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1MedRxiv (October 15) versionRepurposed antiviral drugs for COVID-19–interim WHO SOLIDARITY trial resultsWHO Solidarity trial consortium**A complete list of SOLIDARITY Trial investigators isprovided in the Supplementary Appendix.Hongchao Pan, Ph.D., Richard Peto, F.R.S., Quarraisha Abdool Karim, Ph.D., Marissa Alejandria M.D., M.Sc., Ana Maria HenaoRestrepo, M.D., M.Sc., César Hernández García M.D., Ph.D., Marie-Paule Kieny Ph.D., Reza Malekzadeh M.D., Srinivas MurthyM.D. C.M., Marie-Pierre Preziosi M.D., Ph.D., Srinath Reddy M.D., D.M., Mirta Roses Periago M. D., Vasee SathiyamoorthyB.M.B.Ch., Ph.D., John-Arne Røttingen M.D., Ph.D., and Soumya Swaminathan M.D. , as the members of the Writing Committee,assume responsibility for the content and integrity of this article.International Steering Committee *National PI; ‚NaWional CoordinaWor; ÁE[ecXWiYe GroXp;§Discovery add-on study.Albania: University Hospital Centre, Tirana N Como*; National Agency for Medicines and Medical Devices N Sinani†. Argentina:Fundación del Centro de Estudios Infectológicos G Lopardo*; National Academy of Sciences of Buenos Aires M Roses Periago†Á.Austria:§. Belgium:§. Brazil: Oswaldo Cruz Foundation EP Nunes*, PPS Reges†. Canada: University of British Columbia SMurthy*Á; Public Health Agency of Canada M Salvadori†. Colombia: National University of Colombia CA Alvarez- Moreno*;Ministry of Health ML Mesa Rubio†. Egypt: National Hepatology and Tropical Medicine Research Institute M Hassany*; Ministry ofHealth and population H Zaid†. Finland: Helsinki University Hospital and South Karelian Central Hospital, Lappeenranta KAOTikkinen*; Finnish Institute for Health and Welfare and University of Finland, Helsinki M Perola†. France: Hospices Civils de Lyon,Lyon F Ader*§; Institut National de la Santé Et de la Recherche Médicale, Paris MP Kieny†Á§. Honduras: National AutonomousUniversity of Honduras MT Medina*; Secretaria de Salud de Honduras N Cerrato†. India: ICMR National AIDS Research Institute,Pune S Godbole*†; Public Health Foundation of India KS ReddyÁ. Indonesia: National Institute of Health Research andDevelopment I Irmansyah*; RSUP Persahabatan, Jakarta MR Rasmin†. Iran (Islamic Republic of): Digestive Disease ResearchInstitute, Teheran University of Medical Sciences, Tehran R Malekzadeh*†Á. Ireland: HRB Clinical Research Facility, UniversityCollege, Cork J Eustace*; Department of Health T Maguire†. Italy: University of Verona E Tacconelli*; Italian Medicines Agency NMagrini†. Kuwait: Infectious Diseases Hospital A Alhasawi*; Ministry of Health A Al-Bader†. Lebanon: Rafic Hariri UniversityHospital 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 SManevska†. Norway: Oslo University Hospital P Aukrust*, A Barratt-Due†; Research Council of Norway JA RøttingenÁ. Pakistan:Shaukat Khanum Memorial Cancer Hospital and Research Centre M Hassan*†. Peru: Universidad Peruana Cayetano Heredia PJGarcía*, E Gotuzzo†. Philippines: National Institutes of Health, University of the Philippines, Manila MM Alejandria*†Á. SaudiArabia: Ministry for Preventive Health AO Athari Alotaibi*, A Asiri†. South Africa: University of the Witwatersrand J Nel*; WitsReproductive Health and HIV Institute H Rees†; Centre for the AIDS Programme of Research In South Africa Q Abdool KarimÁ.Spain: Hospital Clinico San Carlos, UCM, IdISSC, Madrid A Portoles*; Agency of Medicine and Medical Devices C HernándezGarcia†Á. Switzerland: Lausanne University Hospital O Manuel*†.Writing committee affiliations: Nuffield Department of Population Health, University of Oxford, Oxford (H.P. and R.P.); Centre forthe 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 Nationalde la Santé Et de la Recherche Médicale (INSERM), Paris, France (M.P.K.); Ministry of Health and Medical Education, Tehran, Iran(R.M.); University of British Columbia, Vancouver, Canada (S.M); Public Health Foundation of India, New Delhi, India (K.S.R.);National Academy of Sciences of Buenos Aires, Buenos Aires, Argentina (M.R.P.); Research Council of Norway, Oslo, Norway (JA.R.); World Health Organization, Geneva, Switzerland (A-M.H-R., M-P.P., V.S.M., S.S.).Address correspondence and reprint requests to WHO R&D Blueprint at 20 Avenue Appia, 1211 Geneva,Switzerland or [email protected] 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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprintNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.2ABSTRACTBACKGROUNDWHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviraldrugs.METHODSStudy drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) andInterferon-ȕ1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients wererandomized equally between whichever study drugs were locally available and open control (up to 5 options: 4active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4pairwise comparisons of each study drug vs its controls (concurrently allocated the same management withoutthat drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) arestratified for age and ventilation at entry.RESULTSIn 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no studydrug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (atmedian 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) andInterferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (inunventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisationduration.CONCLUSIONSThese Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effecton hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospitalstay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and areconsistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151,NCT04315948)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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint3INTRODUCTIONA WHO COVID-19 research forum in February 2020 recommended evaluation of treatments in largerandomized trials,1 and other WHO expert groups identified 4 re-purposed anti-viral drugs that might have atleast a moderate effect on mortality: Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon-ȕ1a.2 InMarch 2020, WHO began a large, simple, multi-country, open-label randomized trial among hospital inpatientsof the effects of these 4 drugs on in-hospital mortality. The trial was adaptive; unpromising drugs could bedropped and others added. Hydroxychloroquine and Lopinavir were eventually dropped, but others, such asmonoclonal antibodies, will be added. We report interim mortality results for the original 4 drugs.METHODSThe 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 ofconsented patients (via a cloud-based GCP-compliant clinical data management system) took just a fewminutes, as did online reporting of death in hospital or discharge alive (plus brief details of respiratory supportin hospital and use of study drugs and certain non-study drugs). No other reporting was required unless doctorssuspected an unexpected serious adverse reaction (SUSAR). National and global monitors resolved queries andchecked progress and data completeness. Eligible patients were age ≥18 years, hospitalized with a diagnosis ofCOVID-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 equalproportions between control and whichever other study drugs were locally available (up to 5 options: thesedrugs, 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 Lopinavirwere 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 riskHydroxychloroquine dosage was based on that for amoebic liver abscess, rather than the lower dosage formalaria.4 (Hydroxychloroquine slightly prolongs QT, and unduly high or rapid dosage might cause arrhythmiasor 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 dailyfor 10 days. Each tablet contained 200mg Hydroxychloroquine sulphate (155mg base/tablet; a little-usedalternative involved 155mg chloroquine base/tablet).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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint4Lopinavir (oral): Two tablets twice daily for 14 days. Each tablet contained 200mg Lopinavir (plus 50mgRitonavir, to slow hepatic clearance of Lopinavir). Other formulations were not provided, so ventilated patientsreceived no study Lopinavir while unable to swallow.Interferon (mainly subcutaneous): Three doses over six days of 44µg subcutaneous Interferon-ß1a; whereintravenous interferon was available, patients on high-flow oxygen, ventilators or ECMO were instead to begiven 10µg intravenously once daily for six days.ENDPOINTSThe protocol-specified primary objective was to assess effects on in-hospital mortality (ie, mortality during theoriginal episode of hospitalization; follow-up ceased at discharge) not only in all patients but also in those withmoderate 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. Althoughno placebos were used, appropriate analyses of these non-fatal outcomes can still be reliably informative. TheCATCO add-on study in Canada and the Discovery add-on study in Europe (mostly France) recorded additionaloutcomes that will be reported elsewhere.SAMPLE SIZEThe protocol stated ³The larger the number entered the more accurate the results will be, but numbers enteredwill depend on how the epidemic develops… it may be possible to enter several thousand hospitalised patientswith relatively mild disease and a few thousand with severe disease, but realistic, appropriate sample sizes couldnot be estimated at the start of the trial.´ The Executive Group, blind to any findings, decided the timing ofrelease of interim results.STATISTICAL ANALYSESThe four main sets of analyses involve the evenly randomized pairwise comparisons of each study drug vs itscontrols. The controls for those randomly allocated one particular drug were those patients who could by chancehave been randomly allocated that drug (at that moment, in that hospital), but instead got allocated standard ofcare. If, for a particular study entrant, more than one study drug was available, allocation to standard of carewould put that patient into the control group for each of them. Hence, there is partial overlap between the fourcontrol 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 anytime trends in patient characteristics or standard of care.