AbbVie contributed some supplies of lopinavir–ritonavir for use in the trial. At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. 38. Estimates of the severity of coronavirus disease 2019: a model-based analysis. ACTT-1, which examined remdesivir, was placebo-controlled,6 which avoids any bias in time to discharge. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who had not been receiving invasive mechanical ventilation at randomization), the precise date of the initiation of invasive mechanical ventilation was not available, so the risk ratio was estimated instead. Abstract Background The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. Armstrong RA, Kane AD, Cook TM. The members of the writing committee (Peter Horby, F.R.C.P., Marion Mafham, M.D., Louise Linsell, D.Phil., Jennifer L. Bell, M.Sc., Natalie Staplin, Ph.D., Jonathan R. Emberson, Ph.D., Martin Wiselka, Ph.D., Andrew Ustianowski, Ph.D., Einas Elmahi, M.Phil., Benjamin Prudon, F.R.C.P., Tony Whitehouse, F.R.C.A., Timothy Felton, Ph.D., John Williams, M.R.C.P., Jakki Faccenda, M.D., Jonathan Underwood, Ph.D., J. Kenneth Baillie, M.D., Ph.D., Lucy C. Chappell, Ph.D., Saul N. Faust, F.R.C.P.C.H., Thomas Jaki, Ph.D., Katie Jeffery, Ph.D., Wei Shen Lim, F.R.C.P., Alan Montgomery, Ph.D., Kathryn Rowan, Ph.D., Joel Tarning, Ph.D., James A. Watson, D.Phil., Nicholas J. Chen Z, Hu J, Zhang Z, et al. DOI: 10.1056/NEJMoa2023184, Tap into groundbreaking research and clinically relevant insights. He is a Senior Physician at Brigham and Women’s Hospital, Distinguished Parker B. Francis Professor of Medicine at Harvard Medical School, Professor of Physiology at the Harvard School of Public Health, and Adjunct Professor of Medicine at the Boston University School of Medicine. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. This does not support the suggestion that remdesivir can prevent a substantial fraction of all deaths. The authorized source of trusted medical research and education for the Chinese-language medical community. 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. Consistent results were seen in all prespecified subgroups of patients. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. 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). White and colleagues provided unpublished data on the pharmacokinetic characteristics of hydroxychloroquine to help the WHO select the regimen, the members of the Discovery data and safety monitoring committee shared clinical variables, the investigators of the Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial shared log-rank statistics, the investigators of the Adaptive Covid-19 Treatment Trial (ACTT-1) shared subgroup hazard ratios, and Bin Cao shared details of the Wuhan trial. 2. No trial drug reduced the initiation of ventilation among patients not already receiving ventilation. ), James Cook University Hospital, Middlesbrough (J.W. Trial treatments ceased on schedule (if the patient was still in the hospital). The subgroup of patients who later underwent a second randomization to tocilizumab versus usual care in the RECOVERY trial included 37 of 1561 patients (2.4%) in the hydroxychloroquine group and 89 of 3155 patients (2.8%) in the usual care group. Virol J 2005;2:69-69. This is the New England Journal of Medicine version of record, which includes all Journal editing and enhancements. J Clin Pharmacol 2020;60:976-977. BMJ 2020;369:m1335-m1335. Biochem Biophys Res Commun 2004;323:264-268. 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. 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. The affiliations of the members of the writing and steering committees are as follows: the Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, Oxford (H.P., R.P. World Health Organization. Zhu N, Zhang D, Wang W, et al. 23. The only exclusions from the intention-to-treat analyses were the few patients with no, or uncertain, consent to follow-up. Values for observed minus expected number of deaths (O−E) are log-rank O−E for the Solidarity trial, O−E from 2-by-2 tables for the Wuhan7 and international8 trials, and w.loge hazard ratio for each stratum in the Adaptive Covid-19 Treatment Trial (ACTT-1)6 (with the weight w being the inverse of the variance of the loge hazard ratio, which was calculated from the confidence interval of the hazard ratio). Each of the three trial treatments that were scheduled to last more than 7 days increased the percentage of patients remaining in the hospital at day 7 (Table 1). Buchwalder PA, Buclin T, Trinchard I, Munafo A, Biollaz J. Pharmacokinetics and pharmacodynamics of IFN-beta 1a in healthy volunteers. Carmichael SJ, Charles B, Tett SE. 18. ), Madrid; INSERM, Paris (M.-P.K. Nicholas J. The only protocol-specified subgroup analyses involved patients who already had severe disease at entry and those who did not. 