sfvrsn=21b0f5c4_1&download=true
(accessed October 3, 2020).
2. World Health Organization, R&D Blueprint. Informal consultation on prioritization of candidate
therapeutic agents for use in novel coronavirus 2019 infection
https://www.who.int/teams/blueprint/covid-19 (accessed October 3, 2020).
3. World Health Organization, R&D Blueprint. An international randomised trial of additional treatments
for COVID-19 in hospitalised patients who are all receiving the local standard of care
https://www.who.int/publications/m/item/an-international-randomised-trial-of-additional-treatments-forcovid-19-in-hospitalised-patients-who-are-all-receiving-the-local-standard-of-care (accessed October 3,
2020).
4. White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J. COVID-19 prevention and
treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med
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report. N Engl J Med 2020 doi:10.1056/NEJMc2022236.
6. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, doubleblind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-78. https://doi.org/10.1016/S0140-
6736(20)31022-9.
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11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA.
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medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint
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9. Peto R. Current misconceptions: that subgroup-specific trial mortality results often provide a good basis
for individualising patient care. British Journal of Cancer (2011) 104, 1057-58 doi:10.1038/bjc.2011.79.
10. RECOVERY collaborative group. Effect of hydroxychloroquine in hospitalized patients with COVID-
19. N Engl J Med DOI: 10.1056/NEJMoa2022926 (online October 8, 2020).
11. RECOVERY Collaborative Group. Lopinavir–ritonavir in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial. Lancet DOI:
https://doi.org/10.1016/S0140-6736(20)32013-4 (Online October 5, 2020).
12. Axfors C, Schmitt AM, Janiaud P, et al. Mortality outcomes with hydroxychloroquine and chloroquine
in COVID-19: an international collaborative meta-analysis of randomized trials. medRxiv preprint,
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19. N Engl J Med 2020;382:1787-99. doi:10.1056/NEJMoa2001282.
14. Venisse N, Peytavin G, Bouchet S et al. Concerns about pharmacokinetic (PK) and pharmacokineticpharmacodynamic (PK-PD) studies in the new therapeutic area of COVID-19 infection.
https://doi.org/10.1016/j.antiviral.2020.104866 Antiviral Res 181 (2020) 104866.
15. Gregoire N, Le Turnier P, Gaborit BJ ey al. Lopinavir pharmacokinetics in COVID-19 patients. J
Antimicrob Chemother doi:10.1093/jac/dkaa195.
16. Jalkanen J, Pettilä V, Huttunen T, et al. Glucocorticoids inhibit type I IFN beta signaling and the
upregulation of CD73 in human lung. Inten Care Med 2020 Oct;46(10):1937-40. doi: 10.1007/s00134-
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administration route. Crit Care 2020;24:Article 335. doi: 10.1186/s13054-020-03048-5.
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint
Table 1. Entry characteristics by random allocation, and compliance with that allocation
Excludes 64 without clear consent to follow-up. Comparisons are of each study drug vs concurrent allocation to the same treatment
without it. As the control groups overlap, the total number (11,266) is less than the sum of the numbers in the pairwise comparisons.
Notes: The few with a particular characteristic unknown are merged with the largest category of that characteristic.
³28-d KM %´ is the Kaplan-Meier 28-day % risk of in-hospital death. ³NR. died´ iQcOXdeV any in-hospital deaths after day 28.
* Interferon randomisation was interferon + Lopinavir vs Lopinavir until 4 July, then it was interferon vs standard of care.
** Albania, Austria, Belgium, Finland, France, Ireland, Italy, Lithuania, Luxembourg, Macedonia, Norway, Spain, Switzerland.
§ Argentina, Brazil, Colombia, Honduras, Peru.
‚ EgSW, IQdia, IQdRQeVia, IUaQ, KXZaiW, LebaQRQ, MaOaVia, PaNiVWaQ, PhiOiSSiQeV, SaXdi AUabia, SRXWh AfUica.
Á CRPSOiaQce iV caOcXOaWed RQO aPRQg WhRVe ZhR died RU ZeUe diVchaUged aOiYe, aQd iV defined as the % taking the study
drug midway through its scheduled duration (or midway through the time from entry to death or discharge, if this is shorter).