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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint5All analyses relate mortality to allocated treatment (ie, they are intent-to-treat analyses). The overall mortalityanalyses were of all randomised patients (drug vs its control), and the only protocol-specified subgroup analysesare those considering separately patients with moderate and with severe COVID (ie, already ventilated; the typeof 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-rankanalyses, stratified for 3×2=6 strata of age and ventilation at entry. If the stratified log-rank Observed minusExpected number of deaths is O-E with variance V, logeRR is calculated as (O-E)/V with variance 1/V and aNormal distribution.8 The few currently uncertain death times were taken as day 7. Analyses censored patientswith outcome not yet reported at day 0, and censored the few inter-hospital transfers at transfer. They did notcensor 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 nop-value given) help interpret any apparent heterogeneity of treatment RRs between subgroups. Analyses usedSASv9.4 and Rv4.02.The Discussion includes meta-analyses of the major trial results, based on the inverse-variance-weightedaverage of b=logeRR from each stratum of each trial, using odds ratios where hazard or death rate ratios wereunavailable. (This weighted average is derived from the sums of [O-E] and of V over strata.8) In general, themore deaths in a stratum the larger V is and, correspondingly, the smaller is the variance of logeRR, so the moreweight that stratum gets. The variance attributed to the result in each stratum and to the overall weightedaverage reflects only the play of chance at randomization. Homogeneity of different RRs is not needed for thisweighted average to be informative.OVERSIGHT AND FUNDINGThe trial is registered (ISRCTN83971151, NCT04315948), with protocol approved by local and WHO ethicscommittees. Study conduct accorded with Helsinki Declaration and Good Clinical Practice principles, andnational trial regulations. Consent forms were signed and retained by patients, but noted for records. Consentwas generally prospective but could (where locally approved) be retrospective. The only exclusions werepatients without clear consent to follow-up. All other randomized patients were included (³intent-to-treatanalyses´). WHO is global co-sponsor and governments national co-sponsors, with trial governance by theInternational Steering Committee¶s Executive Group (EG). External statistical analyses for the independentData and Safety Monitoring Committee (DSMC) were unseen by the EG or WHO, with two exceptions. Afteroutside 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 WHOtrial team and external statisticians.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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint6Participating countries covered almost all local costs and WHO covered all other study costs, receiving no extrafunding. Collaborators, committee members, data analysts and data management systems charged no costs, anddrugs were donated. No donor unduly (see end-material) influenced analyses, manuscript preparation, orsubmission. The Writing Group vouch for protocol fidelity and data accuracy and completeness.RESULTSFrom March 22 to October 4, 2020, 11,330 patients were entered from 405 hospitals in 30 countries in all 6WHO regions. Of these, 64 (0.6%) had no, or uncertain, consent to follow-up, leaving 11,266 for intent-to-treatanalyses: 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 7 days increased the percentages remaining in hospital at day 7. If one of these 3drugs had accelerated recovery then the sizes of these increases should have differed, but they did not: theincreases were strikingly similar. The proportions still hospitalized at day 7, study drug vs control, wereRemdesivir 69%v59%, Hydroxychloroquine 64%v54%, Lopinavir 68%v59% (Table 1). The medicallyinformative 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 (findingonly small absolute differences), provide a multi-variable Cox regression fitting all 4 treatment effectssimultaneously (yielding mortality RRs like those in Figure 3), subdivide 28-day mortality graphs (like those inFigure 2) by ventilation at entry, and give subgroup analyses of mortality RRs by many patient characteristicsand 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 anycardiac 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.