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. The results were consistent across subgroups according to age, sex, race, time since illness onset, level of respiratory support, and baseline-predicted risk. The only protocol-specified secondary outcomes were the initiation of mechanical ventilation and hospitalization duration. Flammer JR, Dobrovolna J, Kennedy MA, et al. Molina JM, Delaugerre C, Le Goff J, et al. Insets show the same data on an expanded y axis. The regimen for hydroxychloroquine (oral) was four tablets at hour 0, four tablets at hour 6, and, starting at hour 12, two tablets twice daily for 10 days. The regimen for lopinavir (oral) was two tablets twice daily for 14 days. NEJM Resident 360 Information, resources, and support needed to approach rotations - and life as a resident. The most trusted, influential source of new medical knowledge and clinical best practices in the world. Hence, there was partial overlap among the four control groups. The enrollment of patients who provided consent took just a few minutes. Remdesivir was administered to less than 0.1% of the patients in each group. Denominators for the few events on day 0, but not thereafter, include patients with no follow-up. With an appropriately weighted average of the stratified results from each of the four trials,5 the rate ratio for death with remdesivir as compared with control was 0.91 (95% CI, 0.79 to 1.05). Among these patients, there were no significant differences between the hydroxychloroquine group and the usual-care group in the frequency of supraventricular tachycardia (7.6% vs. 6.0%), ventricular tachycardia or fibrillation (0.7% vs. 0.4%), or atrioventricular block requiring intervention (0.1% vs. 0.1%) (Table S4). Lu R, Zhao X, Li J, et al. Nature 2020;579:270-273. Subtotals or totals of (O−E) and of V yield inverse-variance–weighted averages of the loge rate ratios. The analyses also (in Figs. Estimates of the between-group difference in absolute risk were also calculated. The patients and local trial staff members were aware of the assigned trial groups. Horby, Mafham, and Linsell and Prof. Juszczak, Dr. Haynes, and Dr. Landray contributed equally to this article. — both in France; the Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran (R.M. ); and the Finnish Institute for Health and Welfare and the University of Finland (M.P.) 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. 23. Beginning January 5, 2021, Rotation Prep will no longer be available as part of an individual or institutional subscription to NEJM or NEJM Journal Watch. 31. Any views expressed are those of the writing committee, not necessarily of the WHO. Intensive Care Med 2020;46:846-848. 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. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. The rate ratios for death were standardized for age and for ventilation status at entry. Among the 167 sites at which at least 1 patient was assigned to receive hydroxychloroquine, the median number of patients who underwent randomization was 20 (interquartile range, 11 to 41). Enrollment and Outcomes in the RECOVERY Trial. S19 and S20). The risk on day N was calculated by first excluding patients with an outcome not reported or an entry fewer than N days before data-set closure (or transferred elsewhere before day N); then, the number of in-hospital deaths on day N was divided by the total number of patients in the hospital on day N or discharged alive before day N. This denominator (or “risk set”), which includes those discharged before day N, was also used to calculate the contribution of day N to log-rank analysis and Cox analysis of in-hospital mortality. The lower boundary of the confidence limit for the primary outcome ruled out any reasonable possibility of a meaningful mortality benefit. — 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. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). 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. Clin Microbiol Infect 2020;26:979-987. (For example, if 99 of 100 patients were discharged alive before the last one died, the in-hospital mortality would be 1% and at the time of that death the probability of not having died in the hospital was multiplied by 99/100; this denominator included those already discharged.). Jalkanen J, Hollmén M, Jalkanen S. Interferon beta-1a for COVID-19: critical importance of the administration route. The type I interferon signaling pathway is a target for glucocorticoid inhibition. 12. Zhou P, Yang X-L, Wang X-G, et al. No funder or donor unduly influenced analyses, manuscript preparation, or submission; their comments merely clarified methods, not changing analyses or conclusions. Biosci Trends 2020;14:72-73. Mortality at 28 Days, According to Subgroup. The Purdue Pharma Opioid Settlement — Accountability, or Just the Cost of Doing Business? † 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. Information was recorded regarding the adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including cause of death). This article was published on October 8, 2020, at NEJM.org. Original Article from The New England Journal of Medicine — Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results 9. Jalkanen J, Pettilä V, Huttunen T, Hollmén M, Jalkanen S. Glucocorticoids inhibit type I IFN beta signaling and the upregulation of CD73 in human lung. