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Editor’s Note: A preliminary version of this article was published on July 17, 2020, at NEJM.org.dexamethasone


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Coronavirus disease 2019 (Covid-19) is associated with diffuse lung compromise. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.dexamethasone

In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment.

A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than
who in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).

In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)dexamethasone

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Dexamethasone and Covid-19
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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 cases either are asymptomatic or result in only mild disease. However, in a substantial percentage of patients, a respiratory illness requiring hospital care develops,2 and such infections can progress to critical illness with hypoxemic respiratory failure requiring prolonged ventilatory support.3-6 Among patients with Covid-19 who were admitted to hospitals in the United Kingdom in the first half of 2020, the case fatality rate was approximately 26% overall and more than 37% among patients who were undergoing invasive mechanical ventilation.7 Although remdesivir has been shown to shorten the time until recovery in hospitalized patients,8 no therapeutic agents have been shown to reduce mortality.

The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with prevalent radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.9 In other severe viral pneumonias, such as highly pathogenic avian influenza,10 SARS,11 and pandemic and seasonal influenza,12 the host immune response is thought to play a key role in the pathophysiology of organ failure. Inflammatory organ injury may occur in severe Covid-19, with a subgroup of patients having markedly elevated levels of inflammatory markers, including C-reactive protein, ferritin, interleukin-1, and interleukin-6.6,13,14 Several therapeutic interventions have been proposed to mitigate inflammatory organ injury in viral pneumonia, but the value of glucocorticoids has been widely debated.15,16dexamethasone

Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,17 the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19. Many guidelines for the treatment of such patients have stated
who glucocorticoids were either contraindicated or not recommended,18 although in China, glucocorticoids have been recommended for severe cases.19 However, in the first 6 months of the pandemic, practice varied widely across the world: in some series, as many as 50% of patients were treated with glucocorticoids.20,21 Here, we report the results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.

The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network. (Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped, the trial continues randomization to other treatments, including REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein), aspirin, colchicine, or usual automobilee alone.

Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible.dexamethasone

Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent. The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net.

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. 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 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.

We collected baseline data using a Web-based case-report form
who included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments
who were being evaluated in the trial.dexamethasone

For some patients, dexamethasone 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. These patients were excluded from the randomized comparison between dexamethasone and usual
vehiculare. The randomly assigned treatment was prescribed by the treating clinician. Patients and local members of the trial staff were aware of the assigned treatments.

A single online follow-up form was to be completed by the local trial staff when each patient was discharged or had died or at 28 days after randomization, whichever occurred first. Information was recorded regarding the patients’ 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 the cause of death). In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy.

The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal dialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Among those receiving invasive mechanical ventilation at the time of randomization, the outcome of successful cessation of invasive mechanical ventilation was defined as cessation within (and survival to) 28 days. All information presented in this report is based on a data cutoff of December 14, 2020. Information regarding the primary and secondary outcomes is complete for 99.9% of trial participants.dexamethasone

As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the Covid-19 pandemic. As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined
who if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups. Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients.

For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period. Cox regression was also used to analyze the secondary outcome of hospital discharge within 28 days and the outcome of successful cessation of invasive mechanical ventilation. For both of these outcomes, data for patients who had died during hospitalization were censored on day 29. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was
usaged to estimate the risk ratio. Risk ratios were also estimated for the outcomes of receipt of noninvasive or invasive mechanical ventilation (among patients who were not receiving oxygen or invasive mechanical ventilation at the time of randomization) and receipt of renal-replacement therapy (among those not receiving such therapy at the time of randomization).

Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1). To account for this imbalance in an
vital prognostic factor, estimates of rate and risk ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years). This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix.dexamethasone

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 mortality risk. In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest. Chi-square tests for heterogeneity or linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan.

All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle. The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford.

Completed follow-up forms were available for 2095 of 2104 patients (99.6%) in the dexamethasone group and 4306 of 4321 patients (99.7%) in the usual care group. The subgroup of patients who later underwent a second randomization to tocilizumab versus usual care in the RECOVERY trial included 95 of 2104 patients (4.5%) in the dexamethasone group and 276 of 4321 patients (6.4%) in the usual care group. In addition, 14 patients were randomly assigned to receive either convalescent plasma or usual care alone (5 [0.2%] in the dexamethasone group and 9 [0.2%] in the usual care group).dexamethasone

Of the 11,303 patients who underwent randomization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexamethasone (i.e., the drug was available in the hospital at the time and the patient had no known indication for or contraindication to dexamethasone). Of these patients, 6425 went through randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients) (Fig. 1). The remaining patients were randomly assigned to one of the other treatment groups being evaluated in the trial.

