repurposed antiviral drugs for covid-19 interim who

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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 Henao-

Restrepo, 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; †National Coordinator; ‡Executive Group;§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†‡.

Austria:§. Belgium:§. Brazil: Oswaldo Cruz Foundation EP Nunes*, PPS Reges†. Canada: University of British Columbia S

Murthy*‡; 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†‡§. 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 Reddy‡. 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*†‡. 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 Røttingen‡. 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*†‡. 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 Karim‡.

Spain: Hospital Clinico San Carlos, UCM, IdISSC, Madrid A Portoles*; Agency of Medicine and Medical Devices C Hernández-

Garcia†‡. 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 (J-

A.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 [email protected]

All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprintthis version posted October 15, 2020. .https://doi.org/10.1101/2020.10.15.20209817doi: medRxiv preprint

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

mailto:[email protected]

https://doi.org/10.1101/2020.10.15.20209817

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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-β1a (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-β1a.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 “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 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 3x2=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 (“intent-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 in-

hospital 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-β1a 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-β1a might be highly effective involved only

about 100 COVID patients (NCT04385095), but the ongoing placebo-controlled ACTT-3 trial of subcutaneous

Interferon-β1a 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-SARS-

Cov-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 β1a by Merck KGaA (subcutaneous) and Faron (intravenous).



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https://doi.org/10.1101/2020.10.15.20209817

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.

“28-d KM %” is the Kaplan-Meier 28-day % risk of in-hospital death. “No. died” includes 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.

† Egypt, India, Indonesia, Iran, Kuwait, Lebanon, Malaysia, Pakistan, Philippines, Saudi Arabia, South Africa.

‡ Compliance is calculated only among those who died or were discharged alive, and is 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*

Entered No. %

No. died

28-d KM%

Active Control Active Control Active Control Active Control

All participants 11266 100 1253 11.8

2743 2708 947 906 1399 1372 2050 2050

Entry characteristics

Age (years)

<50 3995 35 237 6.2 961 952 335 317 511 501 720 697

50-69 5125 45 618 12.8 1282 1287 410 396 597 596 934 973

70+ 2146 19 398 20.4 500 469 202 193 291 275 396 380

Respiratory support

No oxygen at entry 3204 28 78 2.5 661 664 345 341 528 539 482 490

On oxygen at entry 7146 63 844 12.8 1828 1811 517 483 759 719 1429 1430

Already ventilated 916 8 331 39.0 254 233 85 82 112 114 139 130

Bilateral lung lesions

No 1266 11 49 3.7 287 259 154 170 235 256 162 155

Yes 8832 78 1043 12.7 2175 2153 656 618 985 945 1723 1718

Not imaged at entry 1168 10 161 14.9 281 296 137 118 179 171 165 177

Prior days in hospital

0 3289 29 319 9.8 724 712 296 281 423 403 678 677

1 3713 33 384 10.8 917 938 317 312 442 445 681 662

2+ 4264 38 550 14.6 1102 1058 334 313 534 524 691 711

Geographic location

Europe** or Canada 2488 22 188 7.8 715 698 286 267 349 350 254 244

Latin America§ 1941 17 400 22.7 470 514 97 96 145 148 474 478

Asia and Africa† 6837 61 665 10.3 1558 1496 564 543 905 874 1322 1328

Other characteristics

Male 6985 62 852 13.0 1706 1725 574 535 851 802 1303 1278

Current smoking 830 7 93 11.8 178 161 92 82 141 124 136 138

History of – Diabetes 2768 25 379 14.7 707 666 199 205 341 324 489 537

- Heart disease 2337 21 319 14.7 571 567 193 194 289 290 427 456

- Chronic lung disease 635 6 102 17.2 151 145 62 66 95 87 114 109

- Asthma 529 5 56 11.5 139 139 41 46 65 56 75 97

- Chronic liver disease 135 1 21 17.2 36 41 15 14 15 23 11 22

Compliance with allocated treatment

% who were taking the study drug midway through its scheduled duration‡ 95.8 1.6 94.6 5.6 93.6 2.0 93.7 1.9

% of those reported as discharged who were still in hospital on: Day 7

69 59 64 54 68 59 55 51

Day 14 22 19 23 20 31 22 19 18

Day 21 9 8 11 10 12 11 8 7



https://doi.org/10.1101/2020.10.15.20209817

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

954 active Hydroxychloroquine

1,411 active Lopinavir

2,063 active Interferon

651 IFN + Lopinavir 1,412 IFN + Local SoC

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 v 308 Entry ≥ Sep; not reported on in late Sep

7 no/uncertain consent to FU

2,725 control for Remdesivir


909 control for Hydroxychloroquine

1,380 control for Lopinavir

2,064 control for Interferon

679 Lopinavir 1,385 Local SoC

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)



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)



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 Entry ≥ Sep [stop to be Oct 15]; not reported on in late Sep





https://doi.org/10.1101/2020.10.15.20209817

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

0

20

40

60

80

100

0 7 14 21 28

Rate ratio, 1.00 (95% CI, 0.79-1.25) P=0.97 by log-rank test

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

Mo

rta

lity (

%)

0 7 14 21 28 0

5

10

15

Control

Lopinavir

(d) Interferon vs its control

0

20

40

60

80

100

0 7 14 21 28


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


Mo

rta

lity (

%)

0 7 14 21 28 0

5

10

15

Control

Interferon

(a) Remdesivir vs its control

0

20

40

60

80

100

0 7 14 21 28


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


Mo

rta

lity (

%)

0 7 14 21 28 0

5

10

15 Control

Remdesivir

(b) Hydroxychloroquine vs its control

0

20

40

60

80

100

0 7 14 21 28


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


Mo

rta

lity (

%)

0 7 14 21 28 0

5

10

15

Control

Hydroxychloroquine



https://doi.org/10.1101/2020.10.15.20209817

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

<50 61/961 (6.9) 59/952 (6.8) 2.3 29.8 1.08 [0.67-1.73] 50-69 154/1282 (13.8) 161/1287 (14.2) -7.6 77.5 0.91 [0.68-1.21] 70+ 86/500 (20.5) 83/469 (21.6) -2.9 41.5 0.93 [0.63-1.39]

Respiratory support at entry

Ventilated 98/254 (43.0) 71/233 (37.8) 7.6 40.8 1.20 [0.80-1.80] Not ventilated 203/2489 (9.4) 232/2475 (10.6) -15.8 108.0 0.86 [0.67-1.11]

Total 301/2743 (12.5) 303/2708 (12.7) -8.3 148.8 0.95 [0.81-1.11]

2p = 0.50 Heterogeneity around total 3 2 : 3.9

(b) Hydroxychloroquine Age at entry

<50 19/335 (5.7) 19/317 (5.8) 0.9 9.2 1.10 [0.47-2.57] 50-69 55/410 (12.1) 31/396 (7.1) 10.8 21.2 1.66 [0.95-2.91] 70+ 30/202 (14.0) 34/193 (17.8) -3.5 15.8 0.80 [0.42-1.53]


Ventilated 35/85 (39.2) 27/82 (32.3) 3.4 14.8 1.26 [0.65-2.46] Not ventilated 69/862 (7.4) 57/824 (6.6) 4.7 31.4 1.16 [0.73-1.84]

Total 104/947 (10.2) 84/906 (8.9) 8.1 46.2 1.19 [0.89-1.59]


(c) Lopinavir Age at entry

<50 20/511 (3.6) 27/501 (4.9) -3.0 11.7 0.77 [0.36-1.64] 50-69 66/597 (9.8) 57/596 (9.1) 2.7 30.4 1.09 [0.68-1.74] 70+ 62/291 (20.4) 62/275 (22.7) 0.0 30.2 1.00 [0.63-1.60]


Ventilated 35/112 (28.1) 35/114 (28.7) 1.3 16.7 1.08 [0.57-2.03] Not ventilated 113/1287 (8.1) 111/1258 (8.7) -1.6 55.6 0.97 [0.69-1.37]

Total 148/1399 (9.7) 146/1372 (10.3) -0.4 72.3 1.00 [0.79-1.25]


(d) Interferon Age at entry

<50 48/720 (7.5) 35/697 (5.3) 7.5 20.6 1.44 [0.82-2.54] 50-69 122/934 (14.3) 108/973 (11.4) 13.3 56.9 1.26 [0.90-1.78] 70+ 73/396 (19.9) 73/380 (20.9) -4.0 35.8 0.89 [0.58-1.38]


Ventilated 55/139 (42.4) 40/130 (33.8) 7.7 23.0 1.40 [0.82-2.40] Not ventilated 188/1911 (10.9) 176/1920 (9.5) 9.1 90.3 1.11 [0.84-1.45]

Total 243/2050 (12.9) 216/2050 (11.0) 16.8 113.3 1.16 [0.96-1.39]


0.0 0.5 1.0 1.5 2.0 Active better

Active worse

99% or 95% confidence interval (CI), K-M Kaplan-Meier.



https://doi.org/10.1101/2020.10.15.20209817

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 2x2 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 the HR’s CI). RR is got by taking logeRR 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. † For balance, controls in the 2:1 studies count twice in the control totals and subtotals.


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

Solidarity: no O2 11/661 (2.0) 13/664 (2.1) -0.6 6.0 0.90 [0.31-2.58]

Solidarity: low/hi-flow O2 192/1828 (12.2) 219/1811 (13.8) -16.9 101.8 0.85 [0.66-1.09]

Solidarity ventilation 98/254 (43.0) 71/233 (37.8) 7.6 40.8 1.20 [0.80-1.80]

ACTT: no O2 3/75 (4.1) 3/63 (4.8) -0.3 1.5 0.82 [0.10-6.61]

ACTT: low-flow O2 9/232 (4.0) 25/203 (12.7) -8.0 6.7 0.30 [0.11-0.81] ACTT: hi-flow O2 or non-invasive ventilation 19/95 (21.2) 20/98 (20.4) 0.2 9.6 1.02 [0.44-2.34]

ACTT: invasive ventilation 28/131 (21.9) 29/154 (19.3) 1.7 14.3 1.13 [0.57-2.23]

Wuhan: low-flow O2 11/129 (8.5) (7/68) x2† (10.3) -0.8 3.7 0.81 [0.21-3.07] Wuhan: hi-flow O2 or ventilation 11/29 (37.9) (3/10) x2† (30.0) 0.6 1.8 1.40 [0.20-9.52]

SIMPLE: no O2 5/384 (1.3) (4/200) x2† (2.0) -0.9 2.0 0.64 [0.10-3.94]

Subtotals Lower risk groups (with no ventilation) 231/3309 (7.0) 282/3277 (8.6) -27.6 121.6 0.80 [0.63-1.01]

Higher risk groups 156/509 (30.6) 126/505 (25.0) 10.1 66.5 1.16 [0.85-1.60]

Total 387/3818 (10.1) 408/3782 (10.8) -17.5 188.2 0.91 [0.79-1.05]

2p = 0.20

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.



https://doi.org/10.1101/2020.10.15.20209817

1

This page will be deleted before publication, and replaced by the Journal’s cover page

Supplementary online material for

Repurposed antiviral drugs for COVID-19

– interim WHO SOLIDARITY trial results

2

Repurposed antiviral drugs for COVID-19 – interim WHO SOLIDARITY trial results

Contents list for supplementary online material

Page 3 Membership: Writing Committee; Data and Safety Monitoring Committee 4 Membership: International Steering Committee and its Executive Group 5 National investigators and researchers 12 Data managers, statistical analysts and WHO trial co-ordination team 12 Other collaborators in participating countries 14 Acknowledgements 15 Supp. Table S1. Treatment allocation vs respiratory support in hospital in patients not ventilated at entry and eventually discharged alive

16 Supp. Table S2. Use of corticosteroids and other non-study drugs

17 Supp. Table S3. Multivariate analysis simultaneously estimating all 4 treatment effects

18 Supp. Fig S1. Effects on 28-day in-hospital mortality of (a) Remdesivir, (b) Hydroxychloroquine, (c) Lopinavir, (d) Interferon

19 Supp. Fig S2. Effects of Remdesivir on the 28-day risk of death from any cause, subdivided by Respiratory support at entry

20 Supp. Fig S3. Effects of Hydroxychloroquine on the 28-day risk of death from any cause, subdivided by Respiratory support at entry

21 Supp. Fig S4. Effects of Lopinavir on the 28-day risk of death from any cause, subdivided by Respiratory support at entry

22 Supp. Fig S5. Effects of Interferon on the 28-day probability of death from any cause, subdivided by Respiratory support at entry

23 Supp. Fig S6. RRs of any death, Remdesivir vs Control, by entry characteristics

24 Supp. Fig S7. RRs of any death, Hydroxychloroquine vs Control, by entry characteristics

25 Supp. Fig S8. RRs of any death, Lopinavir vs Control, by entry characteristics

26 Supp. Fig S9. RRs of any death, Interferon vs Control, by entry characteristics

27 Supp. Fig S10. RRs for the composite outcome of death or initiation of ventilation

28 Supp. Fig S11. Treatment allocation vs cardiac death

3

Writing Committee

Hongchao Pan, Ph.D., Richard Peto, F.R.S., Quarraisha Abdool Karim, Ph.D., Marissa Alejandria

M.D., M.Sc., Ana Maria Henao-Restrepo, 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., K. Srinath Reddy M.D., D.M., Mirta Roses Periago M.D., MPH, Vasee

Sathiyamoorthy B.M.B.Ch., Ph.D., John-Arne Røttingen M.D., Ph.D., Soumya Swaminathan M.D.

Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom (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, University of the Philippines, Manila, Philippines

(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.), Digestive Disease Research

Institute, Teheran University of Medical Sciences, 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 (J-A.R.), World Health Organization, Geneva, Switzerland (A-

M.H-R., M-P.P., V.S.M., S.S.).

Global Data and Safety Monitoring Committee

Aldo Maggioni (chair), Abdel Babiker, Deborah Cook, Arjen Dondorp, Gagandeep Kang

4

International Steering Committee

*National Principal Investigators; †National Coordinators; ‡Members of the Executive Group.

Albania: University Hospital Centre Mother Theresa, 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†‡.

Austria: Through DISCOVERY add-on study. Belgium: Through DISCOVERY add-on study.

Brazil: Oswaldo Cruz Foundation EP Nunes*, PPS Reges†. Canada: University of British Columbia

S Murthy*‡; 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: Through DISCOVERY add-on study. Hospices Civils de Lyon,

Lyon F Ader*; Institut National de la Santé Et de la Recherche Médicale, Paris MP Kieny†‡.

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 Reddy‡. 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*†‡. Ireland: HRB Clinical Research Facility, University College Cork J Eustace*;

Department of Health T Maguire†. Italy: University of Verona E Tacconelli*; Italian Medicines

Agency (AIFA) 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†. Lithuania: University Hospital Santaros Klinikos, Vilnius L Jancoriene*, L

Griskevicius†. Luxembourg: Through DISCOVERY add-on study. 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

Røttingen‡. 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*†‡. 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 Karim‡. Spain: Hospital Clinico San Carlos,

UCM, IdISSC, Madrid A Portoles*; Agency of Medicine and Medical Devices C Hernández-

Garcia†‡. Switzerland: Lausanne University Hospital O Manuel*†.

Executive Group of the International Steering Committee

John-Arne Røttingen (chair), Quarraisha Abdool Karim, Marissa Alejandria, César Hernández

García, Marie Paule Kieny, Reza Malekzadeh, Srinivas Murthy, K. Srinath Reddy, Mirta Roses

Periago, Soumya Swaminathan, Richard Peto (independent statistician).

5

National investigators and researchers

This does not include members of the International Steering Committee or its Executive Group.

Albania: University Hospital Centre Mother Theresa, Tirana NGJ Gjermeni, E Meta.

Argentina: Health Ministry JB Balbuena, JM Castelli, A Mykietiuk, C Vizzotti; Hospital de

Infecciosas Francisco J Muñiz, Buenos Aires V Chediack, E Cunto, L de Vedia, C Domínguez, J

Fernández, N Lista, A Rodríguez; Hospital General de Agudos José Ramos Mejía, Buenos Aires S

Caimi, C Delgado, M Losso, F Masciottra, V Pachioli, J Toibaro; Hospital General de Agudos Juan

A Fernández, Buenos Aires J Barletta, J Carrillo, N D’Amico, L Hermida, M Jaume, C Luna, M

Padilla, J Patroso, L Perez Blanco, J Presas, MJ Rolon, AL Sisto, S Themines; Hospital Julio C

Perrando, Resistencia, Chaco V Arce, P Arribillaga, RA Ferreyra, ML Lescano, F Tito, L Verón;

Hospital Mariano y Luciano de la Vega, Moreno A Chalco, J Farina, M Provenzano; Hospital

Nacional Profesor Alejandro Posadas, Palomar I Alonso, RA Alzola, M Benedetti, D Di Pilla, P

Díaz Aguiar, C Giudiche, M Golikow, M Jacobo, D Laplume, F Loiacono, A López, L Olleros, C

Pallavicini, F Riveros, G Torales; Hospital Prof. Bernado Houssay, Vicente López M Altamirano, L

Barcelona, V Berdiñas, C Fogar, A Martin; Hospital Provincial Dr José María Cullen, Santa Fé RA

Avila, J Burgui, N Carrizo, M Filippi, M Gomez, V Reichert; Hospital Rawson, Córdoba M Alvarez,

AC Cazaux, M Díaz, HM Hurtado, LR Lorena, ML Marianelli, L Orellano, C Salvay, M Simonetta.

Austria: Through DISCOVERY add-on study. Paracelsus Medical University Salzburg, SCRI-

CCCIT and AGMT A Egle, R Greil; Medizinische Universität Innsbruck, Innsbruck M Joannidis.

Belgium: Through DISCOVERY add-on study. CHR de la Citadelle, Liège A Altdorfer, V Fraipont;

Cliniques Universitaires de Saint Luc, Bruxelles L Belkhir; Hôpital Erasme, Bruxelles M Hites.

Brazil: Fundação Universidade de Pernambuco DB Miranda Filho, P Monteiro; Hospital Couto

Maia VPS Almeida, CX Nunes; Hospital das Clínicas da Universidade Federal de Minas Gerais H

Duani; Hospital das Clínicas da Universidade Federal do Paraná GL Breda, SM Raboni; Hospital

Estadual de Sumaré AJS Colussi, MC Ramos, LF Ruffing; Hospital Federal do Estado do Rio de

Janeiro EC João; Hospital Regional de Mato Grosso do Sul JHC Croda; Hospital Regional de São

José GA Pinto; Hospital São José de Doenças Infecciosas EAG Arruda; Hospital Sírio Libanês

MFDB Corradi; Hospital Universitário Clementino Fraga Filho ES Machado, FCQ Mello; Instituto

de Infectologia Emilio Ribas LC Pereira Junior, TNL Souza, ALC Toscano; Oswaldo Cruz

Foundation VGV Santos.

Canada: Centre Hospitalier de l'Universite de Montreal FM Carrier, M Durand; Centre Hospitalier

Universitaire de Sherbrooke F Lamontagne; CHU de Quebec-Universite Laval D Bellemare, E

Cloutier, O Costerousse, TV Tran, A Turgeon; Grey Nuns Community Hospital H Hoang; Hopital

Montfort N Chagnon; IUCPQ F Lellouche; Lions Gate Hospital J Douglas; Markham Stouffville

Hospital, E Fera; McGill University, Montreal MP Cheng, C Costiniuk, L Harrison, K Khwaja, M

Klein, N Kronfli, TC Lee, J Papenburg, M Semret; McMaster university E Duan; Memorial

University of Newfoundland T Azher; North York General Hospital, Toronto A Geagea; Ottawa

Hospital S English; Queen's University S Perez-Patrigeon; Queensway Carleton Hospital M

Rushton; Royal Alexandra Hospital A Singh; Royal Victoria Regional Health Centre G DiDiodato;

Sinai Health System, Toronto M Fralick; St Paul’s Hospital N Press; Sunnybrook Hospital R Fowler,

A Rishu; Trillium Health Partners C Graham; University Health Network, Toronto I Bogocj;

University of Alberta N Lee, C O'Neil; University of British Columbia D Ovakim; University of

Calgary, Calgary J Conly, CD Fell, R Lim, R Somayaji, A Tremblay, E Vakil; University of

Manitoba Y Keynan, R Zarychanski; Vancouver General Hospital A Mah; Western University S

Parvathy, M Silverman; William Osler Health System A Binnie, S Borgia.

6

Colombia: Clínica Colsanitas, Sede Clínica Iberomérica I Zuluaga; Clínica Colsanitas, Sede

Clínica Reina Sofia J Chacón, D Garzón, F Guevara; Clínica Colsanitas, Sede Clinica Santa Maria

del Lago JS Bravo; Clínica Colsanitas, Sede Clínica Sebastian de Belalcazar JM Oñate; Clínica

Colsanitas, Sede Clínica Universitaria Colombia S Lozano-González; JA Rojas-Murrugarra, CS

Saavedra; Fundación Cardio Infantil, Iinstituto del Corazón EV Váquiro, F Varón-Vega; Fundación

Hospital Universidad del Norte H Macareno; Fundación Santa Fe de Bogotá M Caicedo; Fundación

Valle de Lili F Rosso; Hospital Universitario San Ignacio, Pontificia Universidad Javeriana SL

Valderrama.

Egypt: Ain Shams University G Elassal; AL Azhar University S Zaki; Assuit University S Hassany, E

Moustafa; Cairo University A Abdalmohsen, A Abdelbary, N Asem, H Masoud; Ministry of Health

and Population, W Amin, M Elshesheny, M Fathy, N Fathy, N Fayed, A Hammam, M Solyman

Kabyl, M Mohamed, A Mohamed Gouda, S Okasha, A Rafik, A Sedky, S Tarek, A Tharwat;

National Hepatology and Tropical Medicine Research Institute A Abdel Baki; National Liver

Institute W Abdel-Razek; National Research Center E Kamal.

Finland: Helsinki University Hospital, Helsinki M Myllärniemi, J Paajanen, A Renner; Tampere

University Hospital, Tampere J Rutanen, MU Sinisalo.

France: Through DISCOVERY add-on study. Amiens University, Amiens C Andrejak, JP Lanoix,

Y Zerbib; ANRS, Paris A Diallo, N Mercier; Centre hospitalier Andrée Rosemon, Cayenne, Guyane

F Djossou; Centre Hospitalier Annecy Genevois, Annecy D Bougon, V Tolsma; Centre Hospitalier

Universitaire de Besançon, Besançon K Bouiller, JC Navellou; Centre Hospitalier Universitaire de

Nantes, Nantes B Gaborit, F Raffi, J Reignier; Centre Hospitalier Universitaire Dijon-Bourgogne,

Dijon P Andreu, L Piroth, JP Quenot; Centre Hospitalier Universitaire Grenoble Alpes, Grenoble O

Epaulard, N Terzi; Centre Régional Universitaire de Nancy, Vandoeuvre Lés Nancy F Goehringer, A

Kimmoun; Centre Régional Universitaire de Nice, Nice J Courjeon, J Dellamonica, S Leroy, CH

Marquette; Centre Régional Universitaire de Rennes, Rennes F Laine, B Laviolle, Georges

Pompidou European Hospital, Paris D Lebeaux, Groupe Hospitalier de la région Mulhouse Sud

Alsace, Mulhouse O Hinschberger, Y Mootien; Groupe hospitalier La Pitié-Salpêtrière, Paris J

Mayaux, V Pourcher; Groupe Hospitalier Paris Saint Joseph, Paris C Bruel, B Pilmis; Henri-

Mondor Hospital, Créteil S Gallien, A Mekontso Dessap; Hôpital Bichat, Paris T Alfaiate, D

Belhadi, L Bouadma, C Burdet, A Dechanet, A Dupont, S Laribi, FX Lescure, F Mentre, N Peiffer-

Smadja, G Peyvatin, MC Tellier, JF Timsit, Y Yazdanpanah; Hôpital Cochin, Paris S Kerneis, M

Lachatre, O Launay; Hôpital de Bicêtre, Le Kremlin Bicêtre S Figueiredo, S Jauréguiberry; Hôpital

Delafontaine, Saint Denis J Aboab, F Crockett, N Sayre; Hôpital d'instruction des armées Bégin,

Saint Mandé C Dubost); Hôpital Marie Lannelongue, Le Plessis Robinson J Le Pavec, F Stefan;

Hôpital Saint-Antoine, Paris K Lacombe; Hôpital Saint-Louis, Paris JM Molina, M Noret; Hôpital

Tenon, Paris G Pialoux; Hospices Civils de Lyon, Lyon JC Richard, J Textoris, F Wallet; Institut

National de la Santé Et de la Recherche Médicale, Paris C Delmas, J Saillard; Lapeyronie

University Hospital, Montpellier K Klouche; Lille University Hospital, Lille K Faure, E Faure, J

Poissy; Metz-Thionville hospital, Ars-Laquenexy R Gaci, C Robert; Montpellier University Hospital,

Montpellier V Le Moing, A Makinson; Pontchaillou University Hospital, Rennes F Benezit; Reims

University Hospital, B Mourvillier ; Sorbonne Université, Paris D Costagliola; Strasbourg

University Hospital, Strasbourg R Clere-Jehl, F Danion , F Meziani, V Poindron; Toulouse

University Hospital, Toulouse F Bounes, G Martin-Blondel; Tourcoing Hospital, Tourcoing V Jean-

Michel, E Senneville; Tours University Hospital, Tours D Garot; University Hospital Centre of

Bordeaux, Bordeaux, C Cazanave, D Gruson, D Malvy; University Hospital of Martinique, Fort-de-

France C Chabartier; University Hospital of Saint-Etienne, Saint-Etienne E Botelho-Nevers, A

Gagneux-Brunon, G Thiery; University Hospital, Rennes C Fougerou.