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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint8DISCUSSIONThe main outcomes of mortality, initiation of ventilation and hospitalization duration were not clearly reducedby any study drug. The mortality findings cannot have been appreciably biased by the open-label design withoutplacebos, or by variation in patient characteristics or local care. The effects on ventilation initiation are unlikelyto have been materially biased, and although allocation to 10 days of medication can delay discharge whilemedication is being given, the striking similarity of this delay with 3 different daily medications is evidence thatnone had a pharmacological effect that appreciably reduced time to recovery. Although ACTT-1, with placebocontrol, reported Remdesivir moderately reduced time to recovery, in the present study there were no materialeffects on ventilation initiation or time to discharge.The chief aim was to help determine whether any of 4 re-purposed antivirals could at least moderately affect inhospital mortality, and whether any effects differed between moderate and severe disease. The results should beconsidered in the context of all the evidence on mortality from properly randomized trials, but for Remdesivirand 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 5000randomized), ACTT-1 (136 deaths in about 1000) and two smaller trials (41 deaths).5-7 Figure 4 gives mortalityresults from each trial, subdivided by initial respiratory support. (These like-vs-like comparisons allow for theproportion already on high-flow oxygen or ventilation at entry into ACTT-1 having been, by chance, somewhatlower with Remdesivir than with placebo.) Combining data appropriately from all 4 trials,8 the Remdesivir vscontrol 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 confidenceinterval (0.79-1.05), which shows the range of death rate ratios comfortably compatible with the weightedaverage of the findings from all trials. This absolutely excludes the suggestion that Remdesivir can prevent asubstantial fraction of all deaths. The confidence interval is comfortably compatible with prevention of a smallfraction of all deaths, but is also comfortably compatible with prevention of no deaths (which would beconsistent with the apparent lack of any reduction by Remdesivir in the initiation of ventilation or the durationof hospitalization in Solidarity).The statistical uncertainties are much greater if attention is restricted to particular subgroups or time periods.9 IfRemdesivir has no effect on mortality then chance could still produce somewhat favourable findings in asubgroup of the results for all trials, with more striking findings in a selected subgroup of a particular trial (as inthe one subgroup of ACTT-1 where the death rate ratio appeared to be 0.30: Figure 4). Although both ACTT-1and Solidarity envisaged the possibility of different degrees of benefit in lower- and higher-risk patients, theAll 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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint9particular lower-risk/higher-risk subdivision of the ACTT-1 findings in Figure 4 was unplanned. (The ACTT-1protocol 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 confidenceinterval 0.43-1.55.) Thus, although the all-trials subtotals in Figure 4 suggest some benefit in low-risk patientsand some hazard in high-risk inpatients (with the absolute benefit in low-risk appearing somewhat smaller thanthe absolute hazard in high-risk), neither subtotal should be considered in isolation from the other subtotal, orfrom the CI for the total.For Hydroxychloroquine and Lopinavir, Solidarity found no definite evidence of benefit or of hazard in anysubgroup. The only other substantial trial of these two drugs is Recovery,10,11 which for these drugs is largerthan Solidarity. Combination of log-rank analyses from these two relatively large trials (by the meta-analysismethods 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 noapparent benefit whether ventilated or not. This CI excludes any material benefit from this Hydroxychloroquineregimen in hospitalized COVID. It is compatible with some hazard, but does not demonstrate hazard. Despiteconcerns that the loading dose could be temporarily cardiotoxic, in neither trial was there any excess mortalityduring the first few days, when blood levels were highest. Neither trial recorded dosage/kg, obesity, or cardiacparameters, and cardiac deaths were too few to be reliably informative. A recent meta-analysis identified 27small 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, Recoveryand the only informative smaller trial13) was 1.02, 95% CI 0.91-1.14. Although Lopinavir tablets could not beswallowed by ventilated patients, there was no apparent benefit in analyses restricted to those not already beingventilated 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 unexpectedincrease in creatinine (perhaps because blood levels are higher than in similarly-dosed HIV patients14,15), butSolidarity and Recovery recorded no renal or hepatic deaths with Lopinavir.For Interferon-ȕ1a no large mortality trials have been