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936. Interpretation of this should chiefly reflect not the P value (P=0.20) or point estimate (rate ratio, 0.91) but the confidence interval (0.79 to 1.05), which shows the range of rate ratios for death that are compatible with the weighted average of the findings from all trials. (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.) A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. We thank the thousands of patients and their families who participated in this trial and the hundreds of medical staff who randomly assigned and cared for them. 15. The chief investigators and steering committee members concluded that the data showed no beneficial effect of hydroxychloroquine in patients hospitalized with Covid-19. The primary outcome was 28-day mortality. †† Percentage of patients (rather than number of patients) is shown for this variable. Within each trial, summation of the observed minus expected numbers of deaths with remdesivir in each stratum led to the stratified rate ratio for death in that trial. Clinical features and short-term outcomes of 102 patients with coronavirus disease 2019 in Wuhan, China. BMJ 2020;369:m1849-m1849. ), and Hospices Civils de Lyon, Lyon (F.A.) Using a Web-based unstratified randomization method with the concealment of trial group, we assigned patients to receive either the usual standard of care or the usual standard of care plus hydroxychloroquine or one of the other available treatments that were being evaluated. 22. Trial conduct was in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Med Mal Infect 2020;50:384-384. Despite concerns that the loading dose could be temporarily cardiotoxic,4 in neither trial was there any excess mortality during the first few days, and cardiac deaths were too few to be reliably informative. 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). The committee was then charged with determining whether the randomized comparisons in the trial provided evidence with respect to mortality that was strong enough (with a range of uncertainty around the results that was narrow enough) to affect national and global treatment strategies. 3. Information and tools for librarians about site license offerings. A single online follow-up form was to be completed by the local trial staff members when each trial patient was discharged, at 28 days after randomization, or at the time of death, whichever occurred first. The Kaplan–Meier risk of in-hospital death to day 28 was 11.8%; a few in-hospital deaths occurred later. Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. ), the School of Life Course Sciences, King’s College London (L.C.C. 6. Global Health Observ 35h ago. Elife 2020;9:e58631-e58631. 14. Customer Service and Fulfillment. 29. ), Roslin Institute, University of Edinburgh, Edinburgh (J.K.B. Effect of hydroxychloroquine in hospitalized patients with Covid-19. DOI: 10.1056/NEJMoa2021436. The Solidarity trial has been recruiting approximately 2000 patients per month, and efficient factorial designs may allow it to assess further treatments, such as immune modulators or anti–SARS-Cov-2 monoclonal antibodies. Each comparison between a trial drug and its control, however, was evenly randomized (in a 1:1 ratio) and unbiased, because both groups were affected equally by differences between countries or hospitals and by time trends in patient characteristics or the standard of care. The number of patients who were assigned to receive usual care was twice the number who were assigned to any of the active treatments for which the patient was eligible (e.g., 2:1 ratio in favor of usual care if the patient was eligible for only one active treatment group, 2:1:1 if the patient was eligible for two active treatments, etc.). Concerns about pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) studies in the new therapeutic area of Covid-19 infection. Die Zeitschrift The New England Journal of Medicine (kurz: New Engl J Med oder NEJM) ist eine der angesehensten medizinischen Fachzeitschriften. Cell Res 2020;30:269-271. After oral administration, they are rapidly absorbed, even in severely ill patients. 14. 36. 12. Antiviral Res 2020;181:104866-104866. Approximately 15% of the patients who were hospitalized with Covid-19 in the United Kingdom during the trial period were enrolled, and the percentage of patients in the usual-care group who died was consistent with the hospitalized case fatality rate among hospitalized patients in the United Kingdom and elsewhere.7,30,31 Only essential data were collected at hospital sites, with additional information (including long-term mortality) ascertained through linkage with routine data sources. 13. Axfors C, Schmitt AM, Janiaud P, et al. These absolute differences in the meta-analysis of all four trials are similar to the absolute differences seen when the Solidarity trial is subdivided according to ventilation status at entry. 