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WHO Solidarity Trial Consortium; Pan H; Peto R; Henao-Restrepo AM; Preziosi MP; Sathiyamoorthy V; Abdool Karim Q; Alejandria MM; Hernandez Garcia C; Kieny MP; Malekzadeh R; Murthy S; Reddy KS; Roses ...Repurposed antiviral drugs for covid-19 - interim WHO solidarity trial results. (2020). The New England Journal of Medicine.
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WHO Solidarity Trial Consortium
Pan, Hongchao
Peto, Richard
Henao-Restrepo, Ana-Maria
Preziosi, Marie-Pierre
Sathiyamoorthy, Vasee
Karim, Quarraisha Abdool
Alejandria, Marissa M.
Hernández García, César
Kieny, Marie-Paul
Malekzadeh, Reza
Murthy, Srinivas
Reddy, K. Srinath
Periago, Mirta Roses
Hanna, Pierre Abi
Ader, Florence
Al-Bader, Abdullah M.
Alhasawi, Almonther
Allum, Emma
Alotaibi, Athari
Alvarez-Moreno, Carlos A.
Appadoo, Sheila
Asiri, Abdullah
Aukrust, Pål
Barratt-Due, Andreas
Bellani, Samir
Branca, Mattia
Cappel-Porter, Heike B. C.
Cerrato, Nery
Chow, Ting S.
Como, Najada
Eustace, Joe
García, Patricia J.
Godbole, Sheela
Gotuzzo, Eduardo
Griskevicius, Laimonas
Hamra, Rasha
Hassan, Mariam
Hassany, Mohamed
Hutton, David
Irmansyah, Irmansyah
Jancoriene, Ligita
Kirwan, Jana
Kumar, Suresh
Lennon, Peter
Lopardo, Gustavo
Lydon, Patrick
Magrini, Nicola
Maguire, Teresa
Manevska, Suzana
Manuel, Oriol
McGinty, Sibylle
Medina, Marco T.
Mesa Rubio, María L.
Miranda-Montoya, Maria C.
Nel, Jeremy
Nunes, Estevao P.
Perola, Markus
Portolés, Antonio
Rasmin, Menaldi R.
Raza, Aun
Rees, Helen
Reges, Paula P. S.
Rogers, Chris A.
Salami, Kolawole
Salvadori, Marina I.
Sinani, Narvina
Sterne, Jonathan A. C.
Stevanovikj, Milena
Tacconelli, Evelina
Tikkinen, Kari A. O.
Trelle, Sven
Zaid, Hala
Røttingen, John-Arne
Swaminathan, Soumya
BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)
The new england journal of medicinen engl j med 384;6 nejm.org February 11, 2021 497established in 1812 February 11, 2021 vol. 384 no. 6The members of the writing and steering committees (H. Pan, R. Peto, A.-M. Henao-Restrepo, M.-P. Preziosi, V. Sathi-yamoorthy, Q. Abdool Karim, M.M. Ale-jandria, C. Hernández García, M.-P. Kie-ny, R. Malekzadeh, S. Murthy, K.S. Reddy, M. Roses Periago, P. Abi Hanna, F. Ader, A.M. Al-Bader, A. Alhasawi, E. Al-lum, A. Alotaibi, C.A. Alvarez-Moreno, S. Appadoo, A. Asiri, P. Aukrust, A. Bar-ratt-Due, S. Bellani, M. Branca, H.B.C. Cappel-Porter, N. Cerrato, T.S. Chow, N. Como, J. Eustace, P.J. García, S. Godbole, E. Gotuzzo, L. Griskevicius, R. Hamra, M. Hassan, M. Hassany, D. Hutton, I. Ir-mansyah, L. Jancoriene, J. Kirwan, S. Ku-mar, P. Lennon, G. Lopardo, P. Lydon, N. Magrini, T. Maguire, S. Manevska, O. Manuel, S. McGinty, M.T. Medina, M.L. Mesa Rubio, M.C. Miranda-Montoya, J. Nel, E.P. Nunes, M. Perola, A. Portolés, M.R. Rasmin, A. Raza, H. Rees, P.P.S. Re-ges, C.A. Rogers, K. Salami, M.I. Salva-dori, N. Sinani, J.A.C. Sterne, M. Steva-novikj, E. Tacconelli, K.A.O. Tikkinen, S. Trelle, H. Zaid, J.-A. Røttingen, and S. Swaminathan) assume responsibility for the overall content and integrity of this article. The full names, academic de-grees, and affiliations of the members of the writing and steering committees are listed in the Appendix. Address reprint requests to Dr. Henao-Restrepo at WHO R&D Blueprint, 20 Ave. Appia, 1211 Ge-neva, Switzerland, or at rdblueprint@ who . int.*A complete list of the World Health Or-ganization (WHO) Solidarity trial inves-tigators is provided in the Supplemen-tary Appendix, available at NEJM.org.This article was published on December 2, 2020, at NEJM.org.N Engl J Med 2021;384:497-511.DOI: 10.1056/NEJMoa2023184Copyright © 2020 Massachusetts Medical Society.BACKGROUNDWorld Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and inter-feron beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19).METHODSWe randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses ex-amined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.RESULTSAt 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving inter-feron and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or re-duced initiation of ventilation or hospitalization duration.CONCLUSIONSThese remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortal-ity, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)a bs tr ac tRepurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial ResultsWHO Solidarity Trial Consortium* The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021498Th e n e w e ngl a nd j o u r na l o f m e dic i n eIn February 2020, a World Health Orga-nization (WHO) research forum on corona-virus disease 2019 (Covid-19) recommended evaluation of treatments in large, randomized trials,1 and other WHO expert groups identified four repurposed antiviral drugs that might have at least a moderate effect on mortality: remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a.2 In March 2020, the WHO began a large, simple, international, open-label, randomized trial involving hospital inpatients to evaluate the ef-fects of these four drugs on in-hospital mortality. The trial was adaptive; unpromising drugs could be dropped and others added. Hydroxychloro-quine, lopinavir, and interferon were eventually dropped from the trial, but others, such as mono-clonal antibodies, will be added. We report interim results for the original four drugs.Me thodsTrial DesignThe protocol, which was published previously3 and is available with the full text of this article at NEJM.org, was designed to involve hundreds of hospitals in dozens of countries. Trial procedures were minimal but rigorous, with data entry through a cloud-based Good Clinical Practice–compliant clinical data management system that recorded demographic characteristics, respiratory support, coexisting illnesses, and local availability of trial drugs before generating the treatment assign-ment. Written informed consent was provided by patients, or if they were unable to do so, by their legal representatives.3 Consent forms were retained by signatories and encrypted for records. The en-rollment of patients who provided consent took just a few minutes. Eligible patients were 18 years of age or older, were hospitalized with a diagnosis of Covid-19, were not known to have received any trial drug, were not expected to be transferred elsewhere within 72 hours, and, in the physician’s view, had no contraindication to any trial drug.The same cloud-based system was used to report any suspected unexpected serious adverse reaction. It was also used to record death in the hospital or discharge alive (with documentation of respiratory support in the hospital, trial-drug timing, use of nontrial drugs, and probable cause of death). National and global monitors raised or resolved queries (or both) and checked progress and completeness.Treatment RegimensThe trial drugs were remdesivir, hydroxychloro-quine, lopinavir, and interferon beta-1a (given with lopinavir until July 4). The hydroxychloroquine, lopinavir, and interferon regimens were discon-tinued for futility on, respectively, June 19, July 4, and October 16, 2020. Participants were ran-domly assigned in equal proportions to receive no trial drug or one of the trial drug regimens that was locally available (up to five options; all pa-tients were to receive the local standard of care). In this open-label trial, no placebos were used.The controls for a drug were patients assigned to the standard of care at a time and place in which that drug was locally available (except that when interferon was being given only with lopi-navir, its controls were patients given only lopi-navir). Assignment to the standard of care at a hospital in which more than one trial drug was available would put that patient into the control group for each of those drugs. Hence, there was partial overlap among the four control groups. Each