White, F.R.S., Edmund Juszczak, M.Sc., Richard Haynes, D.M., and Martin J. Landray, Ph.D.) assume responsibility for the overall content and integrity of this article. Spinner CD, Gottlieb RL, Criner GJ, et al. In this open-label trial, no placebos were used. The confidence interval is compatible with prevention of a small fraction of all deaths, but it is also compatible with prevention of no deaths. Patients with a known prolonged corrected QT interval on electrocardiography were ineligible to receive hydroxychloroquine. In February 2020, a World Health Organization (WHO) research forum on coronavirus disease 2019 (Covid-19) recommended evaluation of treatments in large, randomized trials,1 and other WHO expert groups identified four repurposed antiviral drugs that might have at least a moderate effect on mortality: remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a.2 In March 2020, the WHO began a large, simple, international, open-label, randomized trial involving hospital inpatients to evaluate the effects of these four drugs on in-hospital mortality. These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. Any views expressed are those of the writing committee, not necessarily of the WHO. Percentages may not total 100 because of rounding. A recent meta-analysis identified 15 small, randomized trials with nonzero mortality14; combining all 17 hydroxychloroquine trials yields a rate ratio of 1.09 (95% CI, 0.98 to 1.21), which still rules out any material benefit. Ventilation was initiated after randomization in 295 patients receiving remdesivir and in 284 receiving its control, in 75 patients receiving hydroxychloroquine and in 66 receiving its control, in 126 patients receiving lopinavir and in 121 receiving its control, and in 209 patients receiving interferon and in 210 receiving its control (Table S1). Lancet 2020;395:507-513. 5. Hydroxychloroquine causes predictable prolongation of the corrected QT interval on electrocardiography, which is exacerbated by coadministration with azithromycin, as widely prescribed in Covid-19 treatment.16-18 Although torsades de pointes has been described, serious cardiovascular toxicity has been infrequently reported, despite the high prevalence of cardiovascular disease in hospitalized patients, the common occurrence of myocarditis in Covid-19, and the extensive use of hydroxychloroquine and azithromycin together. (In Chinese.). 14. For lopinavir, which was always administered with ritonavir, the joint rate ratio for death (combining the Solidarity and RECOVERY trials and the only informative smaller trial15) was 1.01 (95% CI, 0.91 to 1.13). In the hydroxychloroquine group, patients received hydroxychloroquine sulfate (in the form of a 200-mg tablet containing a 155-mg base equivalent) in a loading dose of four tablets (total dose, 800 mg) at baseline and at 6 hours, which was followed by two tablets (total dose, 400 mg) starting at 12 hours after the initial dose and then every 12 hours for the next 9 days or until discharge, whichever occurred earlier (see the Supplementary Appendix).15 The assigned treatment was prescribed by the attending clinician. S1 through S9) subdivide 28-day mortality graphs according to ventilation status at entry and give subgroup analyses of rate ratios for death according to other characteristics and according to glucocorticoid use (with no noteworthy subgroup-specific or geographic variation). Its results should be considered in the context of the evidence on mortality from all trials, but for remdesivir and for interferon it provides more than three fourths of that evidence (Figure 4). Narrower confidence intervals would be helpful (particularly for remdesivir), but the main need is for better treatments. Vincent MJ, Bergeron E, Benjannet S, et al. 11. 37. A novel coronavirus from patients with pneumonia in China, 2019. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19 @NEJM. Participants were randomly assigned in equal proportions to receive no trial drug or one of the trial drug regimens that was locally available (up to five options; all patients were to receive the local standard of care). In this analysis of the RECOVERY trial, we determined that hydroxychloroquine was not an effective treatment for patients hospitalized with Covid-19. The primary outcome was 28-day mortality. 4. After outside evidence of the futility of hydroxychloroquine and lopinavir became available, the executive group requested unblinded analyses of the findings just for these two drugs. Int J Antimicrob Agents 2020;56:105949-105949. Although lopinavir tablets could not be swallowed by patients receiving ventilation, there was no apparent benefit in analyses that involved only those not already receiving ventilation at entry. Million M, Lagier JC, Gautret P, et al. Lancet 2020;395:1569-1578. Information, resources, and support needed to approach rotations - and life as a resident. * A total of 64 patients who did not provide clear informed consent regarding follow-up were excluded. and Fundación del Centro de Estudios Infectológicos (G.L. and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) Furthermore, the data presented here did not show any excess in ventricular tachycardia or ventricular fibrillation in the hydroxychloroquine group. For each drug, patient characteristics were well balanced by the unstratified 1:1 randomization between it and its control. June 15, 2020 (https://www.fda.gov/media/138945/download). †† Percentage of patients (rather than number of patients) is shown for this variable. ); the Agency of Medicine and Medical Devices (C.H.G.) Subcutaneous and intravenous interferon have different pharmacokinetic characteristics,18,19 and glucocorticoids could affect interferon signaling,20,21 but the clinical relevance of both issues is unclear. 