7

Honduras: Hospital Atlantida, la Ceiba AA Fiallos; Hospital Leonardo Martinez, San Pedro Sula L

Erazo; Hospital Militar, Tegucigalpa R Figueroa; Hospital San Felipe, Tegucigalpa JJ Flores, L

Melendez; Instituto Cardiopulmonar, Tegucigalpa C Aguilar, W Moncada.

India: AIIMS, Bhopal S Atal, R Joshi, S Khadanga, A Ray, S Saigal, S Sharma; AIIMS, Jodhpur A

Avinash, P Bhardwaj, P Bhatia, J Charan, N Chauhan, N Dutt, M Garg, V Nag, B Shadrach; AIIMS,

New Delhi R Aggarwal, DK Baidya, , R Guleria, CA Kayina, A Mittal, N Nischal, M Soneja, K

Soni, S Maitra, A Trikha, N Wig; AIIMS, Rishikesh G Chikara, P Gupta, R Kant, V Krishnan, B

Mohan, P Panda; Apollo Hospitals, Greams Lane, Chennai N Ramakrishnan, BK Tirupakuzhi

Vijayaraghavan, R Venkatasubramanian; Apollo Speciality Hospitals, Vanagaram, Chennai R

Ebenezer, S Krishnamoorthy, D Suresh Kumar; Army Institute of Cardio Thoracic Sciences, Pune G

Bhati, V Marwah, D Peter, TVSVGK Tilak; B. J. Government Medical College & Sassoon General

Hospital, Pune R Borse, B Daswani, S Divhare, D Ogale, S Sangale, M Tambe, R Waghmare; B.J.

Medical College& New Civil Hospital, Ahmedabad C Desai, D Raval, K Upadhyay; Bharati

hospital, Pune N Agrawal, S Iyer, K Reddy, S Rege, J Shah; BYL Nair Hospital, Mumbai R

Bhadade, R de Souza, M Harde; Chirayu Medical College & Hospital, Bhopal A Goenka, A

Mangalgiri, M Maurya, R Parate, K Singh, A Tiwari, R Verma; Christian Medical College, Vellore

OC Abraham, A Balachandran, TD Sudarsanam; Gandhi Hospital, Hyderabad (V Aedula, T C

Bingi, V Jamalapuram, H Kalakuntla, A K Maurya, K Nagmani, K Padma Malini, M Rajarao, KT

Rao, R Sudarsi, M D Suleman; GMERS Medical College & Hospital, Gotri, Vadodara K Mehta, P

Patel, C Rathod; Government Medical College and New Civil Hospital, Surat C Acharya, K Bhatt, M

Chaudhari, V Chaudhary, B Divakar, A Gamit, S Gamit, B Kantharia, A Kavishvar, M Momin, C

Patel, V Patel, S Patel, H Patel, A Vasava, M Verma; Government Medical College, Nagpur S

Khandare, D Chand, M Kalikar, S Mitra, U Narlawar; Government. Siddhartha Medical College,

Vijayawada B Bhargavi, G Chakradhararao, D Durgaprasad, K Seshaiah; ICMR- National AIDS

Research Institute, Pune S Chidrawar, A Kadam, S Kalme, S Kamble, M Mamulwar, S Panda, S

Sane; Indian Council of Medical Research, New Delhi B Bhargava, R Gangakhedkar, N Gupta;

Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai T Banu, V

Damodaran, L Narasimhan, G Natarajan, V Rajendran, KM Sudha, S Sudharshini, E Therani; Rajan

Omandurar Medical College & Hospital, Chennai R Jayanthi, J Komathi, KP Manimaran, T Ramesh

Kumar, A Revathi; Pandit Deendayal Upadhyay Government Medical College, Rajkot M Bhapal, S

Misra, A Singh, A Trivedi); PD Hinduja National Hospital and Medical Research Centre, Mumbai

U Agrawal, Z Udwadia; RCSM GMC CPRH, Kolhapur A Paritekar, G Patil, A Waikar; Sardar

Vallabhbhai Patel Institute of Medical Sciences and Research, Ahmedabad S Malhotra, D Roy; SMS

Medical College & Hospital, Jaipur A Agrawal, S Bhandari, S Mahavar, R Sharma, S Sharma, A

Singh; Voluntary Health Services-Infectious Diseases Medical Centre, Chennai N Kumarasamy, P

Selvamuthu; WHO-India, New Delhi M Ahmad, M Gupta, V Purohit.

Indonesia: National Institute of Health Research and Development AR Afrilia, D Arlinda, R Avrina,

LE Bang, SL Driyah, M Erastuti, T Fajarwati, M Karyana, N Nurhayati, C Opitasari, AA Pradana, Y

Risniati, RI Sugiyono, NH Susanto, AK Syarif, A Yulianto; RS University Airlangga, Surabaya M

Amin; RS University Udayana Bali IKA Somia, RS YARSI, Jakarta I Kusuma; RSJ Prof. Dr.

Soerojo, Magelang HA Mahmudji; RSPAU Dr. Esnawan Antariksa, Jakarta FE Sari; RSPI Prof. Dr.

Sulianto Saroso, Jakarta PA Sitompul; RSUD Dr. Achmad Mochtar, Bukittinggi D Herman; RSUD

Dr. Moewardi, Solo H Harsini; RSUD Dr. Saiful Anwar, Malang YJ Sugiri; RSUD Dr. Soetomo,

Surabaya S Soedarsono; RSUP Dr. Hasan Sadikin, Bandung Y Hartantri; RSUP Dr. Kariadi,

Semarang SB Raharjo; RSUP Dr. M. Djamil, Padang I Medison; RSUP Dr. Sardjito, Yogyakarta BS

Riyanto; RSUP Dr. Wahidin Sudirohusodo, Makassar I Djaharuddin; RSUP Fatmawati, Jakarta

AY Djojo; RSUP H. Adam Malik, Medan A Rahmaini; RSUP Persahabatan, Jakarta F Isbaniah;

RSUP Prof. Dr. R. D Kandou Manado A Nugroho; RSUP Sanglah, Bali GK Sajinadiyasa; RSUPN

Dr. Cipto Mangunkusumo, Jakarta CW Pitoyo.

8

Iran (Islamic Republic of): Ahvaz Jundishapur University of Medical Sciences, Ahvaz F Amini, S

Moogahi, M Varnasseri, MJ Yadyad, F Yousefi; Alborz University of Medical Sciences, Karaj Z

Siami, A Soleimani; Arak University of Medical Sciences, Arak A Kamali, B Mahmoodiyeh, H

Sarmadian, D Shojaei, S Soltanmohammad; Babol University of Medical Sciences, Babol M Bayani,

S Ebrahimpour, M Javanian, M Sadeghi Haddad Zavareh, M Shokri; Golestan University of Medical

Sciences, Gorgan B Khodabakhshi, A Norouzi, S Tavassoli; Guilan University of Medical Sciences,

Rasht F Joukar, L Mahfoozi, F Mansour-Ghanaei, A Pourkazemi; Isfahan University of Medical

Sciences, Isfahan A Hakamifard, M Salahi, K Shirani; Kermanshah University of Medical Sciences,

Kermanshah M Afsharian, A Janbakhsh, F Mansouri, R Miladi, P Mohamadi, Z Mohseni Afshar, B

Sayad, M Shirvani, S Vaziri, MH Zamanian; Mashhad University of Medical Sciences, Mashhad M

Amini, F Barazandeh, S Hafizi Lotfabadi, R Khodashahi, M Mozdourian, SN Saberhosseini, M

Saberi, N Saber-Moghaddam, Y Yazdanpanah; Mazandaran University of Medical Sciences, Sari F

Baba Mahmoodi, F Fallahpoor Golmaee; National Institute for Medical Research Development,

Tehran B Mesgarpour; Qazvin University of Medical Sciences, Qazvin A Karampour, S Kiani Majd,

R Najafipour, H Najari, E Zare Hoseinzade; Qom University of Medical Sciences, Qom SY Foroghi

Ghomi, MR Ghadir, M Gheitani, SS Hashemi Madani, A Hormati, J Khodadadi; Saveh University of

Medical Sciences, Saveh A Akhavi Mirab, M Mesri, H Mozaffar; Shahid Beheshti University of

Medical Sciences, Tehran P Baghaei, F Dastan, P Tabarsi; Shahid Sadoughi University of Medical

Sciences, Yazd SA Mousavi Anari; Shiraz University of Medical Sciences, Shiraz MJ Fallahi, M

Moghadami, S Yaghoubi, F Zand; Tabriz University of Medical Sciences, Tabriz K Ansarin, H

Mikaeili, M Nazemiyeh, A Taghizadieh; Tehran University of Medical Sciences, Tehran S Eghtesad,

F Ghiasvand, H Hosseini, N Khajavirad, M Mohraz, H Poustchi, A Sadeghi, MA Sahraian, MR

Salehi, AR Sima.

Ireland: Beaumont Hospital and Royal College of Surgeons in Ireland E deBarra; Mater

Misericordiae University Hospital E Muldoon; Mercy University Hospital A Jackson; St James's

Hospital and Trinity College, Dublin C Bergin; St Vincent's University Hospital and School of

Medicine University College Dublin C McCarthy; University Hospital Galway JG Laffey.

Italy: AOU Citta della Salute e Scienza, Torino S Corcione, FG De Rosa, S Scabini; ASST di

Monza, Ospedale San Gerardo, Monza L Bisi, P Bonfanti, G gustinetti, F Iannuzzi; ASST

Fatebenefratelli Sacco A Capetti, M Galli, S Rusconi; ASST Santi Paolo e Carlo, Milano F Bai, A

d’Arminion Monforte, E Merlini; ASST Valtellina e Alto Lario, Ospedale di Sondalo E Menatti, P

Zucchi; Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro F Barchiesi, B Canovari;

Azienda Sanitaria Universitaria Friuli Centrale (ASU FC) D Pecori, C Tascini, P Della Siega, M

Merelli; Azienda Socio Sanitaria Territoriale di Cremona N Cocco, B Drera, C Fornabaio, A Pan;

Brescia Spedali Civili General Hospital F Castelli, E Focà, E Roldan; Fondazione IRCCS Ca'

Granda Ospedale Maggiore Policlinico, Milan A Bandera, A Gori; Fondazione Policlinico

Universitario A. Gemelli IRCCS R Cauda, A Cingolani, K de Gaetano Donati, S Lamonica; IRCSS

Ospedale Sacro Cuore – Don Calabria, Negrar Di Valpolicella (Verona) A Agheben, N Riccardi, P

Rodari; Ospedale Cardinal Massaia, Asti M Degioanni, T Lupia; Ospedal Maggiore S Di Bella, D

Giacomazzi, R Luzzati; Ospedale Policlinico San Martino – IRCCS M Bassetti; Ospedale SM

Goretti, Latina B Kertusha, M Lichtner, P Zuccalá; Policlinico di S. Orsola, Bologna C Campoli, P

Viale; ULSS9 Scaligera, Verona P Rovere, M Vincenzi; Unità Operativa Dipartimentale di Malattie

Infettive M Vincenzi; University of Verona E Cremonini, P De Nardo, MD Pezzani.