All in any intent
to-treat analysis
Remdesivir
vs its control
Hydroxychloroquine
vs its control
Lopinavir
vs its control
Interferon
vs its control*
Active Control Active Control Active Control Active Control
Entered
No. %
No.
died
28-d
KM%
All participants
Entry characteristics
Age (years)
<50
50-69
70+
Respiratory support
No oxygen at entry
On oxygen at entry
Already ventilated
Bilateral lung lesions
No
Yes
Not imaged at entry
Prior days in hospital

1
2+
Geographic location
Europe** or Canada
Latin America§
Asia aQd AfUica‚
Other characteristics
Male
Current smoking
History of ± Diabetes
– Heart disease
– Chronic lung disease
– Asthma
– Chronic liver disease
11266 100 1253 11.8
3995 35 237 6.2
5125 45 618 12.8
2146 19 398 20.4
3204 28 78 2.5
7146 63 844 12.8
916 8 331 39.0
1266 11 49 3.7
8832 78 1043 12.7
1168 10 161 14.9
3289 29 319 9.8
3713 33 384 10.8
4264 38 550 14.6
2488 22 188 7.8
1941 17 400 22.7
6837 61 665 10.3
6985 62 852 13.0
830 7 93 11.8
2768 25 379 14.7
2337 21 319 14.7
635 6 102 17.2
529 5 56 11.5
135 1 21 17.2
2743 2708 947 906 1399 1372 2050 2050
961 952 335 317 511 501 720 697
1282 1287 410 396 597 596 934 973
500 469 202 193 291 275 396 380
661 664 345 341 528 539 482 490
1828 1811 517 483 759 719 1429 1430
254 233 85 82 112 114 139 130
287 259 154 170 235 256 162 155
2175 2153 656 618 985 945 1723 1718
281 296 137 118 179 171 165 177
724 712 296 281 423 403 678 677
917 938 317 312 442 445 681 662
1102 1058 334 313 534 524 691 711
715 698 286 267 349 350 254 244
470 514 97 96 145 148 474 478
1558 1496 564 543 905 874 1322 1328
1706 1725 574 535 851 802 1303 1278
178 161 92 82 141 124 136 138
707 666 199 205 341 324 489 537
571 567 193 194 289 290 427 456
151 145 62 66 95 87 114 109
139 139 41 46 65 56 75 97
36 41 15 14 15 23 11 22
Compliance with allocated treatment
% who were taking the study drug midway
through its scheduled durationÁ
% of those reported as discharged
who were still in hospital on: Day 7
Day 14
Day 21
95.8 1.6 94.6 5.6 93.6 2.0 93.7 1.9
69 59 64 54 68 59 55 51
22 19 23 20 31 22 19 18
9 8 11 10 12 11 8 7
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Figure 1. WHO Solidarity Trial – information to October 4, 2020 on entry, follow-up (FU) and intent-to-treat (ITT) analyses
After asking which treatments were locally available, random allocation (with equal probability) was between local standard of care (SoC) and the available treatments. After
excluding 64/11,330 (0.6%) with no/uncertain consent to follow-up, 11,266 remain in the ITT analyses. Each pairwise ITT analysis is between a particular treatment and its
controls, ie, those who could have been allocated it but were concurrently allocated the same management without it. There is partial overlap between the 4 control groups.
2,750 active
Remdesivir
7 no/uncertain
17
954 active
Hydroxychloroquine
9
7 no/uncertain
3
1,411 active
Lopinavir
12
8
2,063 active
Interferon
651 IFN + Lopinavir
1,412 IFN + Local SoC
13
14
2,743 v 2,708 active v control in
Remdesivir ITT analyses
2260 v 2252 Died or left hospital
88 v 72 Entry < Sep; still an
inpatient in late Sep
67 v 76 Entry < Sep; not yet
reported on in late Sep
328 Y 308 EQWU • Sep; not
reported on in late Sep
consent to FU
2,725 control for
Remdesivir
no/uncertain
consent to FU
09 control for
Hydroxychloroquine
no/uncertain
consent to FU
1,380 control for
Lopinavir
2,064 control for
Interferon
679 Lopinavir
1,385 Local SoC
no/uncertain
consent to FU
947 v 906 active v control in
Hydroxychloroquine ITT analyses
932 v 891 Died or left hospital
12 v 13
Entry ” June 19; still an
inpatient in late Sep
3 v 2 Entry ” June 19; not
reported on by late Sep
(Entry ended 19 June)
consent to FU
1,399 v 1,372 active v control in
Lopinavir ITT analyses
1385 v 1349 Died or left hospital
11 v 16
Entry ” July 4; still an
inpatient in late Sep
3 v 7 Entry ” July 4; not
reported on by late Sep
(Entry ended 4 July)
no/uncertain
consent to FU
no/uncertain
consent to FU
2,050 v 2,050 active v control in
Interferon ITT analyses
1756 v 1819 Died or left hospital
65 v 56
Entry < Sep; still an
inpatient in late Sep
30 v 21
Entry < Sep; not yet
reported on in late Sep
199 v 154 EQWU • Sep [stop to be
Oct 15]; not reported on in late Sep
no/uncertain
consent to FU
Figure 2. Effects of (a) Remdesivir, (b) Hydroxychloroquine,
(c) Lopinavir, and (d) Interferon on 28-day mortality
Kaplan-Meier graphs of in-hospital mortality. The inset shows the same data on an expanded y-axis.