3. ); the University of British Columbia, Vancouver (S. Murthy), and the Public Health Agency of Canada, Ottawa (M.I.S.) Other formulations were not provided, so patients who were receiving mechanical ventilation received no trial lopinavir while they were unable to swallow. and Rumah Sakit Umum Pusat Persahabatan (M.R.R. videos in clinical medicine. 33. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. AbbVie contributed some supplies of lopinavir–ritonavir for use in the trial. Written informed consent was obtained from all the patients or from a legal representative if they were too unwell or unable to provide consent. Statistical uncertainties are magnified if attention is restricted to particular subgroups or time periods.10 If remdesivir has no effect on mortality, then chance could well produce somewhat favorable findings in a subgroup of the results for all trials or striking findings in a selected subgroup of a particular trial (as in the unplanned subgroup of ACTT-1 in which the rate ratio for death was 0.30) (Figure 4). — both in France; the Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran (R.M. ), University of Manchester (A.U., T.F. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. and Vilnius University, Institute of Clinical Medicine (L.J. Tang W, Cao Z, Han M, et al. The hydroxychloroquine, lopinavir, and interferon regimens were discontinued for futility on, respectively, June 19, July 4, and October 16, 2020. The percentages show Kaplan–Meier 28-day mortality. NEW! Jalkanen J, Hollmén M, Jalkanen S. Interferon beta-1a for COVID-19: critical importance of the administration route. Editor’s Note: This article was published on June 3, 2020, at NEJM.org. The protocol, which was published previously3 and is available with the full text of this article at NEJM.org, was designed to involve hundreds of hospitals in dozens of countries. This subdivision, however, leaves few deaths in the no-supplemental-oxygen category (death in 3 of 75 patients with remdesivir and in 3 of 63 with placebo in ACTT-1, in 11 of 661 patients with remdesivir and in 13 of 664 with its control in the Solidarity trial, and in 5 of 384 patients with remdesivir and in 4 of 200 with the standard of care in an international trial with a 2:1 randomization ratio8). Gautret P, Lagier J-C, Parola P, et al. The inset shows the same data on an expanded y axis. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. ), the Department of Mathematics and Statistics, Lancaster University, Lancaster (T.J.), the MRC Biostatistics Unit, University of Cambridge, Cambridge (T.J.), and the Respiratory Medicine Department, Nottingham University Hospitals NHS Trust (W.S.L. 16. Severity was not protocol-defined, but separate analyses are provided regarding those receiving some supplemental oxygen or none and for those already receiving ventilation at entry or not. Original Article from The New England Journal of Medicine — Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results Eligible patients were 18 years of age or older, were hospitalized with a diagnosis of Covid-19, were not known to have received any trial drug, were not expected to be transferred elsewhere within 72 hours, and, in the physician’s view, had no contraindication to any trial drug. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. This risk depended on several factors, particularly age (20.4% if ≥70 years and 6.2% if <50 years) and ventilation status (39.0% if the patient was already receiving ventilation and 9.5% otherwise). There was one report of a serious adverse reaction that was deemed by investigators to be related to hydroxychloroquine: a case of torsades de pointes, from which the patient recovered without undergoing intervention. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. In addition, 12 patients (0.4%) in the usual-care group received hydroxychloroquine. Unstratified comparisons yielded similarly null findings (Figure 2), as did analyses that excluded patients receiving glucocorticoids and multivariable sensitivity analyses that estimated trial drug effects simultaneously (Table S3). 18. 1. Goldman JD, Lye DCB, Hui DS, et al. — both in the United Kingdom; the World Health Organization, Geneva (A.-M.H.-R., M.-P.P., V.S., P. Lydon, M.C.M.-M., K.S., S.S.), the University of Bern, Bern (S.A., M.B., S. McGinty, S.T. Add-on studies that were led from Canada, France, India, and Norway recorded other outcomes (not reported here). † Patients who were receiving invasive mechanical ventilation at randomization were excluded from this analysis. This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. Table 1. Global Health Observ 35h ago. ), the Department of Infectious Diseases, Cardiff and Vale University Health Board, and the Division of Infection and Immunity, Cardiff University, Cardiff (J.U. In addition, the results suggest that the patients who received hydroxychloroquine had a longer duration of hospitalization and, among those who were not undergoing mechanical ventilation at baseline, a higher risk of invasive mechanical ventilation or death than those who received usual care. This article was published on October 8, 2020, at NEJM.org. The trial was registered at the ISRCTN Registry and ClinicalTrials.gov, with the core protocol approved by the WHO ethics review committee and local protocols approved by national ethics committees and regulatory authorities. Armstrong RA, Kane AD, Cook TM. Outcomes from intensive care in patients with COVID-19: a systematic review and meta-analysis of observational studies. We are here to help you. For hydroxychloroquine and lopinavir, the Solidarity trial