comparison between a trial drug and its control, however, was evenly randomized (in a 1:1 ratio) and unbiased, because both groups were affected equally by differences between countries or hospitals and by time trends in patient char-acteristics or the standard of care.Daily doses were those already used for other diseases, but to maximize any efficacy without undue cardiac risk, the hydroxychloroquine dose was based on that for amoebic liver abscess rather than the lower dose for malaria.4 (Hydroxy-chloroquine slightly prolongs the QT interval, and an unduly high dose or rapid administration might cause arrhythmias or hypotension.) Treat-ments stopped at discharge.The regimen for remdesivir (intravenous) was 200 mg on day 0 and 100 mg on days 1 through 9. The regimen for hydroxychloroquine (oral) was four tablets at hour 0, four tablets at hour 6, and, starting at hour 12, two tablets twice daily for 10 days. Each tablet contained 200 mg of hydroxychloroquine sulfate (155 mg of hydroxy-chloroquine base per tablet; a little-used alterna-tive involved 155 mg of chloroquine base per tablet). The regimen for lopinavir (oral) was two tablets twice daily for 14 days. Each tablet con-tained 200 mg of lopinavir (plus 50 mg of rito-navir, to slow hepatic lopinavir clearance). Other formulations were not provided, so patients who were receiving mechanical ventilation received The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021 499Repurposed Antivir al Drugs for Covid-19no trial lopinavir while they were unable to swal-low. The regimen for interferon (mainly subcuta-neous) was three doses over a period of 6 days (the day of randomization and days 3 and 6) of 44 μg of subcutaneous interferon beta-1a; where intravenous interferon was available, patients receiving high-flow oxygen, ventilation, or extra-corporeal membrane oxygenation (ECMO) were instead to be given 10 μg intravenously daily for 6 days.OutcomesThe protocol-specified primary objective was to assess effects on in-hospital mortality (i.e., death during the original hospitalization; follow-up ceased at discharge), regardless of whether death occurred before or after day 28. The only proto-col-specified secondary outcomes were the initia-tion of mechanical ventilation and hospitaliza-tion duration. Although no placebos were used, appropriate analyses of these secondary outcomes can still be informative. Add-on studies that were led from Canada, France, India, and Norway re-corded other outcomes (not reported here).Oversight and FundingThe trial was registered at the ISRCTN Registry and ClinicalTrials.gov, with the core protocol approved by the WHO ethics review committee and local protocols approved by national ethics committees and regulatory authorities. Trial con-duct was in accordance with the principles of the Declaration of Helsinki and Good Clinical Prac-tice guidelines. The only exclusions from the intention-to-treat analyses were the few patients with no, or uncertain, consent to follow-up. All other randomly assigned patients were included. The WHO was the global cosponsor and govern-ments the national cosponsors, with trial gover-nance by the executive group of the international steering committee. External statistical analyses for the independent data and safety monitoring committee were unseen by the executive group or the WHO, with two exceptions. After outside evidence of the futility of hydroxychloroquine and lopinavir became available, the executive group requested unblinded analyses of the findings just for these two drugs. In addition, after deciding in a blinded fashion to report all interim results, the executive group revised this manuscript, which has been drafted only by the WHO trial team and external statisticians. Remdesivir was donated by Gilead Sciences, hydroxychloroquine by Mylan, lopinavir by AbbVie, Cipla, and Mylan, and inter-feron beta-1a by Merck (subcutaneous) and Faron Pharmaceuticals (intravenous).Sample SizeThe protocol stated, “The 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 execu-tive group, whose members were unaware of the findings, made the decision to release the interim results.Statistical AnalysisThe intention-to-treat analyses related outcome to assigned treatment. The primary analyses were of in-hospital mortality among all randomly as-signed patients (each drug vs. its control). The only protocol-specified subgroup analyses involved patients who already had severe disease at entry and those who did not. Severity was not protocol-defined, but separate analyses are provided regard-ing those receiving some supplemental oxygen or none and for those already receiving ventilation at entry or not. Rate ratios for death (or, equiva-lently, hazard ratios) and P values are from log-rank analyses stratified according to six strata of age and ventilation status at entry. Graphs of mortality according to time are from unstratified Kaplan–Meier methods, with denominators cho-sen to yield in-hospital mortality. (For example, if 99 of 100 patients were discharged alive before the last one died, the in-hospital mortality would be 1% and at the time of that death the probabil-ity of not having died in the hospital was multi-plied by 99/100; this denominator included those already discharged.)The risk on day N was calculated by first ex-cluding patients with an outcome not reported or an entry fewer than N days before data-set closure (or transferred elsewhere before day N); then, the number of in-hospital deaths on day N was di-vided by the total number of patients in the hos-pital on day N or discharged alive before day N. This denominator (or “risk set”), which includes those discharged before day N, was also used to calculate the contribution of day N to log-rank The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021500Th e n e w e ngl a nd j o u r na l o f m e dic i n eanalysis and Cox analysis of in-hospital mortal-ity. Denominators for the few deaths on day 0, but not on later days, included patients with no follow-up reported (because if any patient died on the day of randomization, this would proba-bly have been reported).If the stratified log-rank observed minus ex-pected number of deaths is O − E with variance V, the loge rate ratio is calculated as (O − E)/V with variance 1/V and a normal distribution. If event times are accurate and b is the log hazard ratio and L(b) the Cox log-likelihood, the first and second derivatives of L(b) at b = 0 are (O − E) and –V.5 Forest plots (with 95% confidence intervals only for overall trial results; otherwise, with 99% confidence intervals to allow for subgroup multiplicity) and chi-square statistics (sum of [O − E]2/V, without any P value) help interpret any heterogeneity of rate ratios between subgroups. All rate ratios describe proportional risk reduc-tions; absolute risk reductions would also depend on background risks. Analyses were performed with the use of SAS software, version 9.4, and R software, version 4.02.Meta-analyses of the major trial results are based on the inverse-variance–weighted average of b = loge rate ratio from each stratum of each trial, with the use of odds ratios when hazard ratios or rate ratios for death were unavailable. (This weighted average is derived from the sums of [O − E] and of V over strata.5) In general, the more deaths in a stratum the larger V is and, correspondingly, the smaller is the variance of the loge rate ratio, so the more weight that stratum gets. The variance that is attributed to the result in each stratum and to the overall weighted aver-age reflects only the play of chance at random-ization. Homogeneity of different rate ratios is not needed for such a weighted average to be informative.R esult sPatient Characteristics and AdherenceFrom March 22 to October 4, 2020, a total of 11,330 patients were entered