(c) Lopinavir vs its control

20
40
60
80
100
0 7 14 21 28
Rate ratio, 1.00 (95% CI, 0.79-
P=0.97 by log-rank test
0 7 14 21
5 0
10
15
Control
Lopinavir
1.25)
1399 1333 1282 1257 1243
1372 1293 1239 1216 1203
57 42 24 15 10
62 48 21 10 5
Numbers at risk at the start of each week, and numbers dying
Lopinavir
Control
Days since Randomization
Mortality (%)
28
(d) Interferon vs its control

20
40
60
80
100
0 7 14 21 28
Rate ratio, 1.16 (95% CI, 0.96-
P=0.11 by log-rank test
0 7 14 21
5 0
10
15
Control
Interferon
1.39)
2050 1669 1554 1483 1410
2050 1725 1636 1563 1498
101 73 31 24 14
91 58 31 21 15
Numbers at risk at the start of each week, and numbers dying
Interferon
Control
Days since Randomization
Mortality (%)
28
(a) Remdesivir vs its control

20
40
60
80
100
0 7 14 21 28
Rate ratio, 0.95 (95% CI, 0.81-
P=0.50 by log-rank test
0 7 14 21
5 0
10
15
Control
ivir
1.11)
2743 2159 2029 1918 1838
2708 2138 2004 1908 1833
129 90 48 18 16
126 93 43 27 14
Numbers at risk at the start of each week, and numbers dying
Remdesivir
Control
Days since Randomization
Mortality (%)
28
Remdes(b) Hydroxychloroquine vs its control

20
40
60
80
100
0 7 14 21 28
Rate ratio, 1.19 (95% CI, 0.89-1.59)
P=0.23 by log-rank test
947 889 854 838 833
906 853 823 814 809
48 31 13 6 6
42 27 8 4 3
Numbers at risk at the start of each week, and numbers dying
Hydroxyc .
Control
Days since Randomization
Mortality (%)
0 7 14 21 28
5 0
10
15
Control
Hydroxychloroquine
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Figure 3. Rate ratios of any death, stratified by age and respiratory support at entry,
(a) Remdesivir, (b) Hydroxychloroquine, (c) Lopinavir, (d) Interferon, each vs its control
Deaths reported / Patients randomized
in ITT analyses (28-day risk, K-M%)
Active Control
Active-group deaths:
log-rank statistics
O-E Variance
Ratio of death rates (RR), &
99% CI (or 95% CI, for total)
Active : Control
(a) Remdesivir
Age at entry
59/952 (6.8) 2.3 29.8
161/1287 (14.2) -7.6 77.5
83/469 (21.6) -2.9 41.5
71/233 (37.8) 7.6 40.8
232/2475 (10.6) -15.8 108.0
Total 301/2743 (12.5) 303/2708 (12.7) -8.3 148.8
Heterogeneity around total F3 2: 3.9
(b) Hydroxychloroquine
Age at entry
19/317 (5.8) 0.9 9.2
31/396 (7.1) 10.8 21.2
34/193 (17.8) -3.5 15.8
27/82 (32.3) 3.4 14.8
57/824 (6.6) 4.7 31.4
Total 104/947 (10.2) 84/906 (8.9) 8.1 46.2
Heterogeneity around total F3 2: 5.0
(c) Lopinavir
Age at entry
27/501 (4.9) -3.0 11.7
57/596 (9.1) 2.7 30.4
62/275 (22.7) 0.0 30.2
35/114 (28.7) 1.3 16.7
111/1258 (8.7) -1.6 55.6
Total 148/1399 (9.7) 146/1372 (10.3) -0.4 72.3
Heterogeneity around total F3 2: 1.2
(d) Interferon
Age at entry
35/697 (5.3) 7.5 20.6
108/973 (11.4) 13.3 56.9
73/380 (20.9) -4.0 35.8
40/130 (33.8) 7.7 23.0
176/1920 (9.5) 9.1 90.3
Total 243/2050 (12.9) 216/2050 (11.0) 16.8 113.3
Heterogeneity around total F3 2: 4.8
1.08 [0.67-1.73]
0.91 [0.68-1.21]
0.93 [0.63-1.39]
1.20 [0.80-1.80]
0.86 [0.67-1.11]
0.95 [0.81-1.11]
2p = 0.50
1.10 [0.47-2.57]
1.66 [0.95-2.91]
0.80 [0.42-1.53]
1.26 [0.65-2.46]
1.16 [0.73-1.84]
1.19 [0.89-1.59]
2p = 0.23