The mean (±SD) age of the patients in this comparison was 66.1±15.7 years, 36% of the patients were female, and 18% were Black, Asian, or from a minority ethnic group (Table 1 and Table S1 in the Supplementary Appendix). A history of diabetes was present in 24% of the patients, heart disease in 27%, and chronic lung disease in 21%, with 56% having at least one major coexisting illness recorded. In this analysis, 89% of the patients had laboratory-confirmed SARS-CoV-2 infection. At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.

In the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid (Table S2). The median duration of treatment was 7 days (interquartile range, 3 to 10). In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care. The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual automotivee group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during follow-up (Table S2). After remdesivir became available in the United Kingdom on May 26, 2020, the drug was administered to 3 patients before randomization and 2 patients during the follow-up period (Table S2).dexamethasone

Shown are Kaplan–Meier survival curves for 28-day mortality among all the patients in the trial (primary outcome) (Panel A) and in three respiratory-support subgroups according to whether the patients were undergoing invasive mechanical ventilation (Panel B), receiving oxygen (with or without noninvasive ventilation) and without invasive mechanical ventilation (Panel C), or receiving no supplemental oxygen (Panel D) at the time of randomization. The Kaplan–Meier curves have not been adjusted for age. The rate ratios have been adjusted for the age of the patients in three categories (<70 years, 70 to 79 years, and ≥80 years). Estimates of the rate ratios and 95% confidence intervals in Panels B, C, and D were derived from a single age-adjusted regression model involving an interaction term between treatment assignment and level of respiratory support at randomization.

Shown are subgroup-specific rate ratios for all the patients and for those who were receiving no oxygen, receiving oxygen with or without noninvasive ventilation, or undergoing invasive mechanical ventilation at the time of randomization. Rate ratios are plotted as squares, with the size of each square proportional to the amount of statistical information that was available; the horizontal lines represent 95% confidence intervals.

Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively (rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001) (Fig. 2A). In a prespecified analysis according to the level of respiratory support
who the patients were receiving at randomization, there was a trend showing the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation (11.6 by chi-square test for trend) (Fig. 3). In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and in those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) (Fig. 2B and 2C). However, there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55) (Fig. 2D). The results were similar in a post hoc exploratory analysis restricted to the 5744 patients (89.4%) with a positive SARS-CoV-2 test result. Likewise, sensitivity analyses without adjustment for age resulted in similar findings (Table S3).dexamethasone

Patients who were receiving invasive mechanical ventilation at randomization were on average 10 years younger than those not receiving any respiratory support and had a history of symptoms before randomization for an average of 7 days longer (Table 1 and Table S4). The age-adjusted absolute reductions in 28-day mortality associated with the
usage of dexamethasone were 12.3 percentage points (95% CI, 6.2 to 17.6) among the patients who were receiving invasive mechanical ventilation and 4.2 percentage points (95% CI, 1.4 to 6.7) among those receiving oxygen only.

Patients with a longer duration of symptoms (who were more likely to have been receiving invasive mechanical ventilation at randomization) had a greater mortality benefit in response to treatment with dexamethasone. The receipt of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days but not among those with a more recent symptom onset (12.4 by chi-square test for trend) (Fig. S1).

Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17) (Table 2). The greatest effect regarding discharge within 28 days was checked out among patients who were receiving invasive mechanical ventilation at randomization (11.7 by chi-square test for trend) (Fig. S2A and Fig. S3).dexamethasone

Among the patients who were not receiving invasive mechanical ventilation at randomization, the number of patients who progressed to the prespecified composite secondary outcome of invasive mechanical ventilation or death was lower in the dexamethasone group than in the usual
vehiculare group (risk ratio, 0.93; 95% CI, 0.85 to 1.01) (Table 2). This effect was greater among the patients who were receiving oxygen at randomization (6.3 by chi-square test for trend) (Fig. S2B). Other prespecified analyses of the effects of dexamethasone on these secondary outcomes among different categories of patients are shown in Figures S4 and S5.