in the trial from 405 hospitals in 30 countries in all six WHO regions. Of these patients, 64 (0.6%) had no, or uncertain, consent to follow-up, which left 11,266 in the intention-to-treat analyses. A total of 2750 patients were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug (Fig. 1); reporting is 97% complete for those who were entered more than 1 month earlier and 99.7% complete for those who were entered more than 3 months earlier. All 3 patients for whom the diagnosis of Covid-19 was later ruled out were included in the analyses and survived. Table 1 shows patient characteristics: 9120 (81%) were younger than 70 years of age, 6985 (62%) were male, 2768 (25%) had diabetes, 916 (8%) were already receiving ventilation, and 7002 (62%) un-derwent randomization on days 0 or 1. For each drug, patient characteristics were well balanced by the unstratified 1:1 randomization between it and its control. Deaths were at a median of day 8 (interquartile range, 4 to 14), and discharges were at a median of day 8 (interquartile range, 5 to 12).There were 1253 in-hospital deaths (the pri-mary outcome, including those before and after day 28). The Kaplan–Meier risk of in-hospital death to day 28 was 11.8%; a few in-hospital deaths occurred later. This risk depended on several factors, particularly age (20.4% if ≥70 years and 6.2% if <50 years) and ventilation status (39.0% if the patient was already receiving ventilation and 9.5% otherwise).Table 1 also shows adherence. For remdesivir, the scheduled treatment duration was 10 days (or to death or discharge). Of those assigned to rem-desivir, 98% began treatment. Midway through this period, 96% of the patients were still taking it (as compared with only 2% of those in the rel-evant group). Similarly, for other drugs adherence midway was 94% to 95%, and crossover was 2 to 6%. Trial treatments ceased on schedule (if the patient was still in the hospital). Absolute differ-ences (active vs. control) in the use of glucocor-ticoids (i.e., corticosteroids) and other nontrial drugs were 0.2 to 3.5 percentage points (Table S2 in the Supplementary Appendix, available at NEJM.org).Primary OutcomeFor each pairwise comparison of a drug and its control, Figure 2 and Figures S1 through S5 show the results of unstratified Kaplan–Meier analyses of in-hospital mortality (with numbers of patients who underwent randomization, in-hospital deaths each week and after day 28, and weekly denominators), along with rate ratios for death stratified according to age and ventilation The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021 501Repurposed Antivir al Drugs for Covid-19Figure 1. Information to October 4, 2020, on Trial Entry, Follow-up, and Intention-to-Treat Analyses.After it was determined which treatments were locally available, random assignment (with equal probability) was between the local standard of care and the available treatments. After the exclusion of 64 of 11,330 patients (0.6%) who had provided either no or uncertain consent regarding follow-up, 11,266 remained in the intention-to-treat analyses. Each pairwise intention-to-treat analysis was between a particular trial drug and its control (i.e., patients who could have been assigned to a particular trial drug but were concurrently as-signed to the same care without it). There is partial overlap of each control group with other groups.11,330 Patients underwent randomization(this total is substantially less than the total number in the combined groups, owing to the overlap of each control group with other groups)14 Had noor unknownconsent tofollow-up13 Had noor unknownconsent tofollow-up2064 Were assignednot to receiveinterferon2063 Were assignedto receiveinterferon8 Had noor unknownconsent tofollow-up12 Had noor unknownconsent tofollow-up3 Had noor unknownconsent tofollow-up7 Had noor unknownconsent tofollow-up2725 Were assignednot to receiveremdesivir 17 Had noor unknownconsent tofollow-up7 Had noor unknownconsent tofollow-up909 Were assignednot to receivehydroxychloroquine954 Were assignedto receivehydroxychloroquine1380 Were assignednot to receivelopinavir5475 Underwent randomization betweenremdesivir and its controls1863 Underwent randomization betweenhydroxychloroquine and its controls2791 Underwent randomization betweenlopinavir and its controls4127 Underwent randomization betweeninterferon and its controls1411 Were assignedto receivelopinavir2750 Were assignedto receiveremdesivir2743 Were includedin the intention-to-treat analyses2260 Died or leftthe hospital88 Entered trialbefore Sept.;still an inpatientin late Sept.67 Entered trialbefore Sept.;not yetreported onin late Sept.328 Entered trialin or afterSept.; notreported onin late Sept.(entry still continuing)2708 Were includedin the intention-to-treat analyses2252 Died or leftthe hospital72 Entered trialbefore Sept.;still an inpatientin late Sept. 76 Entered trialbefore Sept.;not yetreported onin late Sept.308 Entered trialin or afterSept.; notreported onin late Sept.(entry still continuing)947 Were includedin the intention-to-treat analyses932 Died or leftthe hospital12 Entered trialbefore or onJune 19; stillan inpatientin late Sept.3 Entered trialbefore or onJune 19; notreported on in late Sept.(entry ended June 19)906 Were includedin the intention-to-treat analyses891 Died or leftthe hospital13 Entered trialbefore or onJune 19; stillan inpatientin late Sept.2 Entered trialbefore or onJune 19; notreported on in late Sept.(entry ended June 19)1399 Were includedin the intention-to-treat analyses1385 Died or leftthe hospital11 Entered trialbefore or onJuly 4; stillan inpatientin late Sept.3 Entered trialbefore or onJuly 4; notreported onin late Sept.(entry ended July 4)1372 Were includedin the intention-to-treat analyses1349 Died or leftthe hospital16 Entered trialbefore or onJuly 4; stillan inpatientin late Sept.7 Entered trialbefore or onJuly 4; notreported onin late Sept.(entry ended July 4)2050 Were includedin the intention-to-treat analyses1756 Died or leftthe hospital65 Entered trialbefore Sept.;still an in-patient in late Sept.30 Entered trialbefore Sept.;not yetreported onin late Sept.199 Entered trialin or afterSept.; notreported on inlate Sept.(entry ended Oct. 16)2050 Were includedin the intention-to-treat analyses1819 Died or leftthe hospital56 Entered trialbefore Sept.;still an in-patient in late Sept.21 Entered trialbefore Sept.;not yetreported onin late Sept.154 Entered trialin or afterSept.; notreported on inlate Sept.(entry ended Oct. 16)The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021502Th e n e w e ngl a nd j o u r na l o f m e dic i n eTable 1. Entry Characteristics According to Random Assignment, and Adherence to That Assignment.*VariableAny Intention-to-Treat Analysis (N = 11,266)Remdesivir vs. Its ControlHydroxychloroquine vs. Its ControlLopinavir vs. Its ControlInterferon vs. Its Control†Entered TrialDied in Hospital‡28-Day Mortality§Active (N = 2743)Control (N=2708)Active (N = 947)Control (N = 906)Active (N = 1399)Control (N = 1372)Active (N = 2050)Control (N = 2050)no. (%)no.%no. of patientsEntry characteristicsAge<50 yr3995 (35)2376.296195233531751150172069750–69 yr5125 (45)61812.812821287410396597596934973≥70 yr2146 (19)39820.4500469202193291275396380Respiratory supportNo supplemental oxygen at entry3204 (28)782.5661664345341528539482490Supplemental oxygen at entry7146 (63)84412.81828181151748375971914291430Already receiving ventilation916 (8)33139.02542338582112114139130Lesions in both lungsNo1266 (11)493.7287259154170235256162155Yes8832 (78)104312.72175215365661898594517231718Not imaged at entry1168 (10)16114.9281296137118179171165177Previous days in the hospital03289 (29)3199.872471229628142340367867713713 (33)38410.8917938317312442445681662≥24264 (38)55014.611021058334313534524691711Geographic regionEurope and Canada¶2488 (22)1887.8715698286267349350254244Latin America‖1941 (17)40022.74705149796145148474478Asia and Africa**6837 (61)66510.31558149656454390587413221328Other characteristicsMale sex6985 (62)85213.01706172557453585180213031278Current smoker830 (7)9311.81781619282141124136138VariableAny Intention-to-Treat Analysis (N = 11,266)Remdesivir vs. Its ControlHydroxychloroquine vs. Its ControlLopinavir vs. Its ControlInterferon vs. Its Control†Entered TrialDied in Hospital‡28-Day Mortality§Active (N = 2743)Control (N=2708)Active (N = 947)Control (N = 906)Active (N = 1399)Control (N = 1372)Active (N = 2050)Control (N = 2050)no. (%)no.