7. June 15, 2020 (https://www.fda.gov/media/138945/download). — both in Canada; the Public Health Foundation of India, New Delhi (K.S.R. NEW! Gautret P, Lagier J-C, Parola P, et al. Remdesivir in adults with severe Covid-19: a randomised, double-blind, placebo-controlled, multicentre trial. 2. Among the patients who were not undergoing invasive mechanical ventilation at baseline, the number of patients who had progression to the prespecified composite secondary outcome of invasive mechanical ventilation or death was higher among those in the hydroxychloroquine group than among those in the usual-care group (risk ratio, 1.14; 95% CI, 1.03 to 1.27). Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. Huang M, Tang T, Pang P, et al. Shown are Kaplan–Meier graphs of in-hospital mortality at any time (the primary outcome), comparing each treatment with its control without standardization for any initial patient characteristics. and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) The main outcomes of mortality, initiation of ventilation, and hospitalization duration were not definitely reduced by any trial drug, either overall or in any particular subgroup. In particular, it suggests at most only a small effect of remdesivir on time to recovery, a conclusion supported by the directly randomized comparisons between remdesivir and the other three trial drugs. The regimen for remdesivir (intravenous) was 200 mg on day 0 and 100 mg on days 1 through 9. 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). This confidence interval suggests no material effect on mortality and rules out a 10% proportional reduction. Address reprint requests to Dr. Henao-Restrepo at WHO R&D Blueprint, 20 Ave. Appia, 1211 Geneva, Switzerland, or at [email protected]. ), Tegucigalpa; Penang Hospital, Penang (T.S.C. Denominators for the few deaths on day 0, but not on later days, included patients with no follow-up reported (because if any patient died on the day of randomization, this would probably have been reported). An international randomised trial of additional treatments for Covid-19 in hospitalised patients who are all receiving the local standard of care (https://www.who.int/publications/m/item/an-international-randomised-trial-of-additional-treatments-for-covid-19-in-hospitalised-patients-who-are-all-receiving-the-local-standard-of-care). Diamonds show 95% confidence intervals for treatment effects. Group A … NEJM Journal Watch 7. Over 11,500 patients have been enrolled from over 175 NHS hospitals in the UK. A review of Covid-19 treatment guidelines that was produced early in the pandemic showed that chloroquine or hydroxychloroquine was recommended in China, France, Italy, the Netherlands, and South Korea.37 In the United States, the use of chloroquine and hydroxychloroquine was permitted in certain hospitalized patients under an Emergency Use Authorization (EUA) of the Food and Drug Administration (FDA). Beginning January 5, 2021, Rotation Prep will no longer be available as part of an individual or institutional subscription to NEJM or NEJM Journal Watch. 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. 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. There is partial overlap of each control group with other groups. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. After the exclusion of 64 of 11,330 patients (0.6%) who had provided either no or uncertain consent regarding follow-up, 11,266 remained in the intention-to-treat analyses. Entry Characteristics According to Random Assignment, and Adherence to That Assignment. Borba MGS, Val FFA, Sampaio VS, et al. and the Wits Reproductive Health and HIV Institute (H.R. Percentages show Kaplan–Meier 28-day mortality. We did not collect information on physiologic, electrocardiographic, laboratory, or virologic measurements. ), Helsinki, and South Karelian Central Hospital, Lappeenranta (K.A.O.T.) 11. PLoS Med 2020;17(9):e1003252-e1003252. ¶ Severe liver disease was defined as a diagnosis that resulted in ongoing specialist care. Video in Clinical Medicine Monitoring Neuromuscular Function This video demonstrates the assessment of neuromuscular function after administration of neuromuscular blocking agents. ), Vilnius, Lithuania; Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan (M. Hassan, A.R. Similar results were seen across all six prespecified subgroups (Figure 3). Rodrigo C, Fernando SD, Rajapakse S. Clinical evidence for repurposing chloroquine and hydroxychloroquine as antiviral agents: a systematic review. 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. 1. Herausgeber des NEJM ist die Massachusetts Medical Society. In this analysis of the RECOVERY trial, we determined that hydroxychloroquine was not an effective treatment for patients hospitalized with Covid-19. ), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (Covid-19), emerged in China in late 2019 from a zoonotic source.1 The majority of Covid-19 infections are either asymptomatic or result in only mild disease.
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