Kuwait: Infectious Diseases Hospital M Al-Roomi, S Kelly; Kuwait University S Al-Sabah.

Lebanon : Centre Hospitalier Universitaire, Notre Dame des Secours M Matar; Rafic Hariri

University Hospital M Hassoun, M Saliba.

Lithuania: University Hospital Santaros Klinikos, Vilnius B Zablockiene.

9

Luxembourg: Through DISCOVERY add-on study. Centre Hospitalier de Luxembourg J Reuter, T

Staub.

Malaysia: Queen Elizabeth Hospital HG Lee; Institute for Clinical Research, National Institute of

Health CK Chew, PP Goh, WY Mak; Kuala Lumpur Hospital CL Leong; Melaka Hospital NZ

Zaidan; Sarawak General Hospital HH Chua; Sultanah Bahiyah Hospital LL Low; Sungai Buloh

Hospital YG Mohamed Gani; Tengku Ampuan Afzan Hospital D Muhamad; Tuanku Fauziah

Hospital S Ab Wahab.

North Macedonia: University Clinic of Infectious Diseases and Febrile Condition IS Demiri, S

Marinkovikj, B Petreska, K Spasovska.

Norway: Akershus University Hospital O Dalgard; Diakonhjemmet Hospital L Vinge; Haraldsplass

Deaconess Hospital BR Kittang; Haukeland University Hospital B Blomberg; Innlandet Hospital,

Elverum CM Ystrøm; Innlandet Hospital, Lillehammer R Eiken; Levanger Hospital NV Skei;

Lovisenberg Hospital H Hoel; Molde Hospital B Tholin; Møre og Romsdal Hospital DAL Hoff;

Oslo University Hospital AM Dyrhol-Riise, AR Holten, T Kåsine, K Nezvalova-Henriksen, IC

Olsen , M Trøseid; Østfold Hospital S Aballi; Sorlandet Hospital, Arendal RB Olsen; Sorlandet

Hospital, Kristiansand M Haugli; Stavanger University Hospital B Berg; Telemark Hospital HK

Skudal; Trondheim University Hospital R Hannula; University Hospital of North Norway AB Kildal;

Vesfold Hospital A Johannessen; Vestre Viken Hospital Trust, Bærum AA Tveita; Vestre Viken

Hospital Trust, Drammen L Heggelund; Vestre Viken Hospital Trust, Kongsberg G Ernst; Vestre

Viken Hospital Trust, Ringerike L Thoresen.

Pakistan: Agha Khan University Hospital, Karachi D Begum, F Mahmood, N Nasir; Pakistan

Institute of Medical Sciences, Islamabad N Akhtar, U Walayat; Shaukat Khanum Memorial Cancer

Hospital and Research Centre A Raza; The Indus Hospital, Karachi S Bhatti, F Herekar, M Hussain,

S Mustafa, A Rahim, A Rehman, S Sarfaraz, Q Shaikh.

Peru: Centro Médico Naval KH Bernal-Málaga, KCM Del-Aguila-Torres, DY Gastiaburú-

Rodriguez, AA Gomero-Lopez, M Laca-Barrera, CX Peña-Mayorga, J Pro, JM Samanez-Pérez, GM

Sotomayor-Woolcott; Clínica Ricardo Palma GE Gianella-Malca, OJ Ponce, KM Rojas-Murrugarra,

RKA Tapia-Orihuela; Clínica San Pablo CV Luna-Wilson, FJ Ortega-Monasterios, A Peña-

Villalobos; Hospital Cayetano Heredia CR Cornejo-Valdivia, G Málaga, F Mejía-Cordero; Hospital

de la Amistad Perú Corea Santa Rosa II JA Juárez-Eyzaguirre, F León-Jiménez; Hospital III Daniel

Alcides Carrión-ESSALUD LG Barreto-Rocchetti, N Flores-Valdez, MA Hueda-Zavaleta, MA

Inquilla-Castillo, JA Mendoza-Laredo, JP Otazú-Ybáñez, KE Ponte-Fernandez, OJ Vargas-Anahua;

Hospital María Auxiliadora AM Alva-Correa, B Ángeles-Padilla, RA Franco-Vásquez, RC

Gallegos-López, M Olivera-Chaupis, MA Paredes-Moreno, W Torres-Ninapayta, RD Vásquez-

Becerra; Hospital Nacional Alberto Sabogal Sologuren EC Agurto-Lescano, LE Hercilla-Vásquez,

CA Iberico-Barrera, CS Terrazas-Obregón; Hospital Nacional Daniel Alcides Carrión J Castillo-

Espinoza, JN Chacaltana-Huarcaya, E Díaz-Chipana, CM Quispe-Nolazco, ME Ramos-Samanez, JG

Vásquez-Cerro, RM Yauri-Lazo; Hospital Nacional Dos de Mayo HC Arbañil-Huamán, CV

Ibarcena-Llerena, GF Miranda-Manrique, G Santos-Revilla, VF Terrones-Levano, CE Ticona-

Huaroto, DY Ugarte-Mercado; Hospital Nacional Hipólito Unanue A Soto; Hospital Nacional

Hipólito Unanue AM Alcantara-Díaz, JA Azañero-Haro, RJ Carazas-Chavarry, A Cruz-Chereque,

RM Sánchez-Sevillano; Hospital Nacional Sergio E. Bernales IC Casimiro-Porras, ODC Peña-

Vásquez, E Sánchez-Garavito, H Sandoval-Manrique, JA Silva-Ramos, OM Torres-Ruiz; Hospital

Regional Lambayeque ED Meregildo-Rodríguez; Hospital Regional Lambayeque JG Alvarado-

Moreno, PC Ávila-Reyes, JMA Benitez-Peche, LN Cabrera-Portillo, HC Sánchez-Carrillo, MA

Solano-Ico, M Villegas-Chiroque; Universidad Peruana Cayetano Heredia PM Cárcamo, AL

Williams).

10

Philippines: Asian Hospital and Medical Center L Fernandez, M Kwek; Baguio General Hospital

TPT Cajulao; Batangas Medical Center RJ Javier; Cardinal Santos Medical Center MSA Ramos,

LEG Santos; Cebu Doctors' University Hospital MM Chua, G Garcia; Chinese General Hospital KL

Li; Diliman Doctors Hospital GM Europa, D Tagarda; Fe Del Mundo Medical Center KL Ngo-

Sanchez; Lung Center of the Philippines V De los Reyes, MC Orden; Makati Medical Center J

Caoili, MT Gler; Manila Doctors Hospital SMA Andales-Bacolcol, MJ Nepomuceno, D Teo;

ManilaMed, Medical Center Manila EA Roxas, BM Te; Perpetual Succor Hospital, Cebu P Blanco,

MB Chua, MC Mujeres; Research Institute for Tropical Medicine JU Garcia, ADE Roman; San Juan

de Dios Educational Foundation Hospital RD Paez, C Ramos; San Lazaro Hospital JT Arches, AG

Awing, R Solante, DR Ymbong; Southern Philippines Medical Center I Chin, A Lee, K Roa; St.

Luke's Medical Center Global M Panaligan; St. Lukes Medical Center Quezon City RM Llorin, JMA

Quinivista-Yoon, JJ Suaco, CJ Tibayan; St. Luke's Medical Center Quezon City GMA Zabat; The

Medical City CLR Abad, EA Aventura, J Bello, J Francisco, MA Lansang; University of the East

Ramon Magsaysay Memorial Medical Center J Cabrera, V Catambing, MC Rosario; University of

the Philippines, Philippine General Hospital MS Arcegono, SV Buno, A David-Wang, AF Malundo,

RE Villalobos; Vicente Sotto Memorial Medical Center MV Bala, OK Macadato; World Citi Medical

Center SM Reyes, IR Tang.

Saudi Arabia: Al Noor Specialist Hospital Mekkah M Al Gethamy, A Naji; Dammam Central

Hospital MS AL-Mulaify; King Faisal Specialist Hospital and Research Centre, Riyadh A Alrajhi,

R Al Maghraby; King Khaled University Hospital, Riyadh N Alotaibi, F AlShaharani, A Al Sharidi,

M Barry, L Ghonem; Ohud Hospital Al Madinah A Khalel AM Kharaba; Prince Mohammed Bin

Abdulaziz Hospital, Riyadh L Alabdan, MS AlAbdullah; Qatif Central Hospital A Al Shabib.

South Africa: Chris Hani Baragwanath Academic Hospital C Menezes, SA van Blydenstein, M

Venter; Groote Schuur Hospital M Mendelson, B Sossen; Sefako Makgatho Health Sciences

University VL Maluleke, AN Mdladla, M Nchabeleng; Wits Health Consortium University of the

Witwatersrand J Bennet, N Mbhele, N Mwelase, V Parker, M Rassool; Wits Reproductive Health

and HIV Institute T Palanee-Phillips.

Spain: Complejo Asistencial de Segovia EM Ferreira Pasos; Complejo Hospitalario de Toledo J

González Moraleja, MP Toledano; Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona A

Carrillo, M Chumbita, L De la Mora, F Etcheverry, F Garcia, M Hernández, A Inciarte, L Leal, O

Miró, A Moreno, P Puerta, M Solà, A Soriano, A Tomé; Hospital Clinico San Carlos, UCM, IdISSC,

Madrid A Ascaso, I Burruezo, N Cabello-Clotet, V Estrada, A Leone, D Lozano-Martin, FJ Martín,

MJ Nuñez Orantos, AB Rivas Paterna, I Sagastagoitia, R Sandoval, E Vargas; Hospital Clínico

Universitario Lozano Blesa IIS Aragón, Zaragoza MJ Esquillor-Rodrigo, J Guzmán, JR Paño-Pardo,

C Toyas-Miazza; Hospital Comarcal de Blanes E Torres García; Hospital Comarcal Sant Jaume de

Calella J Algarra Vento, O Del Rio Pérez, A Macias Paredes, D Pelleja Munné, S Valero Rovira;

Hospital Consorcio General Universitario Valencia M García Deltoro, P Ortega, F Puchades, F

Sanz, J Tamarit; Hospital de Manises K Jerusalem; Hospital de Mérida AM Pérez Fernández;

Hospital General de Tomelloso MI Elices-Calzón, J González-Cervera, G López-Larramona, AJ

Lucendo, MM Maestre-Muñiz, M Martín-Toledano, S Masegosa-Casanova, AM Ruiz-Chicote;

Hospital General Universitario de Alicante I Agea, V Boix, R García, J Gil, P Llorens, E Merino, S

Reus, R Sánchez, D Torrús-Tendero; Hospital General Universitario de Elche, Alicante F Gutierrez,

M Masiá , S Padilla; Hospital General Universitario Gregorio Marañón J Berenguer, P Diez, C

Diez, C Fanciulli, I Gutiérrez, I Miguens, L Pérez-Latorre, M Ramirez; Hospital La Paz.IdIPAZ JR

Arribas, F de la Calle, B Díaz Pollán, MR Torres; Hospital Puerta de Hierro GAC Adolfo Centeno,

AC Caballero, ADS Diaz De Santiago, AFC Fernandez Cruz, EMR Muñez Rubio, IPP Pintos

Pascual, ARM Ramos Martinez; Hospital Quirón Salud Córdoba A Juan Arribas; Hospital Regional

Universitario de Malaga R Gomez-Huelgas, MD Lopez-Carmona, I Perez-Camacho; Hospital

11

Universitari Sagrat Cor R Salas; Hospital Universitario Araba JC Gainzarain, MA Moran, Z Ortiz

De Zarate, J Portu, E Saez De Adana; Hospital Universitario Basurto JM Baraiaetxaburu Artetxe, M

De La Peña Trigueros, J De Miguel Landiribar, OL Ferrero Beneitez, S Ibarra Ugarte, M Intxausti

Urrutibeaskoa, I Lombide Aguirre, I Lopez Azkarreta, M López Martínez, P Muñoz Sanchez, V Polo

San Ricardo, A Sagarna Aguirrezabala, MZ Zubero Sulibarria; Hospital Universitario de Badajoz FF