%no. of patientsCoexisting conditionsDiabetes2768 (25)37914.7707666199205341324489537Heart disease2337 (21)31914.7571567193194289290427456Chronic lung disease635 (6)10217.215114562669587114109Asthma529 (5)5611.5139139414665567597Chronic liver disease135 (1)2117.23641151415231122Adherence to assigned treatmentPercent taking trial drug midway through scheduled dura-tion††‡‡962956942942Percent ever reported as discharged who were still in the hospital at various times††On day 76959645468595551On day 142219232031221918On day 21981110121187* A total of 64 patients who did not provide clear informed consent regarding follow-up were excluded. Comparisons are of each trial drug with concurrent assignment to the same treatment without it. Because the control groups overlap, the total number (11,266) is less than the sum of the numbers in the pairwise comparisons. The few patients (always <0.4%) with a particular characteristic not yet known were merged with the largest category of that characteristic: 33 were merged with male sex, 40 were merged with an age of 50 to 69, and 45 were merged with previous days in the hospital of 2 or more.† Interferon randomization was interferon plus lopinavir as compared with lopinavir until July 4, 2020, then it was interferon as compared with the local standard of care.‡ Shown are any in-hospital deaths, regardless of whether they occurred before or after day 28 (total, 1253 deaths).§ Shown is the Kaplan–Meier 28-day risk of in-hospital death, expressed as a percentage (overall value, 11.8%). Percentages may not total 100 because of rounding.¶ Countries in Europe were Albania, Austria, Belgium, Finland, France, Ireland, Italy, Lithuania, Luxembourg, North Macedonia, Norway, Spain, and Switzerland.‖ Countries included Argentina, Brazil, Colombia, Honduras, and Peru.** Countries included Egypt, India, Indonesia, Iran, Kuwait, Lebanon, Malaysia, Pakistan, the Philippines, Saudi Arabia, and South Africa.†† Percentage of patients (rather than number of patients) is shown for this variable.‡‡ Adherence was calculated only among patients who died or were discharged alive and was defined as the percentage of patients who were taking the trial drug midway through its scheduled duration (or midway through the time from entry to death or discharge, if this was shorter).The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021 503Repurposed Antivir al Drugs for Covid-19VariableAny Intention-to-Treat Analysis (N = 11,266)Remdesivir vs. Its ControlHydroxychloroquine vs. Its ControlLopinavir vs. Its ControlInterferon vs. Its Control†Entered TrialDied in Hospital‡28-Day Mortality§Active (N = 2743)Control (N=2708)Active (N = 947)Control (N = 906)Active (N = 1399)Control (N = 1372)Active (N = 2050)Control (N = 2050)no. (%)no.%no. of patientsCoexisting conditionsDiabetes2768 (25)37914.7707666199205341324489537Heart disease2337 (21)31914.7571567193194289290427456Chronic lung disease635 (6)10217.215114562669587114109Asthma529 (5)5611.5139139414665567597Chronic liver disease135 (1)2117.23641151415231122Adherence to assigned treatmentPercent taking trial drug midway through scheduled dura-tion††‡‡962956942942Percent ever reported as discharged who were still in the hospital at various times††On day 76959645468595551On day 142219232031221918On day 21981110121187* A total of 64 patients who did not provide clear informed consent regarding follow-up were excluded. Comparisons are of each trial drug with concurrent assignment to the same treatment without it. Because the control groups overlap, the total number (11,266) is less than the sum of the numbers in the pairwise comparisons. The few patients (always <0.4%) with a particular characteristic not yet known were merged with the largest category of that characteristic: 33 were merged with male sex, 40 were merged with an age of 50 to 69, and 45 were merged with previous days in the hospital of 2 or more.† Interferon randomization was interferon plus lopinavir as compared with lopinavir until July 4, 2020, then it was interferon as compared with the local standard of care.‡ Shown are any in-hospital deaths, regardless of whether they occurred before or after day 28 (total, 1253 deaths).§ Shown is the Kaplan–Meier 28-day risk of in-hospital death, expressed as a percentage (overall value, 11.8%). Percentages may not total 100 because of rounding.¶ Countries in Europe were Albania, Austria, Belgium, Finland, France, Ireland, Italy, Lithuania, Luxembourg, North Macedonia, Norway, Spain, and Switzerland.‖ Countries included Argentina, Brazil, Colombia, Honduras, and Peru.** Countries included Egypt, India, Indonesia, Iran, Kuwait, Lebanon, Malaysia, Pakistan, the Philippines, Saudi Arabia, and South Africa.†† Percentage of patients (rather than number of patients) is shown for this variable.‡‡ Adherence was calculated only among patients who died or were discharged alive and was defined as the percentage of patients who were taking the trial drug midway through its scheduled duration (or midway through the time from entry to death or discharge, if this was shorter).The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021504Th e n e w e ngl a nd j o u r na l o f m e dic i n estatus; Figure 3 shows the stratified rate ratios ac-cording to age and according to ventilation status. No trial drug had any definite effect on mortality, either overall (each P>0.10) or in any subgroup defined according to age, ventilation status at entry, other entry characteristics, geographic re-gion, or glucocorticoid use (Figs. S6 through S9).Death occurred in 301 of 2743 patients receiv-Figure 2. Effects of Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon on In-Hospital Mortality.Shown are Kaplan–Meier graphs of in-hospital mortality at any time (the primary outcome), comparing each treatment with its control without standardization for any initial patient characteristics. Insets show the same data on an expanded y axis. The rate ratios for death were standardized for age and for ventilation status at entry. Denominators for the few events on day 0, but not thereafter, include pa-tients with no follow-up. Numbers of deaths are by week, and then deaths after day 28. CI denotes confidence interval.In-Hospital Mortality (%)10080907060403010502000 7 14 21 281551000 7 14 21 28Days since RandomizationA Remdesivir vs. Its ControlRate ratio, 0.95 (95% CI, 0.81–1.11)P=0.50 by log-rank testRemdesivirControl2743270821592138202920041918190818381833DenominatorIn-Hospital Mortality (%)10080907060403010502000 7 14 21 281551000 7 14 21 28Days since RandomizationB Hydroxychloroquine vs. Its ControlRate ratio, 1.19 (95% CI, 0.89–1.59)P=0.23 by log-rank testHydroxychloroquineControl947906889853854823838814833809DenominatorIn-Hospital Mortality (%)10080907060403010502000 7 14 21 281551000 7 14 21 28Days since RandomizationC Lopinavir vs. Its ControlRate ratio, 1.00 (95% CI, 0.79–1.25)P=0.97 by log-rank testLopinavirControl1399137213331293128212391257121612431203DenominatorIn-Hospital Mortality (%)10080907060403010502000 7 14 21 281551000 7 14 21 28Days since RandomizationD Interferon vs. Its ControlRate ratio, 1.16 (95% CI, 0.96–1.39)P=0.11 by log-rank