showed no definite effect on mortality in any subgroup. Nature 2020;579:270-273. A retrospective cohort study involving 1376 patients with Covid-19 who were admitted to the hospital in New York City in March and April 2020 showed that 59% of the patients received hydroxychloroquine.22,38 Since our preliminary results were made public on June 5, 2020, the FDA has revoked the EUA for chloroquine and hydroxychloroquine,39 and the World Health Organization (WHO) and the National Institutes of Health have ceased trials of its use in hospitalized patients on the grounds of a lack of benefit. S19 and S20). § Shown is the Kaplan–Meier 28-day risk of in-hospital death, expressed as a percentage (overall value, 11.8%). The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. A history of diabetes was present in 27% of patients, heart disease in 26%, and chronic lung disease in 22%, with 57% having at least one major coexisting illness that was recorded. 3. The lower boundary of the confidence limit for the primary outcome ruled out any reasonable possibility of a meaningful mortality benefit. Herausgeber des NEJM ist die Massachusetts Medical Society. Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). ); Vilnius University Hospital Santaros Klinikos (L.G.) Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. BMJ 2020;369:m1849-m1849. We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). No trial drug had any definite effect on mortality, either overall (each P>0.10) or in any subgroup defined according to age, ventilation status at entry, other entry characteristics, geographic region, or glucocorticoid use (Figs. Huang M, Tang T, Pang P, et al. The few patients (always <0.4%) with a particular characteristic not yet known were merged with the largest category of that characteristic: 33 were merged with male sex, 40 were merged with an age of 50 to 69, and 45 were merged with previous days in the hospital of 2 or more. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020;49:215-219. ¶ Severe liver disease was defined as a diagnosis that resulted in ongoing specialist care. and Infectious Diseases Hospital (A. Alhasawi), Kuwait City, Kuwait; Universidad Nacional de Colombia and Clinica Colsanitas (C.A.A.-M.) and the Ministry of Health (M.L.M.R. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. 8. Entry Characteristics According to Random Assignment, and Adherence to That Assignment. The authorized source of trusted medical research and education for the Chinese-language medical community. Knight SR, Ho A, Pius R, et al. DOI: 10.1056/NEJMoa2021436. Rate of intensive care unit admission and outcomes among patients with coronavirus: a systematic review and meta-analysis. of days since hospitalization (IQR). Remdesivir in adults with severe Covid-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Kaplan–Meier risk of in-hospital death to day 28 was 11.8%; a few in-hospital deaths occurred later. BMJ 2020;369:m1936-m1936. The similarity of this null effect for all four drugs is further evidence that none has any material effect on major disease progression, a conclusion supported by analyses of the combined outcome of death or ventilation initiation. Watson JA, Tarning J, Hoglund RM, et al. † Interferon randomization was interferon plus lopinavir as compared with lopinavir until July 4, 2020, then it was interferon as compared with the local standard of care. November 19, 2020N Engl J Med 2020; 383:2030-2040 Drs. June 11, 2020 (https://www.biorxiv.org/content/10.1101/2020.06.10.145144v1). For remdesivir, the scheduled treatment duration was 10 days (or to death or discharge). (Details are provided in the Supplementary Appendix.). ), and the Department of Health and Children, Dublin (P. Lennon, T.M.) Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. In such a circumstance, the committee would inform the members of the trial steering committee, who would make the results available to the public and amend the trial accordingly. Hydroxychloroquine has been proposed as a treatment for Covid-19 largely on the basis of its in vitro SARS-CoV-2 antiviral activity and on data from observational studies reporting effective reduction in viral loads. All the analyses were performed according to the intention-to-treat principle. Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. Treating COVID-19 with chloroquine. Assignment to the standard of care at a hospital in which more than one trial drug was available would put that patient into the control group for each of those drugs. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. ‡ The between-group difference was calculated as a risk ratio. Travel Med Infect Dis 2020;34:101663-101663. Axfors C, Schmitt AM, Janiaud P, et al. and Helsinki University Hospital (K.A.O.T. The unpromising overall findings from the regimens tested suffice to refute early hopes, based on smaller or nonrandomized studies, that any of these regimens will substantially reduce inpatient mortality, the initiation of mechanical ventilation, or hospitalization duration. NEJM Career Center Valuable tools for building a rewarding career in health care. (Coadministration with medications that prolong the QT interval was not an absolute contraindication, but attending clinicians were advised to check the QT interval by performing electrocardiography.) On June 4, 2020, in response to a request from the MHRA, the independent data monitoring committee conducted a review of the data and recommended that the chief investigators review the unblinded data for the hydroxychloroquine group. Supported by a grant (MC_PC_19056) to the University of Oxford from UK Research and Innovation and the NIHR and by core funding provided by NIHR Oxford