Rodríguez Vidigal; Hospital Universitario de Ceuta D García Muñiz, E Laza Laza, M Sangüesa

Jareño; Hospital Universitario de Cruces A Basterretxea Ozamiz, MJ Blanco Vidal, M Del Alamo

Martinez, A García de Vicuña Melendez, AJ Goikoetxea Agirre, M Ibarrola Hierro, I Isasi Otaolea, J

Nieto Arana; Hospital Universitario de Getafe DAP Abad Pérez, EAR Aranda Rife, MBR Balado

Rico, ECS Conde Senovilla, MCS Del Cerro Saélices, LFO Fernández de Orueta, AHR Herrera

Rodríguez, NLP López Muñoz, MLL Luengo López, EM Manzone, BMC Martínez Cifre, MMF

Muñoz Flores, SOS Odeh Santana, GPC Pérez Caballero; Hospital Universitario de Jaén C Alarcón-

Payer, MJ Barbero Hernández, C Herrero Rodríguez, F Horno Ureña, FJ La Rosa Salas, G Pérez

Chica; Hospital Universitario de Salamanca JA Martín Oterino; Hospital Universitario Donostia E

Agirre, I Alvarez, A Berroeta, MJ Bustinduy, X Camino, A Couto, A Fuertes, MA Goenaga, M

Ibarguren, JA Iribarren, X Kortajarena, MA Von Wichmann, JJ Zubeldia, B Zubeltzu, A Zufiaurre;

Hospital Universitario Fundación Alcorcón MA Abreu-Galan, O Devora-Ruano, M Galan de Juana,

C Guijarro, J Hernandez-Nuñez, JJ Martínez-Simón, O Martin-Segarra, A Pablo-Esteban, JM Parra-

Ramirez, JT Pérez-Hopkins, MP Pozo-Peña, G Sierra-Torres, A Vegas-Serrano, M Velasco; Hospital

Universitario Infanta Leonor EA Alvaro-Alonso, P Ryan, J Valencia; Hospital Universitario Infanta

Sofía P Ruiz-Seco; Hospital Universitario Río Hortega de Valladolid J Gómez Barquero; Hospital

Universitario San Pedro de Alcántara JFMJ Juan F. Masa; Hospital Universitario Son Espases J

Asensio, F Fanjul, A Ferre, M I Fullana, M Peñaranda, L Ramon; Hospital Universitario Virgen de

la Victoria, Málaga R Jiménez-López, E Nuño, C Pérez-López, J Sánchez-Lora, E Sánchez-Yáñez;

Hospital Universitario Virgen Macarena MD Del Toro, M Gutiérrez-Moreno, I Jiménez-Varo, Z

Palacios-Baena, N Palazón-Carrión, P Retamar, J Rodríguez-Baño, E Salamanca-Rivera, M

Sevillano, A Valiente-Méndez, D Vicente-Baz; Hospital Universitario y Politécnico La Fe, Valencia

PBG Pablo Berrocal Gil, M Salavert Lletí; Hospital Universitario12 de Octubre, Madrid A Lalueza

IIS Aragón M de la Rica, L Diez-Galán; Ramón y Cajal Hospital, Madrid Y Aranda García , P

Borque, S Chamorro Tojeiro , B Comeche, N Diaz Garcia, R Escudero-Sanchez, F Gioia, B Monge-

Maillo, S Moreno Guillen, R Ron Gonzalez, P Vizcarra.

Switzerland: Campus SLB, Lindenhofgruppe Bern A Bosshard, J Wiegand; Clinic of Infectiology

and Infection Control, Kantonsspital Baden M Greiner; Department of Internal Medicine,

Kantonsspital Frauenfeld S Gastberger; Hôpital du Valais Sion N Desbaillets, S Emonet, PA

Petignat, E Stavropoulou; Hôpital fribourgeois Fribourg V Erard; Hôpital Riviera-Chablais Rennaz

F Duss, N Garin; Hôpitaux universitaires de Genève A Calmy, Y Flammer, A Marinosci, V Prendki;

Kantonsspital Aarau A Conen, S Haubitz, B Jakopp, E West; Kantonsspital Baden B Wiggli;

Lausanne University Hospital F Desgranges, D Haefliger, V Suttels, L van den Bogaart; Réseau

hospitalier neuchâtelois Neuchâtel O Clerc; Spital Thurgau AG, Kantonsspital Münsterlingen R

Fulchini, Universitätsspital Basel M Stoeckle.

12

Data management and monitoring

Castor EDC, The Netherlands: D Art, E Kochova.

University of Bern, Switzerland: S Trelle, S McGinty, M Branca, S Appadoo

University of Bristol, United Kingdom: JAC Sterne, CA Rogers, HBC Cappel-Porter, D Hutton, S

Bellani, E Allum, J Kirwan.

University of Oxford, United Kingdom: HC Pan.

WHO HQ, Switzerland: P Boucher, G Vasilache

Statistical analysis

University of Oxford, United Kingdom: HC Pan, R Peto.

WHO trial coordination team

AM Henao-Restrepo, P Lydon, MC Miranda-Montoya, M-P Preziosi, K Salami K, V

Sathiyamoorthy, S Swaminathan.

Other collaborators in participating countries

Special recognition to all the research staff and medical teams in each of the participating hospitals,

in Argentina: Hospital Ramos Mejía Buenos Aires (SA Arrigorriaga, RF Fernandez Deu, AG

Guida), and Hospital Rawson Córdoba (LK Lassen, SF Silva, CT Toledo, AZ Zamora, LZ Zappia);

Austria: AGMT Arbeitsgemeinschaft Medikamentöse Tumortherapie, Salzsburg (S Esmaeilzadeh-

leithner, B Lamprecht, D Wolkersdorfer); Belgium: Cliniques universitaires de Bruxelles (Z Khalil)

Brazil: Ministry of Health (CG Sachetti, FF Soares), Hospital Universitário Clementino Fraga Filho

(RA Medronho), Hospital Estadual de Sumaré (MJ Moraes), Oswaldo Cruz Foundation (BGJ

Grinsztejn, MA Krieger), Hospital Hospital Federal do Rio de Janeiro (ALM Oliveira), Hospital

Regional de São José (M Vieira), and Hospital São José de Doenças Infecciosas (CFV Takeda);

Canada: Hôpital Charles-Le Moyne (G Poirier), Dr Evert Chalmers Hospital (Z Aslam), Montfort

Hospital (N Chagnon), Centre Hospitalier de l'Université de Montréal (M Durand, S Matte), Hôpital

du Sacré-Cœur de Montréal (YA Cavayas), Saint Paul’s Hospital Vancouver (W Connora, N Press),

Sunnybrook Hospital (P KIIza, E Shadowitz), University of Alberta (A Singh), University of British

Columbia (V Chaubey, J Grant, A Mah), University Health Network Toronto (B Coburn, SM

Poutanen), University of Manitoba (A Heendeniya, LE Kelly), McMaster University (J Tsang), and

Unity Health Toronto (KL Schwartz); Colombia: Clínica Reina Sofia, (M Choconta, L Martínez),

Clínica Universitaria Colombia (Y Gil, M Jiménez, A Montañez, O Córdoba), Clínica Santa María

del Lago (O Agudelo, J de La Hoz, M Salazar, A Valencia), Clínica Sebastián de Belalcázar (A

Muriel, J Villabon), Clínica iberoamerica (C Arévalo, C Rebolledo), Fundación Cardio Infantil-

Instituto del Corazón (L Sáenz, J Villar), Fundación Santa fe de Bogotá (S Bello), Fundación Valle

del Lili (K Gómez, A Martínez, A Sotomayor, J Yara), Fundación Universitaria Sanitas (C

Aristizábal, D Castro, M Isaza, P Marín, C Orjuela), Hospital Universitario San Ignacio (V Méndez,

C Gómez), Hospital Universidad del Norte (S Aguilera, F Torres), Ministry of Health (A Moscoso, F

Ruiz), PAHO (L. Ramírez, G Tambini), INVIMA (J Aldana, P Pulgarín); National University of

Colombia (M Jimenez, O Cordoba, A Montañez); Finland: Helsinki University Hospital (P Järvinen,

I Kalliala, TP Kilpeläinen), Occupational Health Helsinki (JMJ Mustonen), and Tampere University

Hospital (RH Hankkio, GM Määttä, VK Virtanen); France: Hôpital Avicenne Paris (O Bouchad),

13

Hôpital d'Instruction des Armées Bégin (C Ficko), Hôpital Bichat Paris (B Basli, A Chair, J Level, M

Schneider, J Guedj, C Laouenan, S Tubiana, V Godard), Hôpital de Bicêtre (X Monnet), Hospices

Civils de Lyon (B Leveau), Centre hospitalier universitaire de Martinique (A Cabie), Pontchaillou

University Hospital (M Revest), Reims University Hospital (F Bani-Sadr, Rennes University

Hospital (A Caro, C Cameli, MJ Ngo Um Tegue); Nouvel Hôpital Civil Strasbourg (JL Diehl), Tours

University Hospital (L Bernard), ANRS (V Petrov-Sanchez, S Le Mestre, C Cagnot, D Lebrasseur, C

Birkle, C Moins, S Gibowski, C Paul, E Landry, E Balssa, L Wadouachi, A le Goff, L Moachon),

ANSES (C Semaille), Imagine Institute Paris (L Abel), Inserm (H Esperou, S Couffin-Cadiergues, E

d'Ortenzio, B Hamze, O Puechal), Inserm ANRS Villejuif (Y Riault, E Netzer), Infective Agents

Institute Lyon (M Bouscambert-Duchamp, V Icard, B Lina, F Morfin-Sherpa, A Gaymard),

Université Bordeaux Inserm (L Wittkop, L Moinot, A Gelley), Université Paris Saclay Inserm (A

Essat, M Ghislain, M Brossard), and Université Sorbonne Inserm (L Beniguel, M Genin);

Honduras: Hospital Atlantida la Ceiba (M Juarez); Instituto Cardiopulmonar Tegucigalpa (N

Maradiaga), Hospital Leonardo Martinez San Pedro Sula (J Samara), Hospital Militar Tegucigalpa

(JS Jerez), Hospital San Felipe Tegucigalpa (E Cruz, H Rodriguez), Agencia de Regulación Sanitaria

(F Contreras), National Autonomous University of Honduras (F Herrera, S Moncada, W Murillo),

Secretaria de Salud de Honduras (A Flores, R Aplicano), and PAHO (P Huerta); India: SVP

Institute of Medical Sciences and Research Ahmedabad (N Suthar, S Shah, P Palat, A Chandwani, A

Pandya,V Buch, S Talati, D Patel), AIIMS Bhopal (V Ingle, A Singhai, N Shrivastava), Apollo

Hospitals Greams Lane Chennai (S Pavithra, E Elvira, G Parthasarathy, Y Arun Chander, A Afsal,

NK Hilda), Apollo Speciality Hospitals Vanagaram Chennai (J Krishnan, S Hilda, K Kirubanandam,

C Poongavanam, J Swaminathan), Madras Medical College Chennai (G Arathi, G Jayashree, T

Meenakshi, S Gomathi), Omandurar Medical College Chennai (C R Anuradha, R Pravin Kumar, S

Sai Vishal, C Praveen Kumar), VHS Infectious Diseases Medical Centre Chennai (F Beulah, S

Ramu, G Narayanan), Gandhi Hospital Hyderabad (B Sheshadri, MD Iqbal Ahmed), SMS Medical

College & Hospital Jaipur (B Goyal), BYL Nair Hospital Mumbai (R Singh, A Bhamare), PD

Hinduja National Hospital and Medical Research Centre Mumbai (A Sunavala, S Mehendale, RS

Raju), Government Medical College Nagpur (M Faisal, P Gomase, P Gosavi, S Bhelekar, P Agrawal,

N Agrawal, R Sabu), AIIMS New Delhi (R Subramaniam, A Anant, S Bhatnagar, L Dar, S Bhoi, P

Mathur, A Kumar, M Ved Prakash, P Tiwari), Indian Council of Medical Research New Delhi (M

Murhekar, S Agrawal, B John), the Army Institute of Cardio Thoracic Sciences Pune (V Mangal),

Bharati hospital Pune (S Palkar), ICMR- National AIDS Research Institute Pune (S Krishnan, R

Bangar, P Kerkar, K Chaudhari, P Kokate, A Kashikar), AIIMS Rishikesh (M Singh, A Chauhan),