testInterferonControl2050205016691725155416361483156314101498DenominatorRemdesivirControl1291269093484318271614No. Who DiedHydroxychloroquineControl484231271386463No. Who DiedLopinavirControl5762424824211510105No. Who DiedInterferonControl101917358313124211415No. Who DiedRemdesivirHydroxychloroquineControlControlLopinavirControlInterferonControlThe New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021 505Repurposed Antivir al Drugs for Covid-19ing remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiv-ing lopinavir and in 146 of 1372 receiving its con-trol (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, Figure 3. Rate Ratios for In-Hospital Death, Subdivided by Age and Respiratory Support at Trial Entry.Analyses in subgroups of age are stratified according to respiratory status at trial entry and vice versa, so each total is stratified for both factors. The percentages show Kaplan–Meier 28-day mortality. O − E denotes the observed minus expected number of deaths in patients assigned to active treatment. Diamonds show 95% confidence intervals for treatment effects. Squares and horizontal lines show treat-ment effects in particular subgroups and their 99% confidence intervals, with an arrow if the upper 99% confidence limit is outside the range shown. The area of each square is proportional to the variance of O − E in the subgroup it describes.0.5 1.51.0 2.0Control BetterActive TreatmentBetterRemdesivirAge at entry<50 yr50–69 yr≥70 yrRespiratory support at entryNo mechanical ventilationMechanical ventilationTotalHeterogeneity around total: χ23=3.9HydroxychloroquineAge at entry<50 yr50–69 yr≥70 yrRespiratory support at entryNo mechanical ventilationMechanical ventilationTotalHeterogeneity around total: χ23=5.0LopinavirAge at entry<50 yr50–69 yr≥70 yrRespiratory support at entryNo mechanical ventilationMechanical ventilationTotalHeterogeneity around total: χ23=1.2InterferonAge at entry<50 yr50–69 yr≥70 yrRespiratory support at entryNo mechanical ventilationMechanical ventilationTotalHeterogeneity around total: χ23=4.8Active TreatmentRate Ratio for Death(99% CI; 95% CI for total)ControlLog-Rank Statistics for No. of Deaths in Active-Treatment GroupO – E VarianceSubgroupno. of deaths reported/no. of patients (%)61/961 (6.9) 59/952 (6.8)0.01.08 (0.67–1.73) 154/1282 (13.8) 161/1287 (14.2) 0.91 (0.68–1.21) 86/500 (20.5) 83/469 (21.6) 0.93 (0.63–1.39)203/2489 (9.4) 232/2475 (10.6) 0.86 (0.67–1.11) 98/254 (43.0) 71/233 (37.8) 1.20 (0.80–1.80) 301/2743 (12.5) 303/2708 (12.7) 0.95 (0.81–1.11)P=0.5019/335 (5.7) 19/317 (5.8) 1.10 (0.47–2.57) 55/410 (12.1) 31/396 (7.1) 1.66 (0.95–2.91) 30/202 (14.0) 34/193 (17.8) 0.80 (0.42–1.53)69/862 (7.4) 57/824 (6.6) 1.16 (0.73–1.84)35/85 (39.2) 27/82 (32.3) 1.26 (0.65–2.46)104/947 (10.2) 84/906 (8.9) 1.19 (0.89–1.59)P=0.2320/511 (3.6) 27/501 (4.9) 0.77 (0.36–1.64)66/597 (9.8) 57/596 (9.1) 1.09 (0.68–1.74) 62/291 (20.4) 62/275 (22.7) 1.00 (0.63–1.60)113/1287 (8.1) 111/1258 (8.7) 0.97 (0.69–1.37) 35/112 (28.1) 35/114 (28.7) 1.08 (0.57–2.03)148/1399 (9.7) 146/1372 (10.3) 1.00 (0.79–1.25)P=0.9748/720 (7.5) 35/697 (5.3) 1.44 (0.82–2.54)122/934 (14.3) 108/973 (11.4) 1.26 (0.90–1.78) 73/396 (19.9) 73/380 (20.9) 0.89 (0.58–1.38) 188/1911 (10.9) 176/1920 (9.5) 1.11 (0.84–1.45) 55/139 (42.4) 40/130 (33.8) 1.40 (0.82–2.40) 243/2050 (12.9) 216/2050 (11.0)2.3−7.6−2.9−15.87.6−8.30.910.8−3.54.73.48.1−3.02.70.0−1.61.3−0.47.513.3−4.09.17.716.829.877.541.5108.040.8148.89.221.215.831.414.846.211.730.430.255.616.772.320.656.935.890.323.0113.3 1.16 (0.96–1.39)P=0.11The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021506Th e n e w e ngl a nd j o u r na l o f m e dic i n e1.16; 95% CI, 0.96 to 1.39; P = 0.11). Unstratified comparisons yielded similarly null findings (Fig. 2), as did analyses that excluded patients receiving glucocorticoids and multivariable sensitivity analy-ses that estimated trial drug effects simultane-ously (Table S3). If mechanical ventilation pre-vented oral administration of lopinavir or other trial drugs, then this could have reduced any ef-fects on mortality of assignment to those drugs, but prespecified analyses of mortality among patients not already receiving ventilation at entry also indicated no definite protective effect of any trial drug (Fig. 3).Secondary OutcomesThe prespecified secondary outcomes were venti-lation and time to discharge. No trial drug reduced the initiation of ventilation among patients not already receiving ventilation. Ventilation was initi-ated after randomization in 295 patients receiving remdesivir and in 284 receiving its control, in 75 patients receiving hydroxychloroquine and in 66 receiving its control, in 126 patients receiving lopinavir and in 121 receiving its control, and in 209 patients receiving interferon and in 210 receiv-ing its control (Table S1). Figure S10 shows the results for the combined outcome of in-hospital death or ventilation initiation.In this open-label trial, patients who would be considered fit for discharge might be kept in the hospital somewhat longer just because they were being given a trial drug, but information on time to recovery can be obtained by comparing the effects of different drugs on time to discharge. Each of the three trial treatments that were scheduled to last more than 7 days increased the percentage of patients remaining in the hospital at day 7 (Table 1). If one of these three drugs had appreciably accelerated recovery, then the sizes of these effects should have differed, but they did not. Figures S11 through S16 plot time to dis-charge for all patients, those receiving supplemen-tal oxygen, those not receiving supplemental oxy-gen, those receiving ventilation, those not receiving ventilation, and those receiving any respiratory support. Each drug delayed discharge by approxi-mately 1 to 3 days while it was being given. Di-rectly randomized comparisons of one trial drug with another (Fig. S17) likewise showed no ap-preciable differences in discharge rates while both drug regimens continued or after both had ended.The supplementary analyses (Tables S2 and S3) tabulate co-medication (only small absolute dif-ferences were found between each trial drug and its control) and provide a multivariable Cox re-gression fitting all four treatment effects simul-taneously (rate ratios for death were similar to those in Fig. 3). The analyses also (in Figs. S1 through S9) subdivide 28-day mortality graphs according to ventilation status at entry and give subgroup analyses of rate ratios for death ac-cording to other characteristics and according to glucocorticoid use (with no noteworthy sub-group-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 were seven with remdesivir and eight with its control, four with hydroxychlo-roquine and two with its control, six with lopi-navir and three with its control, and six with interferon and eight with its control (Fig. S18). Many deaths from Covid-19 involve multiorgan failure, but no death in a patient assigned to a trial drug was attributed specifically by the doctor reporting the death to renal or hepatic disease.Meta-AnalysesThere are four trials that have compared remde-sivir with control: the Solidarity trial (604 deaths in 5451 randomly assigned patients), the Adaptive Covid-19 Treatment Trial (ACTT-1) (136 deaths in 1062 patients; mortality was a secondary outcome), and two smaller trials (41 deaths).6-9 Figure 4 shows the mortality results from each trial, strati-fied according to initial respiratory support. With-in each trial, summation of the observed minus expected numbers of deaths with remdesivir in each stratum led to the stratified rate ratio for death in that trial. Summation of these trial-specific observed-minus-expected subtotals then led to an appropriately weighted average of the results from all trials, which yielded a rate ratio for death (remdesivir