4. 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. Follow-up is ongoing to evaluate long-term survival. June 11, 2020 (https://www.biorxiv.org/content/10.1101/2020.06.10.145144v1). Armstrong RA, Kane AD, Cook TM. N Engl J Med 2020;382:727-733. To augment these small numbers of deaths, the subtotals in Figure 4 include low-flow oxygen with no supplemental oxygen, which yields a large lower-risk subgroup and a small higher-risk subgroup. NEJM Knowledge+ Pain Management and Opioids (FM) only This Enduring Material activity, NEJM Knowledge+ Pain Management and Opioids, has been reviewed and is acceptable for up to 10.00 Prescribed credit(s) by the American Academy of Family Physicians. For hydroxychloroquine, the joint rate ratio for death (combining the Solidarity and RECOVERY trials) was 1.10 (95% CI, 0.98 to 1.23), with no apparent benefit whether the patient was receiving ventilation or not. 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). 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. In Wuhan, as infection incidence declined, more than 40% of frontline workers experienced depression, anxiety, or other psychological burden. Clinical features and short-term outcomes of 102 patients with coronavirus disease 2019 in Wuhan, China. There was no difference between the hydroxychloroquine group and the usual-care group in 28-day mortality that was ascribed to Covid-19 (24.0% vs. 23.5%). Rate ratios were calculated by taking the loge rate ratio to be (O−E)/V with a Normal distribution and variance 1/V. 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). For interferon beta-1a, no other large trials exist. VIEW MORE. Customer Service and Fulfillment. Knight SR, Ho A, Pius R, et al. The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Information and tools for librarians about site license offerings. The regimen for lopinavir (oral) was two tablets twice daily for 14 days. Valuable tools for building a rewarding career in health care. NEJM Career Center Valuable tools for building a rewarding career in health care. Lancet Infect Dis 2020;20:669-677. 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). Homogeneity of different rate ratios is not needed for such a weighted average to be informative. ), University Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology and Infection, University of Birmingham, Birmingham (T.W. Trial conduct was in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020;49:215-219. — both in Canada; the Public Health Foundation of India, New Delhi (K.S.R. 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). Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Characteristics of the Patients at Baseline.*. The hydroxychloroquine that was used in the trial was supplied by the NHS. Summation of these trial-specific observed-minus-expected subtotals then led to an appropriately weighted average of the results from all trials, which yielded a rate ratio for death (remdesivir vs. control) of 0.91 (95% CI, 0.79 to 1.05).5 Figures S19 and S20 show the mortality results in the trials of hydroxychloroquine (rate ratio, 1.09; 95% CI, 0.98 to 1.21) and of lopinavir (rate ratio, 1.01; 95% CI, 0.91 to 1.13). BMJ 2020;370:m3339-m3339. The trial was conducted in accordance with Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. JAMA Netw Open 2020;3(4):e208857-e208857. The stratified rate ratios for death in the Solidarity trial and ACTT-1 are compatible with each other, and either singly or together they are compatible with there being little or no effect of remdesivir on mortality. Chen N, Zhou M, Dong X, et al. NEJM Journal Watch Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. ), and Lausanne University Hospital, Lausanne (O.M.) VIEW VIDEOS . Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. BMJ 2020;369:m1936-m1936. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. It is compatible with some adverse effect but is not good evidence for any adverse effect and is not a safety signal. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. Medicines and Healthcare Products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee. Valuable tools for building a rewarding career in health care. 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. 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. In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. and Rumah Sakit Umum Pusat Persahabatan (M.R.R. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. 39. 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. Death at 28 days (the primary outcome) occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group. 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.). Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P=0.15). 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. In all patients and in those not receiving ventilation, assignment to each active trial drug increased the time to discharge by approximately 1 to 3 days while treatment continued. Verity R, Okell LC, Dorigatti I, et al. JAMA 2020;324:1048-1057. In addition, after deciding in a blinded fashion to report all interim results, the executive group revised this manuscript, which has been drafted only by the WHO trial team and external statisticians. and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) 36. Read the NEJM Journal Watch Summary. Intensive Care Med 2020;46:1937-1940. Fantini J, Chahinian H, Yahi N. Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal. Case Records of the Massachusetts General Hospital. PARIS, 11 décembre 2020 /PRNewswire/ -- MicroPort Cardio Rhythm Management (CRM) a annoncé le premier recrutement pour l'essai clinique Astral-4LV[1] visant à évaluer la sécurité et l'efficacité de Axone™, une sonde ventriculaire gauche quadripolaire innovante et révolutionnaire. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. 17. Scope, quality, and inclusivity of clinical guidelines produced early in the covid-19 pandemic: rapid review. Information, resources, and support needed to approach rotations - and life as a resident. NEJM uses the power of digital media to deliver reliable, leading-edge medical knowledge. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Peto R. Current misconception 3: that subgroup-specific trial mortality results often provide a good basis for individualising patient care. of days since symptom onset (IQR), Median no. Percentages show Kaplan–Meier 28-day mortality. The only protocol-specified subgroup analyses involved patients who already had severe disease at entry and those who did not. 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). Zhou P, Yang X-L, Wang X-G, et al. Wang Y, Zhang D, Du G, et al. 26. Axfors C, Schmitt AM, Janiaud P, et al. Meta-analyses of the major trial results are based on the inverse-variance–weighted average of b=loge rate ratio from each stratum of each trial, with the use of odds ratios when hazard ratios or rate ratios for death were unavailable. group (group B), 96.36% reached a negative PCR at a mean of 6.99days and were symptoms-free at 9.33days. Table 1 shows patient characteristics: 9120 (81%) were younger than 70 years of age, 6985 (62%) were male, 2768 (25%) had diabetes, 916 (8%) were already receiving ventilation, and 7002 (62%) underwent randomization on days 0 or 1. The Kaplan–Meier risk of in-hospital death to day 28 was 11.8%; a few in-hospital deaths occurred later. 17. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. Nicholas J. The primary outcome was 28-day mortality. The protocol with its statistical analysis plan are available at NEJM.org, with additional information in the Supplementary Appendix and on the trial website at www.recoverytrial.net. Letter from the U.S. Food and Drug Administration re: revocation of the Emergency Use Authorization (EUA) letter of March 20, 2020. Derk Arts of Castor EDC donated and managed Castor’s cloud-based clinical data capture and management system, with blinding to trial findings. ); the National Hepatology and Tropical Medicine Research Institute (M. Hassany) and the Ministry of Health and Population (H.Z. All rate ratios describe proportional risk reductions; absolute risk reductions would also depend on background risks. Each tablet contained 200 mg of hydroxychloroquine sulfate (155 mg of hydroxychloroquine base per tablet; a little-used alternative involved 155 mg of chloroquine base per tablet). The inset shows the same data on an expanded y axis. No funder or donor unduly influenced analyses, manuscript preparation, or submission; their comments merely clarified methods, not changing analyses or conclusions. The Author Final Manuscript, which is the author’s version after external peer review and before publication in the Journal, is available under a CC BY license at PMC7556338. AbbVie contributed some supplies of lopinavir–ritonavir for use in the trial. March 2020 (https://www.who.int/blueprint/priority-diseases/key-action/Coronavirus_Roadmap_V9.pdf?ua=1). 37. 12. Combination of both trials reinforces these null findings (Figs. ), University of Manchester (A.U., T.F. Therefore, the enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, and the preliminary result for the primary outcome was made public. preprint. The Ministries of Health of participating member states and national institutions provided critical support in trial implementation. 30. Cappel-Porter, M.Math., Nery Cerrato, M.D., Ting S. Chow, M.D., Najada Como, Ph.D., Joe Eustace, B.Ch., M.H.S., Patricia J. García, Ph.D., Sheela Godbole, M.B., B.S., Eduardo Gotuzzo, M.D., Laimonas Griskevicius, Ph.D., Rasha Hamra, Pharm.D., Mariam Hassan, M.B., B.S., Mohamed Hassany, M.D., David Hutton, B.Sc., Irmansyah Irmansyah, M.D., Ligita Jancoriene, Ph.D., Jana Kirwan, M.A., Suresh Kumar, M.B., B.S., Peter Lennon, B.B.S., Gustavo Lopardo, M.D., Patrick Lydon, M.Sc., Nicola Magrini, M.D., Teresa Maguire, Ph.D., Suzana Manevska, M.D., Oriol Manuel, M.D., Sibylle McGinty, Ph.D., Marco T. Medina, M.D., María L. Mesa Rubio, M.D., Maria C. Miranda-Montoya, M.D., Jeremy Nel, M.B., Ch.B., Estevao P. Nunes, Ph.D., Markus Perola, Ph.D., Antonio Portolés, Ph.D., Menaldi R. Rasmin, M.D., Aun Raza, M.D., Helen Rees, M.R.C.G.P., Paula P.S. 32. * Percentages may not total 100 because of rounding. Graphs of mortality according to time are from unstratified Kaplan–Meier methods, with denominators chosen to yield in-hospital mortality. 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. November 19, 2020N Engl J Med 2020; 383:2030-2040 ), Roslin Institute, University of Edinburgh, Edinburgh (J.K.B. PREVIOUS NEXT. Crit Care 2020;24:335-335. World Health Organization. Rate Ratios for In-Hospital Death, Subdivided by Age and Respiratory Support at Trial Entry. NEJM Catalyst NEW! ), the Medical Research Council (MRC) Population Health Research Unit (N.S., J.R.E., R.H., M.J.L. This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. “NEJM Knowledge+ has been a positive step for our program and reflects our commitment to residents’ success. Jalkanen J, Hollmén M, Jalkanen S. Interferon beta-1a for COVID-19: critical importance of the administration route. ), Helsinki, and South Karelian Central Hospital, Lappeenranta (K.A.O.T.) Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19. 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).