Government Medical College Surat (A Patel, K Chauhan), and Christian Medical College Vellore (T

George, L Audrin, G Karthik, GM Varghese, P Rupali, T Balamugesh, V Surekha, B Chacko, M

Moorthy, K P P Abhilash, SC Nair, S Chandy, R Charles, A Jacob, D Mathew, E Inbarani, R Moses,

N Stanely); Lebanon: Ministry of Public Health (R Hamra); Lithuania: Hospital Santaros klinikos,

Vilnius, (M Paulauskas, U Sakalauskiene) Luxembourg: Clinical and Epidemiological Investigation

Center, Strassen (M Alexandre), Hôpitaux Robert Schuman, Luxembourg (M Berna) Pakistan:

Hayatabad Medical Complex Peshawar (S Jamal), Shaukat Khanum Memorial Cancer Hospital (S

Hassan, S Abbas, S Khan, MR Khan), and Shifa International Hospital (E Khan, S Azam);

Philippines: Asian Hospital and Medical Center (MIL Fernandez), Baguio General Hospital (MLF

de Leon, RG Dagwasi), Batangas Medical Center (ML Almero, M Mercado), Cardinal Santos

Medical Center (A Vergara), Cebu Doctors' University Hospital (F Repunte), Chinese General

Hospital (SO Tan, MK Ong-Tantuco, RC Reyes, PLG Co, ALG Gabriel-Chan, AO Reyes-Addatu,

JT Li-Yu, SA Ang), Diliman Doctors Hospital (KI Del Ayre), Fe Del Mundo Medical Center (SMA

Santos, A Torrico), Lung Center of the Philippines (H Basobas, Z Del rosario), Makati Medical

Center (KM Taladua, HF Ricaforte-Docuyanan), Manila Doctors Hospital (A Ramos-Precilla, SA

Limson), Medical Center Manila (TAE Nunez), The Medical City (A Santiago), Perpetual Succor

Hospital, Cebu (TR Cuevas), Philippine Council for Health Research and Development (JC

14

Montoya ), Philippine General Hospital (JP Benedicto, M Llanes, G Astudillo, P Nala, R Abaya),

Research Institute for Tropical Medicine (A Yabut), San Juan de Dios Educational Foundation

Hospital (JD Cruz), San Lazaro Hospital (SM Ligutan), St. Lukes Medical Center Quezon City (AR

Cumpas), Vicente Sotto Memorial Medical Center (M Bagano, MP Pablo-Villamor, GM Aquino Jr,

JD Bancat), Southern Philippines Medical Center (MYC Barez, LL Torno, P Ferrer, EA Sibal),St.

Lukes Medical Center Global (G Dy-Arga, R Enecilla, CE Villavicencio, DD Ona, S Unson, JD

Gargar, BM Samonte), University of the East Ramon Magsaysay Memorial Medical Center (MTF

Sumagaysay), University of the Philippines (FM Climacosa, ME Mercado, CDA Rozul, P Tagle, M

Recana), World Citi Medical Center (DJD Reotita), Philippine Clinical Research Professionals (G

Mendoza, J Arellano, AR Baniqued), Department of Health Philippines (FT Duque III, MR

Vergeire), Food and Drug Administration Philippines (RE Domingo), and WHO WPRO (JP

Tonolete); Saudi Arabia: King Faisal Specialist Hospital and Research Centre, Riyadh (N

Alorayyidh, R Moslmani), King Khaled University Hospital, Riyadh (A Abdurrahman, D Bintaleb);

Spain: Hospital Clinico San Carlos, UCM, IdISSC, Madrid (V Alvarez, C Perez-Ingidua, N Pérez

Macias, O Bueno, MJ Tellez), and Hospital La Paz Madrid (A Borobia); South Africa: Chris Hani

Baragwanath Academic Hospital (D Kalambay, WBT Lechuti), Groote Schuur Hospital (S

Koekemoer, S Moosa, T Morar), Sefako Makgatho Health Sciences University (SC Shaku, VM

Ramothwala), Wits Health Consortium (C Barker, J Chelliah, J Ferreira, M Knight, LI Koeberg, Y

Kilian, A Rama, D Strydom, S Naidoo), and Wits Reproductive Health and HIV Institute (F Docrat,

A Jacques, K Moodley, T Msomi, R Boikanya, S Cornell); Switzerland: Kantonsspital Baden (A

Friedl, J Rutishauser, F Rutz), Campus SLB Lindenhofgruppe Bern (C Groen, J Evison),

Kantonsspital Frauenfeld (P Rochat, P Hackman, P Wiesli, A Kistler, R Ursprung, S Danioth, R

Werner, S Dias, M Schuster), Hôpitaux universitaires de Genève (P Vazquez, Y Gosmain), Lausanne

University Hospital (M Cavassini, A Fayet-Mello, L Vallotton, L Warpelin-Decrausaz, V Sormani,

D Niksch), and Hôpital du Valais Sion (M Eyer, E Schaefer, S Schwery, MSavet, A Luyet); and

WHO teams: AFRO (C Garapo, JP Okeibunor), EMRO (A Hashish, C Kodama, A Mandil), EURO

(C Butu, M Dara, A Kuli, A Mesi, N Mamulashvili, I Zurlyte), PAHO/AMRO (L Reveiz), SEARO

(T Azim, M Gupta, R Takahashi), WPRO (A Cawthorne, YR Lo, JP Tonolette) and Headquarters (V

Benassi, S Benitez, A Borges, T Bouquet, S Chuffart, E Egorova, R Embaye, S Kone, C Merle, P

Molinaro, R La Rotta, MJ Ryan, N Mafunga, A Mazur, G Queyras).

Acknowledgments

The chief acknowledgement is to the thousands of patients and their families who participated in this

trial and made it possible, and the hundreds of medical staff who randomized and cared for patients.

The Ministries of Health of the participating Member States and their institutions provided critical

support in the implementation of the trial.

Castor EDC donated and managed their cloud-based clinical data capture and management system.

Anonymized data handling and analysis was at the Universities of Berne, Bristol and Oxford.

Remdesivir was donated by Gilead Sciences, Hydroxychloroquine by Mylan, Lopinavir-Ritonavir

by Abbvie, Cipla and Mylan and Interferon β1a by Merck KGaA (subcutaneous) and Faron

(intravenous).

Add-on studies were conducted in Canada, France, India and Norway.

15

Table S1. Treatment allocation vs initiation of ventilation in those not already being ventilated at the time of randomization

Ventilation includes invasive or non-invasive mechanical ventilation or extra-corporeal membrane oxygenation.

Remdesivir vs its control

Hydroxychloroquine vs its control

Lopinavir vs its control

Interferon vs its control*

Active Control Active Control Active Control Active Control

Not ventilated at entry 2489 2475 862 824 1287 1258 1911 1920

Ventilated later; died 117 108 29 19 50 44 108 91

Ventilated later; discharged 139 146 42 44 67 68 81 98

Ventilated later; pending* 39 30 4 3 7 7 20 21

Total ventilated (number, and %)†

295 11.9

284 11.5

75

8.7 66

8.0

124 9.6

119 9.5

209

10.9 210

10.9

* Ventilation can be reported in patients who have not yet died or been discharged. † More complete follow-up will increase the numbers known to have been ventilated or died.

16

Table S2. Use of corticosteroids and other non-study drugs

Numbers and percentages are tabulated

. Remdesivir

vs its control Hydroxychloroquine

vs its control Lopinavir

vs its control Interferon

vs its control*

Corticosteroids 1310 1288 140 140 316 328 981 1053

Number & percentage

47.8 47.6 14.8 15.5 22.6 23.9 47.9 51.4

Convalescent plasma 52 58 7 3 24 15 43 33

1.9 2.1 0.7 0.3 1.7 1.1 2.1 1.6

Anti-IL-6 drug 133 143 21 18 42 42 52 68

4.9 5.3 2.2 2.0 3.0 3.1 2.5 3.3

Non-trial interferon 3 25 2 1 4 0 1 26

0.1 0.9 0.2 0.1 0.3 0.0 0.1 1.3

Non-trial antiviral 65 152 62 54 86 90 102 144

2.4 5.6 6.6 6.0 6.2 6.6 5.0 7.0

Number entered 2743 2708 947 906 1399 1372 2050 2050

100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

17

Table S3. Multivariate analysis simultaneously estimating all 4 effects

The pre-planned primary analyses in the main text involved 4 pairwise comparisons, one

between each treatment group and its controls, as indicated in the flowchart (Figure 1).

These 4 primary analyses were stratified by age and by whether the patient was already

ventilated at the time of randomization, and found no definitely favourable or definitely

unfavourable effect of any of the 4 study drugs on all-cause in-hospital mortality (Figure 3).

The RRs in these 4 pre-planned pairwise comparisons were:

Remdesivir vs its control (pre-planned analysis) RR=0.95 (95% CI 0.81-1.11; P=0.50),

Hydroxychloroquine vs its control (pre-planned analysis) RR=1.19 (0.89-1.59; P=0.23),

Lopinavir vs its control (pre-planned analysis) RR=1.00 (0.79-1.25; P=0.97), and

Interferon vs its control (pre-planned analysis) RR=1.16 (0.96-1.39; P=0.11).

As there was some overlap between the 4 control groups, an exploratory sensitivity

analysis used multivariate Cox regression to fit all 4 treatment effects simultaneously,

assuming the independence of any effects of Lopinavir and of Interferon. This multivariate

analysis was stratified by the set of study drugs that was locally available at randomization

(13 occupied strata) and was adjusted for several of the prognostic factors listed in Table 1:

age (<40, 40-49, 50-59, 60-69, 70-79, 80+ years), sex, diabetes, bilateral lung lesions at

entry (no, yes, not imaged at entry), and respiratory support at entry (no oxygen, oxygen

but no ventilation, ventilation). This multivariate sensitivity analysis had not been pre-

planned as a primary or a secondary analysis. For each of the 4 study drugs it yielded

mortality rate ratios (RRs) for active treatment vs local standard of care (SoC) that were

similar to those in the pre-planned primary pairwise comparisons, again finding no definitely

favourable or unfavourable effect of any of the 4 study drugs:

Remdesivir vs local SoC (in multivariate analysis) RR=0.95 (95% CI 0.81-1.11; P=0.49),

Hydroxychloroquine vs local SoC (in multivariate analysis) RR=1.14 (0.89-1.46; P=0.31),

Lopinavir vs local SoC (in multivariate analysis) RR=0.94 (0.76-1.16; P=0.56), and

Interferon vs local SoC (in multivariate analysis) RR=1.14 (0.96-1.35; P=0.13).