vs. control) of 0.91 (95% CI, 0.79 to 1.05).5 Figures S19 and S20 show the mortality results in the trials of hydroxychloro-quine (rate ratio, 1.09; 95% CI, 0.98 to 1.21) and of lopinavir (rate ratio, 1.01; 95% CI, 0.91 to 1.13).DiscussionThe main outcomes of mortality, initiation of ventilation, and hospitalization duration were not definitely reduced by any trial drug, either overall The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021 507Repurposed Antivir al Drugs for Covid-19or in any particular subgroup. The findings for mortality and for initiation of ventilation cannot have been appreciably biased by the open-label design without placebos, or by variation in local care or patient characteristics, and were little affected when homogeneity was increased by stratification according to geographic region, age, or use of ventilation at entry. No trial drug reduced the initiation of mechanical ventilation. The simi-larity of this null effect for all four drugs is further evidence that none has any material ef-fect on major disease progression, a conclusion supported by analyses of the combined outcome of death or ventilation initiation.Although assignment to any of the active trial treatments in this open-label trial somewhat delayed discharge from the hospital, this could have been because some recovered patients oth-erwise fit for discharge were kept in the hospital merely to continue their trial treatment. In all patients and in those not receiving ventilation, assignment to each active trial drug increased Figure 4. Meta-Analysis of Mortality in Trials of Random Assignment of Remdesivir or Its Control to Hospitalized Patients with Covid-19.Percentages show Kaplan–Meier 28-day mortality. Values for observed minus expected number of deaths (O − E) are log-rank O − E for the Solidarity trial, O − E from 2-by-2 tables for the Wuhan7 and international8 trials, and w.loge hazard ratio for each stratum in the Adap-tive Covid-19 Treatment Trial (ACTT-1)6 (with the weight w being the inverse of the variance of the loge hazard ratio, which was calculated from the confidence interval of the hazard ratio). Rate ratios were calculated by taking the loge rate ratio to be (O − E)/V with a Normal distribution and variance 1/V. Subtotals or totals of (O − E) and of V yield inverse-variance–weighted averages of the loge rate ratios. For balance, controls in the 2:1 trials were counted twice in the control totals and subtotals. Diamonds show 95% confidence intervals for treatment effects. Squares and horizontal lines show treatment effects in particular subgroups and their 99% confidence intervals, with an arrow if the upper 99% confidence limit is outside the range shown. The area of each square is proportional to the variance of O − E in the subgroup it describes.0.5 1.0 2.0 2.51.5 3.0Control BetterRemdesivir BetterSolidarity (stratified according tooxygen use and ventilation)No supplemental oxygenLow-flow or high-flow oxygenVentilationStratified total: SolidarityACTT-1 (stratified according to 4 ordinal score levels)No supplemental oxygenLow-flow oxygenHigh-flow oxygen or noninvasiveventilationInvasive ventilationStratified total: ACTT-1Trials with few deaths (and randomization ratio of 2:1)Wuhan: low-flow oxygenWuhan: high-flow oxygen or ventilationInternational: no supplemental oxygenStratified total: 2:1 trialsRisk groups (calculated by summationof relevant strata)Lower risk: strata with noventilationHigher riskStratified totalHeterogeneity between trials (Solidarity vs. ACTT-1 vs. 2:1 trials): χ22=0.5RemdesivirRate Ratio for Death(99% CI; 95% CI for totals)Observed–ExpectedNo. of Deaths in Remdesivir GroupControlSubgroupno. of deaths reported/no. of patients (%)Value Variance11/661 (2.0) 13/664 (2.1)0.00.90 (0.31–2.58) 192/1828 (12.2) 219/1811 (13.8) 0.85 (0.66–1.09) 98/254 (43.0) 71/233 (37.8) 1.20 (0.80–1.80) 301/2743 (12.5) 303/2708 (12.7) 0.94 (0.80–1.10)3/75 (4.1) 3/63 (4.8) 0.82 (0.10–6.61) 9/232 (4.0) 25/203 (12.7) 0.30 (0.11–0.81)19/95 (21.2) 20/98 (20.4) 1.02 (0.44–2.34) 28/131 (21.9) 29/154 (19.3) 1.13 (0.57–2.23) 59/533 (11.1) 77/518 (14.9) 0.82 (0.58–1.16)11/129 (8.5) (7/68)×2 (10.3) 0.81 (0.21–3.07)11/29 (37.9) (3/10)×2 (30.0) 1.40 (0.20–9.52)5/384 (1.3) (4/200)×2 (2.0) 0.64 (0.10–3.94)27/542 (5.0) (14/278)×2 (5.0) 0.86 (0.42–1.77)231/3309 (7.0) 282/3277 (8.6) 0.80 (0.63–1.01)156/509 (30.6) 126/505 (25.0) 1.16 (0.85–1.60) 387/3818 (10.1) 408/3782 (10.8)−0.6−16.97.6−10.0−0.3−8.00.21.8−6.4−0.80.6−0.9−1.1−27.610.16.0101.840.8148.61.56.79.614.332.13.71.82.07.5121.666.5−17.5 188.1 0.91 (0.79–1.05)P=0.20The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021508Th e n e w e ngl a nd j o u r na l o f m e dic i n ethe time to discharge by approximately 1 to 3 days while treatment continued. Because no treatment had much effect on death or progression to ven-tilation, the similarity of these four moderate delays of discharge suggests that none of the four treatments had a pharmacologic effect that substantially reduced time to recovery (i.e., fit-ness for discharge). In particular, it suggests at most only a small effect of remdesivir on time to recovery, a conclusion supported by the directly randomized comparisons between remdesivir and the other three trial drugs.ACTT-1, which examined remdesivir, was pla-cebo-controlled,6 which avoids any bias in time to discharge. In that trial, however, the proportion of lower-risk patients (i.e., those not already re-ceiving high-flow oxygen or ventilation) happened to be appreciably greater in the remdesivir group than in the placebo group. This chance imbal-ance might account for some of the differences in time to recovery between ACTT-1 and the Soli-darity trial.The chief aim of the Solidarity trial was to help determine whether any of four repurposed antivirals could at least moderately affect in-hospital mortality. Its results should be consid-ered in the context of the evidence on mortality from all trials, but for remdesivir and for inter-feron it provides more than three fourths of that evidence (Fig. 4). Stratification of the findings according to initial respiratory support again facilitates allowance for the remdesivir group in ACTT-1 having, by chance, started with a greater proportion of low-risk patients and a smaller proportion of high-risk patients than the placebo group. The stratified rate ratios for death in the Solidarity trial and ACTT-1 are compatible with each other, and either singly or together they are compatible with there being little or no effect of remdesivir on mortality.With an appropriately weighted average of the stratified results from each of the four trials,5 the rate ratio for death with remdesivir as com-pared with control was 0.91 (95% CI, 0.79 to 1.05). Interpretation of this should chiefly reflect not the P value (P = 0.20) or point estimate (rate ratio, 0.91) but the confidence interval (0.79 to 1.05), which shows the range of rate ratios for death that are compatible with the weighted average of the findings from all trials. This does not sup-port the suggestion that remdesivir can prevent a substantial fraction of all deaths. The confi-dence interval is compatible with prevention of a small fraction of all deaths, but it is also com-patible with prevention of no deaths.Statistical uncertainties are magnified if at-tention is restricted to particular subgroups or time periods.10 If remdesivir has no effect on mortality, then chance could well produce some-what favorable findings in a subgroup of the results for all trials or striking findings in a selected subgroup of a particular trial (as in the unplanned subgroup of ACTT-1 in which the rate ratio for death was 0.30) (Fig. 4). Although both the Solidarity trial and ACTT-1 envisaged sepa-rate analyses involving lower-risk and higher-risk patients, they did not define how this