Among patients who were not receiving invasive mechanical ventilation at randomization, the risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group (risk ratio, 0.79; 95% CI, 0.64 to 0.97) (Table 2). Among those who were receiving invasive mechanical ventilation at randomization, successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual automobilee group (rate ratio, 1.47; 95% CI, 1.20 to 1.78) (Table 2 and Fig. S6). Among the patients who were not receiving renal-replacement therapy (renal dialysis or hemofiltration) at randomization, the number of patients who received this treatment within 28 days was lower in the dexamethasone group than in the usual automotivee group (risk ratio, 0.61; 95% CI, 0.48 to 0.76) (Table 2).

Most deaths were due to Covid-19, and such deaths were less frequent in the dexamethasone group than in the usual care group (Table S5). The incidence of death from other causes was similar in the dexamethasone group and the usual care group. In the subgroup of patients with available data, the incidence of new cardiac arrhythmia was similar in the dexamethasone group and the usual care group (Table S6). There were four reports of a serious adverse reaction that was deemed by the investigators to be related to dexamethasone: two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis (all recognized adverse effects of glucocorticoids).dexamethasone

Our results show
who among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization (by 12.3 age-adjusted percentage points, a proportional reduction of approximately one third) and those who were receiving oxygen without invasive mechanical ventilation (by 4.2 age-adjusted percentage points, a proportional reduction of approximately one fifth). However, there was no evidence
who dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup.
The benefit was also clear in patients who were being treated more than 7 days after symptom onset, when inflammatory lung damage is likely to have been more common. A subsequent meta-analysis of seven trials of glucocorticoids for critically ill patients with Covid-19, including RECOVERY, has confirmed the findings of our trial.22 Our results also show that among the patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation or, for those already receiving invasive mechanical ventilation, a greater chance of successful cessation. In both these groups, the use of dexamethasone increased the chance of being discharged from the hospital alive within 28 days.

The RECOVERY trial was designed to provide a rapid and robust assessment of the effect of readily available potential treatments for Covid-19 on 28-day mortality. Approximately 10% of all hospitalized patients with Covid-19 in the United Kingdom were enrolled in the trial, and mortality in the usual care group was consistent with the overall case fatality rate for hospitalized patients with Covid-19 in the United Kingdom at the time that the dexamethasone comparison was active.7 Only essential data were collected at hospital sites, with additional information (including longer-term mortality) ascertained through linkage with routine data sources. We did not collect information on physiologic, laboratory, or virologic measures. The protocol combines the methods
who were used in large, simple trials of treatments for acute myocardial infarction in the 1980s with the opportunities provided by digital health care in the 2020s.23-25 The trial has progressed rapidly, as is essential for studies during epidemics.26 The preliminary results for dexamethasone were announced on June 16, 2020, less than 100 days after the protocol was first drafted, and were adopted into U.K. practice later the same day.27

Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS, Middle East respiratory syndrome (MERS), severe influenza, and community-acquired pneumonia. However, the evidence to support or discourage the use of glucocorticoids under these conditions has been weak owing to the lack of data from sufficiently powered randomized, controlled trials.28-31 In addition, the evidence base has suffered from heterogeneity in glucocorticoid doses, medical conditions, and disease severity. It is likely that the beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on the selection of the right dose, at the right time, in the right patient. High doses may be more harmful than helpful, as may such treatment given at a time when control of viral replication is paramount and inflammation is minimal. Slower clearance of viral RNA has been saw in patients with SARS, MERS, and influenza who were treated with systemic glucocorticoids, but the clinical significance of these findings is unknown.29,32,33 Unlike with SARS, in which viral replication peaks in the second week of illness,34 viral shedding in SARS-CoV-2 appears to be higher early in the illness and declines thereafter.35-38 The greater mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role. This hypothesis would caution against extrapolation of the effect of dexamethasone in patients with Covid-19 to patients with other viral respiratory diseases with a different natural history.dexamethasone

The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support. We found no benefit (and the possibility of harm) among patients who did not require oxygen. Before the completion of the trial, many Covid-19 treatment guidelines stated
who the use of glucocorticoids was either contraindicated or not recommended.18 Dexamethasone is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost. Guidelines issued by the U.K. chief medical officers, the European Medicines Agency, the World Health Organization, and the National Institutes of Health in the United States have been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19 requiring oxygen with or without ventilatory support.27,39,40

Supported by a grant (MC_PC_19056) to the University of Oxford from the Medical Research Council of United Kingdom Research and Innovation and the National Institute for Health Research (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. Dr. Lim is supported by core funding provided by NIHR Nottingham Biomedical Research Centre, Dr. Felton by the NIHR Manchester Biomedical Research Centre, and Dr. Jaki by a grant (MC_UU_0002/14) from the UK Medical Research Council and by an NIHR Senior Research Fellowship (NIHR-SRF-2015-08-001). Tocilizumab was provided free of charge for this study by Roche. AbbVie contributed some supplies of lopinavir–ritonavir for use in the trial. Regeneron contributed supplies of REGN-COV2 for use in the clinical trial. Other medications, including dexamethasone, that were used in the trial were supplied by the National Health Service (NHS).