18

Figure S1. Effects on 28-day in-hospital mortality of (a) Remdesivir, (b) Hydroxychloroquine, (c) Lopinavir, (d) Interferon

(a) Remdesivir vs its control

0 7 14 21 28 0

4

8

12

Mo

rtality

(%

)

Days

Nos. at risk at start of each week, and nos. dying

Remdesivir 2743 129 2159 90 2029 48 1918 18 1838 16 Control 2708 126 2138 93 2004 43 1908 27 1833 14

9.5

12.5% Remdesivir

9.6

12.7% Control

Stratified rate ratio, 0.95 (95% CI 0.81-1.11) p=0.50 by log-rank test

(b) Hydroxychloroquine vs its control

0 7 14 21 28 0

4

8

12

Mo

rtality

(%

)

Days


Hydroxychlor . 947 48 889 31 854 13 838 6 833 6 Control 906 42 853 27 823 8 814 4 809 3

8.4

10.2% Hydroxychloroquine

7.7

8.9% Control


(c) Lopinavir vs its control

0 7 14 21 28 0

4

8

12

Mo

rtality

(%

)

Days


Lopinavir 1399 57 1333 42 1282 24 1257 15 1243 10 Control 1372 62 1293 48 1239 21 1216 10 1203 5

7.1

9.7% Lopinavir

8.1

10.3% Control


(d) Interferon vs its control

0 7 14 21 28 0

4

8

12

Mo

rtality

(%

)

Days


Interferon 2050 101 1669 73 1554 31 1483 24 1410 14 Control 2050 91 1725 58 1636 31 1563 21 1498 15

9.8

12.9% Interferon

8.2

11.0% Control


19

Figure S2. Subdivision by ventilation at randomization on the apparent effects of Remdesivir on the 28-day probability of death from any cause

0 7 14 21 28

0

10

20

30

40

Mo

rtality

(%

)

Days

Nos. at risk at the start of each week, and nos. dying

Remdesivir 254 44 167 25 138 18 118 3 112 8

Control 233 29 151 22 123 12 108 5 102 3

Remdesivir 2489 85 1992 65 1891 30 1800 15 1726 8

Control 2475 97 1987 71 1881 31 1800 22 1731 11

Ventilated

Not ventilated

32.5

43.0% Remdesivir

28.3

37.8% Control

7.2

9.4% Remdesivir 8.0

10.6% Control

Ventilated

Not ventilated

Age-stratified rate ratio, 1.20 (95% CI 0.89-1.64) p=0.24 by log-rank test

Rate ratio, 0.86 (95% CI 0.72-1.04), p=0.13

20

Figure S3. Subdivision by ventilation at randomization on the apparent effects of Hydroxychloroquine on the 28-day probability of death from any cause

0 7 14 21 28

0

10

20

30

40

Mo

rtality

(%

)

Days


Hydroxyc . 85 18 66 10 56 4 52 2 50 1

Control 82 13 69 9 57 3 54 2 53 0

Hydroxyc . 862 30 823 21 798 9 786 4 783 5

Control 824 29 784 18 766 5 760 2 756 3

Ventilated

Not ventilated

33.3


27.2

32.3% Control

6.0 7.4% Hydroxychloroquine

5.8

6.6% Control

Ventilated

Not ventilated


Rate ratio, 1.16 (95% CI 0.82-1.65), p=0.40

21

Figure S4. Subdivision by ventilation at randomization on the apparent effects of Lopinavir on the 28-day probability of death from any cause

0 7 14 21 28

0

10

20

30

40 M

ort

ality

(%

)

Days


Lopinavir 112 10 101 10 90 7 82 5 78 3

Control 114 15 98 10 85 5 80 3 78 2

Lopinavir 1287 47 1232 32 1192 17 1175 10 1165 7

Control 1258 47 1195 38 1154 16 1136 7 1125 3

Ventilated

Not ventilated

18.0

28.1% Lopinavir

22.3

28.7% Control

6.2

8.1% Lopinavir

6.8 8.7% Control

Ventilated

Not ventilated


Rate ratio, 0.97 (95% CI 0.75-1.26), p=0.83

22

Figure S5. Subdivision by ventilation at randomization on the apparent effects of Interferon on the 28-day probability of death from any cause

0 7 14 21 28

0

10

20

30

40

Mo

rtality

(%

)

Days


Interferon 139 23 91 15 76 8 68 4 65 5

Control 130 11 99 12 86 8 78 6 72 3

Interferon 1911 78 1578 58 1478 23 1415 20 1345 9

Control 1920 80 1626 46 1550 23 1485 15 1426 12

Ventilated

Not ventilated

32.7

42.4% Interferon

21.0

33.8% Control

8.2 10.9% Interferon

7.3

9.5% Control

Ventilated

Not ventilated


Rate ratio, 1.11 (95% CI 0.90-1.36), p=0.34

23

Figure S6. Rate ratios of any death, stratified by age and respiratory support at entry,

Remdesivir versus Control, by entry characteristics and steroid use at any time*


Remdesivir Control

Remdesivir deaths: log-rank statistics O-E Variance

Ratio of death rates (RR), & 99% CI (or 95% CI, for total) Remdesivir : Control

Sex Male 199/1706 (13.6) 211/1725 (13.8) -9.8 100.6 0.91 [0.70-1.17] Female 102/1037 (10.8) 92/983 (10.8) 2.1 47.9 1.05 [0.72-1.52]

Age at entry <50 61/961 (6.9) 59/952 (6.8) 2.3 29.8 1.08 [0.67-1.73] 50-69 154/1282 (13.8) 161/1287 (14.2) -7.6 77.5 0.91 [0.68-1.21] 70+ 86/500 (20.5) 83/469 (21.6) -2.9 41.5 0.93 [0.63-1.39]

Days from hospital admission to randomization 0 79/724 (11.3) 77/712 (11.0) -1.3 38.0 0.97 [0.64-1.47] 1 81/917 (10.1) 95/938 (11.4) -8.8 42.9 0.82 [0.55-1.21] 2+ 141/1102 (15.7) 131/1058 (15.3) -0.2 66.4 1.00 [0.73-1.37]

Respiratory support at entry Ventilated 98/254 (43.0) 71/233 (37.8) 7.6 40.8 1.20 [0.80-1.80] On oxygen 192/1828 (12.2) 219/1811 (13.8) -16.9 101.8 0.85 [0.66-1.09] Neither 11/661 (2.0) 13/664 (2.1) -0.6 6.0 0.90 [0.31-2.58]

Bilateral lung lesions Not imaged at entry 36/281 (15.0) 29/296 (11.9) 3.0 15.5 1.22 [0.63-2.34] Yes 254/2175 (13.3) 264/2153 (13.9) -5.4 127.7 0.96 [0.76-1.20] No 11/287 (4.5) 10/259 (4.0) -0.9 5.1 0.84 [0.27-2.62]

Current smoking Yes 17/178 (10.7) 24/161 (17.1) -4.5 9.7 0.63 [0.28-1.43] No 284/2565 (12.6) 279/2547 (12.4) -3.4 138.4 0.98 [0.78-1.21]

Diabetes Yes 98/707 (15.9) 86/666 (14.9) -0.6 44.6 0.99 [0.67-1.45] No 203/2036 (11.3) 217/2042 (12.0) -8.6 103.6 0.92 [0.71-1.19]

Heart disease Yes 77/571 (15.3) 75/567 (15.4) 1.3 37.3 1.04 [0.68-1.58] No 224/2172 (11.8) 228/2141 (12.0) -10.0 110.7 0.91 [0.72-1.17]

Chronic liver disease Yes 7/36 (24.4) 6/41 (17.6) 1.5 2.4 1.82 [0.35-9.45] No 294/2707 (12.3) 297/2667 (12.6) -8.9 145.6 0.94 [0.76-1.16]

Chronic lung disease Yes 25/151 (18.2) 19/145 (16.9) 1.5 10.6 1.15 [0.52-2.54] No 276/2592 (12.2) 284/2563 (12.5) -9.7 138.0 0.93 [0.75-1.16]

Asthma Yes 20/139 (16.2) 15/139 (14.0) 2.0 8.4 1.27 [0.52-3.10] No 281/2604 (12.3) 288/2569 (12.7) -11.0 140.0 0.92 [0.74-1.15]

Corticosteroids at entry or later (ignoring any biases*) Yes 210/1310 (16.6) 225/1288 (17.9) -5.6 106.8 0.95 [0.74-1.22] No 91/1433 (8.0) 78/1420 (6.9) 1.2 41.1 1.03 [0.69-1.54]

Geographic location Europe or Canada 33/715 (5.2) 27/698 (5.1) -1.1 14.5 0.93 [0.47-1.82] Latin America 82/470 (20.6) 115/514 (23.8) -4.4 46.2 0.91 [0.62-1.33] Asia and Africa 186/1558 (13.3) 161/1496 (12.0) 3.4 84.1 1.04 [0.79-1.38]

Total 301/2743 (12.5) 303/2708 (12.7) -8.3 148.8 0.95 [0.81-1.11] 2p = 0.50

0.0 0.5 1.0 1.5 2.0 Remdesivir

better Remdesivir

worse

Heterogeneity test: 18 2

= 12.4; p = 0.82 99% or 95% confidence interval (CI), K-M Kaplan-Meier.

* RRs in steroid subgroups may be somewhat biased by later steroid use.

24


Hydroxychloroquine vs. Control, by entry characteristics and steroid use at any time*


HCQ Control

HCQ deaths: log-rank statistics

O-E Variance


HCQ : Control

Sex Male 80/574 (12.9) 50/535 (9.1) 13.4 31.9 1.52 [0.97-2.40] Female 24/373 (6.2) 34/371 (8.7) -5.3 14.2 0.69 [0.35-1.36]

Age at entry <50 19/335 (5.7) 19/317 (5.8) 0.9 9.2 1.10 [0.47-2.57] 50-69 55/410 (12.1) 31/396 (7.1) 10.8 21.2 1.66 [0.95-2.91] 70+ 30/202 (14.0) 34/193 (17.8) -3.5 15.8 0.80 [0.42-1.53]

Days from hospital admission to randomization 0 23/296 (7.8) 20/281 (6.8) 0.6 10.6 1.06 [0.48-2.34] 1 39/317 (10.8) 29/312 (9.0) 2.8 16.1 1.19 [0.63-2.26] 2+ 42/334 (12.0) 35/313 (10.8) 3.7 19.0 1.21 [0.67-2.19]

Respiratory support at entry Ventilated 35/85 (39.2) 27/82 (32.3) 3.4 14.8 1.26 [0.65-2.46] On oxygen 61/517 (10.8) 52/483 (10.5) 2.9 28.1 1.11 [0.68-1.80] Neither 8/345 (2.3) 5/341 (1.2) 1.4 3.2 1.56 [0.37-6.54]

Bilateral lung lesions Not imaged at entry 20/137 (11.9) 18/118 (14.8) 0.2 9.3 1.02 [0.44-2.36] Yes 78/656 (11.6) 63/618 (9.8) 5.9 34.3 1.19 [0.77-1.85] No 6/154 (3.3) 3/170 (1.8) 1.5 1.9 2.16 [0.34-13.77]

Current smoking Yes 14/92 (14.2) 8/82 (9.9) 3.1 4.1 2.09 [0.59-7.41] No 90/855 (9.8) 76/824 (8.8) 5.3 40.7 1.14 [0.76-1.71]

Diabetes Yes 35/199 (17.8) 20/205 (8.3) 8.3 13.2 1.87 [0.92-3.81] No 69/748 (8.2) 64/701 (9.1) 0.8 32.7 1.02 [0.65-1.61]

Heart disease Yes 25/193 (12.0) 20/194 (9.9) 2.5 10.9 1.25 [0.58-2.74] No 79/754 (9.8) 64/712 (8.7) 5.1 34.9 1.16 [0.75-1.79]

Chronic liver disease Yes 2/15 (6.7) 3/14 (21.4) -1.4 0.9 0.21 [0.01-3.14] No 102/932 (10.3) 81/892 (8.7) 8.9 45.0 1.22 [0.83-1.79]

Chronic lung disease Yes 9/62 (14.7) 7/66 (10.7) 0.9 3.9 1.27 [0.35-4.65] No 95/885 (9.9) 77/840 (8.8) 6.8 42.2 1.17 [0.79-1.75]

Asthma Yes 3/41 (7.4) 4/46 (6.7) 0.2 1.2 1.16 [0.11-11.85] No 101/906 (10.4) 80/860 (9.1) 7.8 44.3 1.19 [0.81-1.75]

Corticosteroids at entry or later (ignoring any biases*) Yes 33/140 (23.3) 31/140 (22.2) 4.9 14.0 1.42 [0.71-2.83] No 71/807 (8.0) 53/766 (6.5) 6.5 30.5 1.24 [0.78-1.97]

Geographic location Europe or Canada 24/286 (6.7) 17/267 (6.1) 3.2 10.1 1.38 [0.61-3.09] Latin America 28/97 (27.9) 21/96 (20.8) 4.6 11.4 1.50 [0.70-3.21] Asia and Africa 52/564 (9.0) 46/543 (8.2) 3.2 23.5 1.15 [0.67-1.95]

Total 104/947 (10.2) 84/906 (8.9) 8.1 46.2 1.19 [0.89-1.59] 2p = 0.23

0.0 0.5 1.0 1.5 2.0 Hydroxychloroquine

better Hydroxychloroquine

worse




25


Lopinavir versus Control, by entry characteristics and steroid use at any time*


Lopinavir Control

Lopinavir deaths: log-rank statistics O-E Variance


Lopinavir : Control

Sex Male 98/851 (10.4) 91/802 (11.0) 1.1 46.3 1.02 [0.70-1.49] Female 50/548 (8.7) 55/570 (9.4) -1.8 25.7 0.93 [0.56-1.55]