0.77 [0.36-1.64]
1.09 [0.68-1.74]
1.00 [0.63-1.60]
1.08 [0.57-2.03]
0.97 [0.69-1.37]
1.00 [0.79-1.25]
2p = 0.97
1.44 [0.82-2.54]
1.26 [0.90-1.78]
0.89 [0.58-1.38]
1.40 [0.82-2.40]
1.11 [0.84-1.45]
1.16 [0.96-1.39]
2p = 0.11
<50 61/961 (6.9) 50-69 154/1282 (13.8) 70+ 86/500 (20.5) Respiratory support at entry
Ventilated 98/254 (43.0) Not ventilated 203/2489 (9.4) <50 19/335 (5.7) 50-69 55/410 (12.1) 70+ 30/202 (14.0) Respiratory support at entry
Ventilated 35/85 (39.2) Not ventilated 69/862 (7.4) <50 20/511 (3.6) 50-69 66/597 (9.8) 70+ 62/291 (20.4) Respiratory support at entry
Ventilated 35/112 (28.1) Not ventilated 113/1287 (8.1) <50 48/720 (7.5) 50-69 122/934 (14.3) 70+ 73/396 (19.9) Respiratory support at entry
Ventilated 55/139 (42.4) Not ventilated 188/1911 (10.9) 0.0 0.5 1.0 1.5 2.0
Active
better
Active
worse
99% or 95% confidence interval (CI), K-M Kaplan-Meier.
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Figure 4. Remdesivir vs control – Meta-analysis of mortality in trials of random allocation
of hospitalised COVID-19 patients to Remdesivir or the same treatment without it
* Log-rank O-E for Solidarity, O-E from 2×2 tables for Wuhan and SIMPLE, and w.logeHR for
ACTT strata (with the weight w being the inverse of the variance of logeHR, which is got from
Whe HR¶V CI). RR iV gRW b WaNiQg ORgeRR to be (O-E)/V with Normal variance 1/V. Subtotals
or totals of (O-E) and of V yield inverse-variance-weighted averages of the logeRR values.
‚ FRU baOaQce, cRQWUROV iQ Whe 2:1 VWXdieV cRXQW WZice iQ Whe cRQWURO WRWaOV aQd VXbWRWaOV.
Deaths reported / Patients randomized
in ITT analyses (28-day risk, K-M%)
Remdesivir Control
Remdesivir deaths:
Observed-Expected
(O-E)* Var (O-E)
Ratio of death rates (RR), &
99% CI (or 95% CI, for total)
Remdesivir : Control
Trial name, and initial respiratory support
13/664 (2.1) -0.6 6.0
219/1811 (13.8) -16.9 101.8
71/233 (37.8) 7.6 40.8
3/63 (4.8) -0.3 1.5
25/203 (12.7) -8.0 6.7
ACTT: hi-flow O2 or
non-invasive ventilation
19/95 (21.2) 20/98 (20.4) 0.2 9.6
ACTT: invasive ventilation 28/131 (21.9) 29/154 (19.3) 1.7 14.3
Wuhan: low-flow O2 11/129 (8.5) (7/68) [2‚ (10.3) -0.8 3.7
Wuhan: hi-flow O2 or
ventilation
11/29 (37.9) (3/10) [2‚ (30.0) 0.6 1.8
SIMPLE: no O2 5/384 (1.3) (4/200) [2‚ (2.0) -0.9 2.0
Subtotals
Lower risk groups
(with no ventilation) -27.6 121.6
Higher risk groups 10.1 66.5
Total 387/3818 (10.1) 408/3782 (10.8) -17.5 188.2
0.90 [0.31-2.58]
0.85 [0.66-1.09]
1.20 [0.80-1.80]
0.82 [0.10-6.61]
0.30 [0.11-0.81]
1.02 [0.44-2.34]
1.13 [0.57-2.23]
0.81 [0.21-3.07]
1.40 [0.20-9.52]
0.64 [0.10-3.94]
0.80 [0.63-1.01]
1.16 [0.85-1.60]
0.91 [0.79-1.05]
2p = 0.20
Solidarity: no O2 11/661 (2.0) Solidarity: low/hi-flow O2 192/1828 (12.2) Solidarity ventilation 98/254 (43.0) ACTT: no O2 3/75 (4.1) ACTT: low-flow O2 9/232 (4.0) 231/3309 (7.0) 282/3277 (8.6) 156/509 (30.6) 126/505 (25.0) 0.0 0.5 1.0 1.5 2.0 2.5 3.0
Remdesivir
better
Remdesivir
worse
/ 99% or 95% confidence interval (CI), K-M Kaplan-Meier.
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