sub-division would apply to mortality analyses. The ACTT-1 protocol prespecified separate analyses of time to recovery among those with mild-to-moderate disease not receiving supplemental oxygen, as did the recent Food and Drug Admin-istration reanalyses,11 which categorized anyone receiving even low-flow supplemental oxygen as having severe disease. This subdivision, however, leaves few deaths in the no-supplemental-oxygen category (death in 3 of 75 patients with remde-sivir and in 3 of 63 with placebo in ACTT-1, in 11 of 661 patients with remdesivir and in 13 of 664 with its control in the Solidarity trial, and in 5 of 384 patients with remdesivir and in 4 of 200 with the standard of care in an international trial with a 2:1 randomization ratio8).To augment these small numbers of deaths, the subtotals in Figure 4 include low-flow oxy-gen with no supplemental oxygen, which yields a large lower-risk subgroup and a small higher-risk subgroup. With this nonprespecified sub-grouping, there appears to be an absolute reduc-tion of approximately 1 to 2 percentage points in mortality among lower-risk inpatients and an absolute increase of approximately 5 to 6 percent-age points among higher-risk inpatients. These absolute differences in the meta-analysis of all four trials are similar to the absolute differences seen when the Solidarity trial is subdivided ac-cording to ventilation status at entry. Neither subgroup should, however, be considered in isola-tion from the other or from the confidence in-terval for overall mortality.For hydroxychloroquine and lopinavir, the Solidarity trial showed no definite effect on mor-tality in any subgroup. The only other substantial trial is the Randomized Evaluation of Covid-19 The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021 509Repurposed Antivir al Drugs for Covid-19Therapy (RECOVERY) trial,12,13 which for these two drugs was larger than the Solidarity trial and also showed no benefit. Combination of both trials reinforces these null findings (Figs. S19 and S20).For hydroxychloroquine, the joint rate ratio for death (combining the Solidarity and RECOVERY trials) was 1.10 (95% CI, 0.98 to 1.23), with no apparent benefit whether the patient was receiv-ing ventilation or not. This confidence interval rules out any material benefit from this hydroxy-chloroquine regimen in hospitalized patients with Covid-19. It is compatible with some adverse ef-fect but is not good evidence for any adverse effect and is not a safety signal. Despite concerns that the loading dose could be temporarily cardio-toxic,4 in neither trial was there any excess mor-tality during the first few days, and cardiac deaths were too few to be reliably informative. A recent meta-analysis identified 15 small, randomized trials with nonzero mortality14; combining all 17 hydroxychloroquine trials yields a rate ratio of 1.09 (95% CI, 0.98 to 1.21), which still rules out any material benefit.For lopinavir, which was always administered with ritonavir, the joint rate ratio for death (combining the Solidarity and RECOVERY trials and the only informative smaller trial15) was 1.01 (95% CI, 0.91 to 1.13). Although lopinavir tablets could not be swallowed by patients receiving ven-tilation, there was no apparent benefit in analyses that involved only those not already receiving ventilation at entry. This confidence interval sug-gests no material effect on mortality and rules out a 10% proportional reduction. An add-on study within the Solidarity trial, Discovery, re-corded many clinical variables and identified an unexpected increase in the creatinine level (per-haps because blood lopinavir levels are higher than in patients with human immunodeficiency virus infection receiving similar doses16,17), but the Solidarity and RECOVERY trials recorded no specifically renal or hepatic deaths with lopinavir.For interferon beta-1a, no other large trials exist. With 4000 patients, the rate ratio for death in the Solidarity trial was 1.16 (95% CI, 0.96 to 1.39), or 1.12 (95% CI, 0.83 to 1.51) without lopinavir co-administration; these findings sug-gest no mortality reduction. Subcutaneous and intravenous interferon have different pharmaco-kinetic characteristics,18,19 and glucocorticoids could affect interferon signaling,20,21 but the clinical relevance of both issues is unclear. Most interferon was administered subcutaneously, be-cause intravenous interferon was used only in patients receiving high-flow oxygen or ventilation, and distribution of it began only in late May, just before strong evidence emerged of glucocorticoid efficacy in such patients.22,23 Hence, few patients received intravenous interferon without a gluco-corticoid. Approximately half the patients who were assigned to interferon (and half their con-trols) received glucocorticoids, but the rate ratio for death with interferon as compared with its control seemed unaffected by glucocorticoid use. Randomization to interferon was discontinued on October 16, but other trials continue. A re-port that nebulized interferon beta-1a might be effective involved only approximately 100 pa-tients with Covid-19 (ClinicalTrials.gov number, NCT04385095), but the ongoing placebo-con-trolled ACTT-3 of subcutaneous interferon beta-1a aims to involve 1000 patients (NCT04492475), with examination of time to recovery.For each of these four repurposed nonspecific antivirals, several thousand patients have now undergone randomization in various trials. The unpromising overall findings from the regimens tested suffice to refute early hopes, based on smaller or nonrandomized studies, that any of these regimens will substantially reduce inpatient mortality, the initiation of mechanical ventilation, or hospitalization duration. Narrower confidence intervals would be helpful (particularly for rem-desivir), but the main need is for better treat-ments. The Solidarity trial has been recruiting approximately 2000 patients per month, and ef-ficient factorial designs may allow it to assess further treatments, such as immune modulators or anti–SARS-Cov-2 monoclonal antibodies.Manuscript preparation, revision, and submission were con-trolled by the World Health Organization (WHO) trial team and writing committee. Any views expressed are those of the writing committee, not necessarily of the WHO. No funder or donor unduly influenced analyses, manuscript preparation, or submis-sion; their comments merely clarified methods, not changing analyses or conclusions. Donors of trial drugs were shown the main results for their drug in the last week of September.Supported by the World Health Organization. Other grants are listed in the Supplementary Appendix.