Age at entry <50 20/511 (3.6) 27/501 (4.9) -3.0 11.7 0.77 [0.36-1.64] 50-69 66/597 (9.8) 57/596 (9.1) 2.7 30.4 1.09 [0.68-1.74] 70+ 62/291 (20.4) 62/275 (22.7) 0.0 30.2 1.00 [0.63-1.60]

Days from hospital admission to randomization 0 34/423 (7.6) 33/403 (7.7) -0.8 16.6 0.95 [0.51-1.80] 1 48/442 (9.4) 46/445 (10.4) 0.7 23.1 1.03 [0.60-1.76] 2+ 66/534 (11.8) 67/524 (12.3) 1.9 31.9 1.06 [0.67-1.67]

Respiratory support at entry Ventilated 35/112 (28.1) 35/114 (28.7) 1.3 16.7 1.08 [0.57-2.03] On oxygen 92/759 (11.1) 95/719 (13.2) -6.9 46.1 0.86 [0.59-1.26] Neither 21/528 (4.0) 16/539 (2.6) 3.2 9.2 1.42 [0.61-3.33]

Bilateral lung lesions Not imaged at entry 31/179 (17.0) 24/171 (13.8) 2.2 13.4 1.18 [0.58-2.37] Yes 111/985 (10.2) 110/945 (11.3) -0.7 54.3 0.99 [0.70-1.40] No 6/235 (2.1) 12/256 (4.4) -2.3 3.9 0.55 [0.15-2.02]

Current smoking Yes 14/141 (9.2) 12/124 (9.0) 0.6 5.7 1.11 [0.38-3.27] No 134/1258 (9.8) 134/1248 (10.5) -1.1 66.1 0.98 [0.72-1.35]

Diabetes Yes 44/341 (12.4) 33/324 (9.6) 1.9 18.7 1.10 [0.61-2.00] No 104/1058 (8.9) 113/1048 (10.6) -2.5 52.9 0.95 [0.67-1.36]

Heart disease Yes 44/289 (15.0) 39/290 (13.2) 4.0 20.3 1.22 [0.69-2.16] No 104/1110 (8.4) 107/1082 (9.6) -4.7 51.9 0.91 [0.64-1.31]

Chronic liver disease Yes 1/15 (6.7) 4/23 (18.0) -1.4 1.2 0.33 [0.03-3.37] No 147/1384 (9.8) 142/1349 (10.2) 0.9 71.1 1.01 [0.75-1.37]

Chronic lung disease Yes 15/95 (13.9) 12/87 (13.9) 0.7 6.4 1.12 [0.41-3.09] No 133/1304 (9.4) 134/1285 (10.1) -1.9 65.5 0.97 [0.71-1.33]

Asthma Yes 6/65 (7.7) 7/56 (12.7) 0.2 1.9 1.10 [0.17-7.01] No 142/1334 (9.8) 139/1316 (10.2) -0.1 69.2 1.00 [0.73-1.36]


Geographic location Europe or Canada 47/349 (12.1) 42/350 (11.3) 2.9 21.8 1.14 [0.66-1.98] Latin America 30/145 (17.2) 34/148 (23.0) -0.2 15.2 0.99 [0.51-1.91] Asia and Africa 71/905 (7.7) 70/874 (7.8) -1.5 34.2 0.96 [0.62-1.49]

Total 148/1399 (9.7) 146/1372 (10.3) -0.4 72.3 1.00 [0.79-1.25] 2p = 0.97

0.0 0.5 1.0 1.5 2.0 Lopinavir

better Lopinavir

worse




26


Interferon versus Control, by entry characteristics and steroid use at any time


Interferon Control

Interferon deaths: log-rank statistics

O-E Variance


Interferon : Control

Sex Male 173/1303 (14.4) 148/1278 (11.9) 11.8 79.3 1.16 [0.87-1.55] Female 70/747 (10.4) 68/772 (9.6) 4.5 33.5 1.14 [0.73-1.78]

Age at entry <50 48/720 (7.5) 35/697 (5.3) 7.5 20.6 1.44 [0.82-2.54] 50-69 122/934 (14.3) 108/973 (11.4) 13.3 56.9 1.26 [0.90-1.78] 70+ 73/396 (19.9) 73/380 (20.9) -4.0 35.8 0.89 [0.58-1.38]

Days from hospital admission to randomization 0 75/678 (11.6) 69/677 (10.3) 5.5 34.7 1.17 [0.76-1.81] 1 70/681 (10.6) 74/662 (11.0) -3.4 35.5 0.91 [0.59-1.40] 2+ 98/691 (17.0) 73/711 (11.7) 14.8 41.0 1.44 [0.96-2.15]

Respiratory support at entry Ventilated 55/139 (42.4) 40/130 (33.8) 7.7 23.0 1.40 [0.82-2.40] On oxygen 178/1429 (14.1) 163/1430 (11.9) 10.5 84.5 1.13 [0.86-1.50] Neither 10/482 (2.1) 13/490 (2.9) -1.3 5.7 0.80 [0.27-2.35]

Bilateral lung lesions Not imaged at entry 29/165 (18.7) 26/177 (15.9) 3.1 13.4 1.26 [0.62-2.54] Yes 206/1723 (13.3) 184/1718 (11.3) 13.0 96.1 1.14 [0.88-1.49] No 8/162 (4.0) 6/155 (3.4) 0.5 3.2 1.17 [0.28-4.92]

Current smoking Yes 12/136 (10.3) 19/138 (14.8) -2.7 7.0 0.68 [0.26-1.80] No 231/1914 (13.1) 197/1912 (10.7) 19.5 105.7 1.20 [0.94-1.55]

Diabetes Yes 74/489 (16.5) 58/537 (11.4) 11.7 32.0 1.44 [0.92-2.28] No 169/1561 (11.8) 158/1513 (10.9) 3.1 80.1 1.04 [0.78-1.39]

Heart disease Yes 58/427 (14.9) 59/456 (14.2) 1.3 28.3 1.05 [0.65-1.70] No 185/1623 (12.4) 157/1594 (10.1) 15.1 84.5 1.20 [0.90-1.58]

Chronic liver disease Yes 3/11 (35.2) 3/22 (15.8) 0.6 0.9 1.93 [0.13-29.39] No 240/2039 (12.8) 213/2028 (11.0) 16.1 111.8 1.15 [0.90-1.47]

Chronic lung disease Yes 22/114 (20.3) 22/109 (20.9) 0.6 10.4 1.06 [0.48-2.36] No 221/1936 (12.5) 194/1941 (10.5) 15.7 102.4 1.17 [0.90-1.50]

Asthma Yes 3/75 (4.5) 10/97 (10.7) -1.8 2.7 0.52 [0.11-2.49] No 240/1975 (13.3) 206/1953 (11.0) 19.4 110.1 1.19 [0.93-1.52]


Geographic location Europe or Canada 27/254 (9.1) 23/244 (9.0) 1.7 12.3 1.15 [0.55-2.40] Latin America 103/474 (27.1) 87/478 (18.1) 14.6 45.4 1.38 [0.94-2.02] Asia and Africa 113/1322 (9.3) 106/1328 (8.8) 4.1 54.1 1.08 [0.76-1.53]

Control Type Lopinavir 87/649 (12.3) 67/671 (8.9) 10.5 37.9 1.32 [0.87-2.01] Standard care 156/1401 (13.3) 149/1379 (12.2) 8.3 74.9 1.12 [0.83-1.51]

Total 243/2050 (12.9) 216/2050 (11.0) 16.8 113.3 1.16 [0.96-1.39] 2p = 0.11

0.0 0.5 1.0 1.5 2.0 Interferon

better Interferon

worse




27

Figure S10. RRs for the composite outcome of death or initiation of ventilation: effects of

(a) Remdesivir, (b) Hydroxychloroquine, (c) Lopinavir, (d) Interferon, each vs its control

Events reported / Patients randomized in ITT analyses (and 28-day risk, %)

Active Control

Active-group events: log-rank statistics

O-E Variance

Ratio of event rates (RR), & 99% CI (or 95% CI, for total)

Active : Control

(a) Remdesivir Age at entry

<50 114/961 (12.2) 113/952 (12.4) 1.0 53.2 1.02 [0.72-1.45] 50-69 240/1282 (20.1) 245/1287 (20.2) -6.0 111.2 0.95 [0.74-1.21] 70+ 125/500 (27.2) 121/469 (29.1) -2.8 55.1 0.95 [0.67-1.35]

Respiratory support at entry Ventilated 98/254 (43.0) 71/233 (37.8) 7.6 40.8 1.20 [0.80-1.80] Not ventilated 381/2489 (16.0) 408/2475 (17.3) -15.3 178.7 0.92 [0.76-1.11]

Total 479/2743 (18.5) 479/2708 (18.9) -7.7 219.5 0.97 [0.85-1.10] 2p = 0.60 Heterogeneity around total

3 2 : 2.6

(b) Hydroxychloroquine Age at entry

<50 29/335 (8.7) 30/317 (9.6) -0.2 14.1 0.99 [0.50-1.96] 50-69 79/410 (18.6) 54/396 (13.2) 11.1 31.2 1.43 [0.90-2.27] 70+ 42/202 (20.4) 47/193 (24.5) -3.9 20.8 0.83 [0.47-1.46]

Respiratory support at entry Ventilated 35/85 (39.2) 27/82 (32.3) 3.4 14.8 1.26 [0.65-2.46] Not ventilated 115/862 (13.2) 104/824 (12.6) 3.6 51.2 1.07 [0.75-1.54]

Total 150/947 (15.5) 131/906 (14.3) 7.1 66.1 1.11 [0.87-1.42] 2p = 0.38 Heterogeneity around total

3 2 : 4.3

(c) Lopinavirir Age at entry

<50 36/511 (6.9) 51/501 (9.9) -7.5 21.0 0.70 [0.40-1.23] 50-69 110/597 (17.8) 89/596 (14.5) 9.8 45.8 1.24 [0.85-1.81] 70+ 76/291 (25.2) 81/275 (29.5) -3.8 36.1 0.90 [0.59-1.38]


Total 222/1399 (15.3) 221/1372 (15.8) -1.5 102.9 0.99 [0.81-1.20] 2p = 0.88 Heterogeneity around total

3 2 : 5.3

(d) Interferon Age at entry

<50 68/720 (10.0) 73/697 (10.6) -2.4 33.5 0.93 [0.60-1.45] 50-69 177/934 (19.5) 164/973 (17.4) 12.3 78.3 1.17 [0.88-1.57] 70+ 99/396 (26.1) 98/380 (26.8) -3.0 44.0 0.93 [0.63-1.38]


Total 344/2050 (17.4) 335/2050 (16.7) 7.0 155.8 1.05 [0.89-1.22] 2p = 0.58 Heterogeneity around total

3 2 : 4.3

0.0 0.5 1.0 1.5 2.0 Active better

Active worse

99% or 95% confidence interval (CI)

28

Figure S11. Effects of (a) Remdesivir, (b) Hydroxychloroquine, (c) Lopinavir, (d) Interferon on 14- and 28-day probability of cardiac death

(a) Remdesivir vs its Control

0 7 14 21 28 0

0.2

0.4

0.6

Mo

rtality

(%

)

Days


Remdesivir 2743 6 2159 1 2029 0 1918 0 1838 0 Control 2708 4 2138 4 2004 0 1908 0 1833 0

0.3 0.3% Remdesivir

0.4 0.4% Control

(b) Hydroxychloroquine vs its Control

0 7 14 21 28 0

0.2

0.4

0.6

Mo

rtality

(%

)

Days


Hydroxyc . . 947 4 889 0 854 1 838 1 833 3 Control 906 2 853 0 823 0 814 0 809 1

0.4


0.2 0.2% Control

(c) Lopinavir vs its Control

0 7 14 21 28 0

0.2

0.4

0.6

Mo

rtality

(%

)

Days


Lopinavir 1399 4 1333 2 1282 0 1257 1 1243 0 Control 1372 2 1293 1 1239 0 1216 0 1203 0

0.4

0.5% Lopinavir

0.2 0.2% Control

(d) Interferon vs its Control

0 7 14 21 28 0

0.2

0.4

0.6

Mo

rtality

(%

)

Days


Interferon 2050 4 1669 2 1554 1 1483 0 1410 1 Control 2050 5 1725 3 1636 1 1563 1 1498 0

0.3

0.4% Interferon

0.5

0.6% Control

repurposed antiviral drugs for covid-19 interim who

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