Biomedical Research Centre, Wellcome, the Bill and Melinda Gates Foundation, the Department for International Development, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. Beigel JH, Tomashek KM, Dodd LE, et al. Of the eligible patients, 1561 were assigned to receive hydroxychloroquine and 3155 were assigned to receive usual care; the remainder of the patients were randomly assigned to one of the other treatment groups. There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. We collected baseline data using a Web-based case-report form that included demographic data, level of respiratory support, major coexisting illnesses, the suitability of the trial treatment for a particular patient, and treatment availability at the trial site. In addition, 6 patients were randomly assigned to receive either convalescent plasma or usual care alone (1 patient [0.1%] in the hydroxychloroquine group and 5 patients [0.2%] in the usual-care group) in accordance with protocol version 6.0. 23. Effects of Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon on In-Hospital Mortality. ), and Manchester University NHS Foundation Trust (T.F. The authorized source of trusted medical research and education for the Chinese-language medical community. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. 4. World Health Organization. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.). Because the control groups overlap, the total number (11,266) is less than the sum of the numbers in the pairwise comparisons. For some patients, hydroxychloroquine was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. O−E denotes the observed minus expected number of deaths in patients assigned to active treatment. Combination of both trials reinforces these null findings (Figs. Group A … Mahévas M, Tran V-T, Roumier M, et al. 19 In tandem with addressing the continued clinical demands of Covid-19, the next steps in recovery for our employees will focus on coping with trauma and recognizing the sacrifices … It is compatible with some adverse effect but is not good evidence for any adverse effect and is not a safety signal. 32. ); the National Hepatology and Tropical Medicine Research Institute (M. Hassany) and the Ministry of Health and Population (H.Z. Carmichael SJ, Charles B, Tett SE. The RECOVERY trial is an investigator-initiated platform trial to evaluate the effects of potential treatments in patients hospitalized with Covid-19. Jeffrey Drazen, MD, is a pulmonologist, critical care physician, and NEJM Group Editor. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. R&D blueprint and Covid-19 (https://www.who.int/teams/blueprint/covid-19). BMJ 2020;370:m3339-m3339. Zhou F, Yu T, Du R, et al. NEW! Voilà qui s'ajoute à d'autres données similaires. ), the Department of Respiratory Medicine, North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees (B.P. Although every resident develops his or her own style for each of these roles, the following practical strategies were discussed in a NEJM Resident 360 discussion (How to Lead a Team on the Wards: The Art to Being an Effective Resident). N Engl J Med 2020;382:2411-2418. After it was determined which treatments were locally available, random assignment (with equal probability) was between the local standard of care and the available treatments. N Engl J Med 2020;383:1827-1837. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Stratification of the findings according to initial respiratory support again facilitates allowance for the remdesivir group in ACTT-1 having, by chance, started with a greater proportion of low-risk patients and a smaller proportion of high-risk patients than the placebo group. Midway through this period, 96% of the patients were still taking it (as compared with only 2% of those in the relevant group). The protocol-specified primary objective was to assess effects on in-hospital mortality (i.e., death during the original hospitalization; follow-up ceased at discharge), regardless of whether death occurred before or after day 28. Although no placebos were used, appropriate analyses of these secondary outcomes can still be informative. 12. Numbers of deaths are by week, and then deaths after day 28. An add-on study within the Solidarity trial, Discovery, recorded many clinical variables and identified an unexpected increase in the creatinine level (perhaps because blood lopinavir levels are higher than in patients with human immunodeficiency virus infection receiving similar doses16,17), but the Solidarity and RECOVERY trials recorded no specifically renal or hepatic deaths with lopinavir. Patients in the hydroxychloroquine group had a longer duration of hospitalization than those in the usual-care group (median, 16 days vs. 13 days) and a lower probability of discharge alive within 28 days (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98) (Table 2). The full database is held by the trial team, which collected the data from the trial sites and performed the analyses, at the Nuffield Department of Population Health at the University of Oxford. N Engl J Med 2020;383:2030-2040. The only other substantial trial is the Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial,12,13 which for these two drugs was larger than the Solidarity trial and also showed no benefit. Meta-Analysis of Mortality in Trials of Random Assignment of Remdesivir or Its Control to Hospitalized Patients with Covid-19. ), Bogota, Colombia; the Ministry for Preventive Health, Riyadh, Saudi Arabia (A. Asiri, A. Alotaibi); Oslo University Hospital (P.A., A.B.-D.) and Research Council of Norway (J.-A.R. preprint. The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee.

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