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org..A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.We thank the thousands of patients and their families who participated in this trial and the hundreds of medical staff who randomly assigned and cared for them. The Ministries of Health of participating member states and national institutions provided critical support in trial implementation. Derk Arts of The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. n engl j med 384;6 nejm.org February 11, 2021510Th e n e w e ngl a nd j o u r na l o f m e dic i n eCastor EDC donated and managed Castor’s cloud-based clinical data capture and management system, with blinding to trial findings. Anonymized data handling or analysis was performed at the Universities of Bern, Bristol, and Oxford. Nicholas J. White and colleagues provided unpublished data on the phar-macokinetic characteristics of hydroxychloroquine to help the WHO select the regimen, the members of the Discovery data and safety monitoring committee shared clinical variables, the investigators of the Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial shared log-rank statistics, the investigators of the Adaptive Covid-19 Treatment Trial (ACTT-1) shared sub-group hazard ratios, and Bin Cao shared details of the Wuhan trial. Collaborators, committee members, data analysts, and data management systems charged no costs.AppendixThe members of the writing and steering committees are as follows: Hongchao Pan, Ph.D., Richard Peto, F.R.S., Ana-Maria Henao-Restrepo, M.D., Marie-Pierre Preziosi, Ph.D., Vasee Sathiyamoorthy, Ph.D., Quarraisha Abdool Karim, Ph.D., Marissa M. Ale-jandria, M.D., César Hernández García, Ph.D., Marie-Paule Kieny, Ph.D., Reza Malekzadeh, M.D., Srinivas Murthy, M.D., K. Srinath Reddy, M.D., Mirta Roses Periago, M.D., Pierre Abi Hanna, M.D., Florence Ader, Ph.D., Abdullah M. Al-Bader, Ph.D., Almonther Al-hasawi, M.D., Emma Allum, M.Math., Athari Alotaibi, M.Sc., Carlos A. Alvarez-Moreno, Ph.D., Sheila Appadoo, M.P.H., Abdullah Asiri, M.B., B.S., Pål Aukrust, Ph.D., Andreas Barratt-Due, Ph.D., Samir Bellani, B.Sc., Mattia Branca, Ph.D., Heike B.C. Cappel-Porter, M.Math., Nery Cerrato, M.D., Ting S. Chow, M.D., Najada Como, Ph.D., Joe Eustace, B.Ch., M.H.S., Patricia J. García, Ph.D., Sheela Godbole, M.B., B.S., Eduardo Gotuzzo, M.D., Laimonas Griskevicius, Ph.D., Rasha Hamra, Pharm.D., Mariam Hassan, M.B., B.S., Mohamed Hassany, M.D., David Hutton, B.Sc., Irmansyah Irmansyah, M.D., Ligita Jancoriene, Ph.D., Jana Kirwan, M.A., Suresh Kumar, M.B., B.S., Peter Lennon, B.B.S., Gustavo Lopardo, M.D., Patrick Lydon, M.Sc., Nicola Magrini, M.D., Teresa Maguire, Ph.D., Suzana Manevska, M.D., Oriol Manuel, M.D., Sibylle McGinty, Ph.D., Marco T. Medina, M.D., María L. Mesa Rubio, M.D., Maria C. Miranda- Montoya, M.D., Jeremy Nel, M.B., Ch.B., Estevao P. Nunes, Ph.D., Markus Perola, Ph.D., Antonio Portolés, Ph.D., Menaldi R. Rasmin, M.D., Aun Raza, M.D., Helen Rees, M.R.C.G.P., Paula P.S. Reges, M.D., Chris A. Rogers, Ph.D., Kolawole Salami, M.D., Marina I. Salvadori, M.D., Narvina Sinani, Pharm.D., Jonathan A.C. Sterne, Ph.D., Milena Stevanovikj, Ph.D., Evelina Tacconelli, Ph.D., Kari A.O. Tikkinen, Ph.D., Sven Trelle, M.D., Hala Zaid, Ph.D., John-Arne Røttingen, Ph.D., and Soumya Swaminathan, M.D.The affiliations of the members of the writing and steering committees are as follows: the Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, Oxford (H.P., R.P.), and the University of Bristol, Bristol (E.A., S.B., H.B.C.C.-P., D.H., J.K., C.A.R., J.A.C.S.) — both in the United Kingdom; the World Health Organization, Geneva (A.-M.H.-R., M.-P.P., V.S., P. Lydon, M.C.M.-M., K.S., S.S.), the University of Bern, Bern (S.A., M.B., S. McGinty, S.T.), and Lausanne University Hospital, Lausanne (O.M.) — all in Switzerland; the Centre for the AIDS Programme of Research in South Africa, Durban (Q.A.K.), and the University of the Witwatersrand (J.N.) and the Wits Reproductive Health and HIV Institute (H.R.), Johannesburg — all in South Africa; the Institute of National Epidemiology, National Institutes of Health, University of the Philippines, Manila (M.M.A.); the Agency of Medicine and Medical Devices (C.H.G.) and Hospital Clínico San Carlos, Universidad Complutense de Madrid, Spanish Clinical Research Network, Instituto de Investigación Sanitaria San Carlos (A.P.), Madrid; INSERM, Paris (M.-P.K.), and Hospices Civils de Lyon, Lyon (F.A.) — both in France; the Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran (R.M.); the University of British Columbia, Vancouver (S. Murthy), and the Public Health Agency of Canada, Ottawa (M.I.S.) — both in Canada; the Public Health Foundation of India, New Delhi (K.S.R.), and the Indian Council of Medical Research, National AIDS Re-search Institute, Pune (S.G.) — both in India; the National Academy of Sciences of Buenos Aires (M.R.P.) and Fundación del Centro de Estudios Infectológicos (G.L.), Buenos Aires; Rafic Hariri University Hospital (P.A.H.) and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) and Infectious Diseases Hospital (A. Alhasawi), Kuwait City, Kuwait; Universidad Nacional de Colombia and Clinica Colsanitas (C.A.A.-M.) and the Ministry of Health (M.L.M.R.), Bogota, Colombia; the Ministry for Preventive Health, Riyadh, Saudi Arabia (A. Asiri, A. Alotaibi); Oslo University Hospital (P.A., A.B.-D.) and Research Council of Norway (J.-A.R.), Oslo; Secretaria de Salud de Honduras (N. Cerrato) and the National Autonomous University of Honduras (M.T.M.), Tegucigalpa; Penang Hospital, Penang (T.S.C.), and Hospital Sungai Buloh and Jalan Hospital, Selangor (S.K.) — both in Malaysia; University Hos-pital Center Mother Theresa (N. Como) and the National Agency for Medicines and Medical Devices (N.S.), Tirana, Albania; the HRB Clinical Research Facility, University College Cork, Cork (J.E.), and the Department of Health and Children, Dublin (P. Lennon, T.M.) — both in Ireland; Universidad Peruana Cayetano Heredia, Lima, Peru (P.J.G., E.G.); Vilnius University Hospital Santaros Klinikos (L.G.) and Vilnius University, Institute of Clinical Medicine (L.J.), Vilnius, Lithuania; Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan (M. Hassan, A.R.); the National Hepatology and Tropical Medicine Research Institute (M. Hassany) and the Ministry of Health and Population (H.Z.), Cairo; the National Institute of Health Research and Development (I.I.) and Rumah Sakit Umum Pusat Persahabatan (M.R.R.), Jakarta, Indonesia; the Italian Medicines Agency, Rome (N.M.), and the University of Verona, Verona (E.T.) — both in Italy; the Ministry of Health (S. Manevska) and the University Clinic of Infectious Diseases and Febrile Condi-tions (M.S.), Skopje, North Macedonia; the Oswaldo Cruz Foundation, Rio de Janeiro (E.P.N., P.P.S.R.); and the Finnish Institute for Health and Welfare and the University of Finland (M.P.) and Helsinki University Hospital (K.A.O.T.), Helsinki, and South Karelian Central Hospital, Lappeenranta (K.A.O.T.) — all in Finland.References1. World Health Organization. A coor-dinated global research roadmap: 2019 novel coronavirus. March 2020 (https://www.who.int/publications/m/item/ a-coordinated-global-research-roadmap).2. World Health Organization. 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All rights reserved. n engl j med 384;6 nejm.org February 11, 2021 511Repurposed Antivir al Drugs for Covid-195. Early Breast Cancer Trialists’ Collab-orative Group (EBCTCG). Effects of che-motherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687-717.6. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 — final report. N Engl J Med 2020; 383: 1813-26.7. Wang Y, Zhang D, Du G, et al. Remde-sivir in adults with severe Covid-19: a ran-domised, double-blind, placebo-controlled, multicentre trial. Lancet 2020; 395: 1569-78.8. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate Covid-19: a randomized clinical trial. JAMA 2020; 324: 1048-57.9. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 2020; 383: 1827-37.10. Peto R. 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Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. In-tensive Care Med 2020; 46: 1937-40.21. Flammer JR, Dobrovolna J, Kennedy MA, et al. The type I interferon signal-ing pathway is a target for glucocorti-coid inhibition. Mol Cell Biol 2010; 30: 4564-74.22. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa2021436.23. World Health Organization. Corti-costeroids for COVID-19: living guidance, 2 September 2020 (https://apps . who . int/ iris/ handle/ 10665/ 334125).Copyright © 2020 Massachusetts Medical Society.The New England Journal of Medicine Downloaded from nejm.org at The University of British Columbia Library on June 11, 2021. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved.
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Repurposed Antiviral Drugs for Covid-19 : Interim WHO Solidarity Trial Results
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