reported. Based on about 4000 patients, the mortality RRin 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 reductionin these circumstances. About half the interferon-allocated patients (and half their controls) receivedcorticosteroids,16 but the interferon vs control mortality RR seemed unaffected by corticosteroids. MostAll 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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint10interferon was subcutaneous, and subcutaneous and intravenous interferon have different pharmacokinetics,17but the clinical relevance of this is unclear. Randomization to Interferon is ceasing in Solidarity on October 16,but other evidence will emerge: a report that nebulized Interferon-ȕ1a might be highly effective involved onlyabout 100 COVID patients (NCT04385095), but the ongoing placebo-controlled ACTT-3 trial of subcutaneousInterferon-ȕ1a aims to involve 1000 (NCT04492475).For each of these 4 repurposed non-specific antivirals, several thousand patients have now been randomized invarious trials. The unpromising overall findings from the regimens tested suffice to refute early hopes, based onsmaller or non-randomized studies, that any will substantially reduce inpatient mortality, initiation of ventilationor hospitalisation duration. Narrower confidence intervals would be helpful (particularly for Remdesivir), butthe main need is for better treatments. Solidarity is still recruiting about 2000 patients per month, and efficientfactorial designs will allow it to assess further treatments, such as immune-modulators and specific anti-SARSCov-2 monoclonal antibodies.The chief acknowledgement is to the thousands of patients and their families who participated in this trial, and thehundreds of medical staff who randomized and cared for the patients. The Ministries of Health of the participatingMember States and their national institutions provided critical implementation support. The views expressed are those ofthe Writing Group, not necessarily those of WHO. NJ White et al4 provided unpublished Hydroxychloroquinepharmacokinetic 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 nofunders for the main Solidarity trial, but the Discovery add-on study received EU Horizon 2020 research and innovationprogram 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 nocosts, and drugs were donated. Castor EDC donated and managed their cloud-based clinical data capture and managementsystem, blind to study findings. Anonymized data handling and analysis was by the Universities of Berne, Bristol andOxford. Remdesivir was donated by Gilead Sciences, Hydroxychloroquine by Mylan, Lopinavir by Abbvie, Cipla andMylan, and Interferon ȕ1a by Merck KGaA (subcutaneous) and Faron (intravenous).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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprint11REFERENCES1. World Health Organization, R&D Blueprint. A coordinated global research roadmap: 2019 novelcoronavirus. Geneva, Switzerland March 2020 https://www.who.int/docs/defaultsource/coronaviruse/coordinated-global-research-roadmap.pdf?sfvrsn=21b0f5c4_1&download=true(accessed October 3, 2020).2. World Health Organization, R&D Blueprint. 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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.medRxiv preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15, 2020. The copyright holder for this preprintTable 1. Entry characteristics by random allocation, and compliance with that allocationExcludes 64 without clear consent to follow-up. Comparisons are of each study drug vs concurrent allocation to the same treatmentwithout it. As the control groups overlap, the total number (11,266) is less than the sum of the numbers in the pairwise comparisons.Notes: The few with a particular characteristic unknown are merged with the largest category of that characteristic.³28-d KM %´ is the Kaplan-Meier 28-day % risk of in-hospital death. ³NR. died´ iQcOXdeV any in-hospital deaths after day 28.* Interferon randomisation was interferon + Lopinavir vs Lopinavir until 4 July, then it was interferon vs standard of care.** Albania, Austria, Belgium, Finland, France, Ireland, Italy, Lithuania, Luxembourg, Macedonia, Norway, Spain, Switzerland.§ Argentina, Brazil, Colombia, Honduras, Peru.‚ EgSW, IQdia, IQdRQeVia, IUaQ, KXZaiW, LebaQRQ, MaOaVia, PaNiVWaQ, PhiOiSSiQeV, SaXdi AUabia, SRXWh AfUica.Á CRPSOiaQce iV caOcXOaWed RQO aPRQg WhRVe ZhR died RU ZeUe diVchaUged aOiYe, aQd iV defined as the % taking the studydrug midway through its scheduled duration (or midway through the time from entry to death or discharge, if this is shorter). All in any intentto-treat analysisRemdesivirvs its controlHydroxychloroquinevs its controlLopinavirvs its controlInterferonvs its control*Active Control Active Control Active Control Active ControlEnteredNo. %No.died28-dKM%All participantsEntry characteristicsAge (years)

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