All 3 patients for whom the diagnosis of Covid-19 was later ruled out were included in the analyses and survived. 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. The time to recovery averaged 11 days among those who got the drug, compared with 15 days for those who got the placebo. Rosenke K, Jarvis MA, Feldmann F, et al. Consistent results were seen in all prespecified subgroups of patients. The primary concern with short-term, high-dose 4-aminoquinoline regimens is cardiovascular toxicity. 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. 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. Daily doses were those already used for other diseases, but to maximize any efficacy without undue cardiac risk, the hydroxychloroquine dose was based on that for amoebic liver abscess rather than the lower dose for malaria.4 (Hydroxychloroquine slightly prolongs the QT interval, and an unduly high dose or rapid administration might cause arrhythmias or hypotension.) The enrollment number that is shown is the total number of patients in the RECOVERY platform trial during the period in which adult patients could be recruited for the comparison between hydroxychloroquine and usual care. — both in Canada; the Public Health Foundation of India, New Delhi (K.S.R. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Physicians should claim only the credit … ), Manchester, the Research and Development Department, Northampton General Hospital, Northampton (E.E. The hydroxychloroquine that was used in the trial was supplied by the NHS. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed as of May 9, 2020. Patients could have more than one reason for not participating in the hydroxychloroquine trial. 12. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score. 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 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. Address reprint requests to Dr. Horby or Dr. Landray at the RECOVERY Central Coordinating Office, Richard Doll Bldg., Old Road Campus, Roosevelt Dr., Oxford OX3 7LF, United Kingdom, or at [email protected]. White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J. COVID-19 prevention and treatment: a critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. … it may be possible to enter several thousand hospitalised patients with relatively mild disease and a few thousand with severe disease, but realistic, appropriate sample sizes could not be estimated at the start of the trial.” The executive group, whose members were unaware of the findings, made the decision to release the interim results. R&D blueprint and Covid-19 (https://www.who.int/teams/blueprint/covid-19). N Engl J Med 2020;383:2041-2052. The hydroxychloroquine that was used in this phase of the trial was supplied by the U.K. National Health Service (NHS). Collaborators, committee members, data analysts, and data management systems charged no costs. N Engl J Med. The controls for a drug were patients assigned to the standard of care at a time and place in which that drug was locally available (except that when interferon was being given only with lopinavir, its controls were patients given only lopinavir). 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. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. In this open-label trial, patients who would be considered fit for discharge might be kept in the hospital somewhat longer just because they were being given a trial drug, but information on time to recovery can be obtained by comparing the effects of different drugs on time to discharge. Hence, there was partial overlap among the four control groups. Mortality outcomes with hydroxychloroquine and chloroquine in Covid-19: an international collaborative meta-analysis of randomized trials. There were fewer deaths in … 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. 13. Other grants are listed in the Supplementary Appendix. PLoS Med 2020;17(9):e1003252-e1003252. 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. † 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. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Chen N, Zhou M, Dong X, et al. Prespecified analyses of the primary outcome were performed in six subgroups, as defined by characteristics at randomization: age, sex, race, level of respiratory support, days since symptom onset, and predicted 28-day risk of death. 11. ), and Hospices Civils de Lyon, Lyon (F.A.) 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). (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.). In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France. The trial is being conducted at 176 hospitals in the United Kingdom. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. 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. The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months. 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. Although no placebos were used, appropriate analyses of these secondary outcomes can still be informative. and Rumah Sakit Umum Pusat Persahabatan (M.R.R. This article was published on October 8, 2020, at NEJM.org. Each drug delayed discharge by approximately 1 to 3 days while it was being given. 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. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. (In Chinese.). N Engl J Med 2020;383:1813-1826. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19 @NEJM. Manuscript preparation, revision, and submission were controlled by the World Health Organization (WHO) trial team and writing committee. Numbers of deaths are by week, and then deaths after day 28. Group A … These findings indicate that hydroxychloroquine is not an effective treatment for hospitalized patients with Covid-19 but do not address its use as prophylaxis or in patients with less severe SARS-CoV-2 infection managed in the community. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate Covid-19: a randomized clinical trial. National and global monitors raised or resolved queries (or both) and checked progress and completeness. 3. and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) 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. Yao X, Ye F, Zhang M, et al. 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. — 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. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.). 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. No children were enrolled. A novel coronavirus from patients with pneumonia in China, 2019. After oral administration, they are rapidly absorbed, even in severely ill patients. 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. ), Skopje, North Macedonia; the Oswaldo Cruz Foundation, Rio de Janeiro (E.P.N., P.P.S.R. VIEW … 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%). Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 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. 4. — all in Finland. However, in that study, chloroquine was administered at a base dose of 600 mg twice daily for 10 days, a higher total dose than those that were used in other trials, including the RECOVERY trial.35,36 Pharmacokinetic modeling in combination with information regarding blood levels and mortality from a case series involving 302 patients with chloroquine overdose predicts that a chloroquine regimen that was equivalent to the hydroxychloroquine regimen used in our trial should have an acceptable safety profile.36 There was a small absolute excess of cardiac mortality of 0.4 percentage points in the hydroxychloroquine group on the basis of very few events, but we did not observe excess mortality in the first 2 days of treatment with hydroxychloroquine, the time when early effects of dose-dependent toxicity might be expected. 11. 1. The area of each square is proportional to the variance of O−E in the subgroup it describes. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. ), Tegucigalpa; Penang Hospital, Penang (T.S.C. of days since hospitalization (IQR). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. 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. NEJM Career Center Valuable tools for building a rewarding career in health care. preprint. 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. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. The prespecified secondary outcomes were ventilation and time to discharge.