Disclosure forms provided by the
writers are available with the full text of this article at NEJM.org.dexamethasone

Dr. Lim reports receiving grant support from Pfizer; Dr. Emberson, receiving grant support from Boehringer Ingelheim; Dr. Mafham, receiving grant support and provision of materials from the Medicines Company/Novartis; Dr. Staplin, receiving grant support from Boehringer Ingelheim; Dr. Faust, receiving grant support, lecture fees, and advisory board fees, all paid to his institution, from Pfizer, advisory board fees, paid to his institution, from AstraZeneca, Seqirus, Sandoz, and MedImmune, grant support and advisory board fees, all paid to his institution, from Sanofi and Merck, and grant support, paid to his institution, from GSK and Johnson & Johnson; Dr. Haynes, receiving grant support from the Medicines Company and Boehringer Ingelheim; Dr. Landray, receiving grant support from Novartis, Boehringer Ingelheim, and Merck Sharp & Dohme. No other potential conflict of interest relevant to this article was reported.

Drs. Horby, Lim, and Emberson and Drs. Haynes and Landray contributed ngạiqually to this article.

The members of the writing committee (Peter Horby, F.R.C.P., Wei Shen Lim, F.R.C.P., Jonathan R. Emberson, Ph.D., Marion Mafham, M.D., Jennifer L. Bell, M.Sc., Louise Linsell, D.Phil., Natalie Staplin, Ph.D., Christopher Brightling, F.Med.Sci., Andrew Ustianowski, Ph.D., Einas Elmahi, M.Phil., Benjamin Prudon, F.R.C.P., Christopher Green, D.Phil., Timothy Felton, Ph.D., David Chadwick, Ph.D., Kanchan Rege, F.R.C.Path., Christopher Fegan, M.D., Lucy C. Chappell, Ph.D., Saul N. Faust, F.R.C.P.C.H., Thomas Jaki, Ph.D., Katie Jeffery, Ph.D., Alan Montgomery, Ph.D., Kathryn Rowan, Ph.D., Edmund Juszczak, M.Sc., J. Kenneth Baillie, M.D., Ph.D., Richard Haynes, D.M., and Martin J. Landray, F.R.C.P.) assume responsibility for the overall content and integrity of this article.dexamethasone

The views expressed in this article are those of the authors and do not necessarily reflect those of the National Health Service, the National Institute for Health Research, the Medical Research Council of United Kingdom Research and Innovation, or the Department of Health and Social Care.

A preliminary version of this article was published on July 17, 2020, at NEJM.org.

A data sharing statement provided by the
writers is available with the full text of this article at NEJM.org.dexamethasone

We thank the thousands of patients who participated in this trial; the doctors, nurses, pharmacists, other allied wellness professionals, and research administrators at 176 NHS hospital organizations across the United Kingdom, supported by staff at the NIHR Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health and Social Care, the Intensive Care National Audit and Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure Anonymised Information Linkage (SAIL) at University of Swansea, and the NHS in England, Scotland, Wales, and Northern Ireland; and the members of the independent data monitoring committee: Peter Sandercock, Janet Darbyshire, David DeMets, Robert Fowler, David Lalloo, Ian Roberts, and Janet Wittes.

From the Nuffield Department of Medicine (P.H.), Nuffield Department of Population Health (J.R.E., M.M., J.L.B., L.L., N.S., E.J., R.H., M.J.L.), and MRC Population Health Research Unit (J.R.E., N.S., R.H., M.J.L.), University of Oxford, the Oxford University Hospitals NHS Foundation Trust (K.J.), and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (M.J.L.), Oxford, the Respiratory Medicine Department, Nottingham University Hospitals NHS Trust (W.S.L.), and the School of Medicine, University of Nottingham (A.M.), Nottingham, the Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester (C.B.), the Regional Infectious Diseases Unit, North Manchester General Hospital and University of Manchester (A.U.), and the University of Manchester and Manchester University NHS Foundation Trust (T.F.), Manchester, the Research and Development Department, Northampton General Hospital, Northampton (E.E.), the Department of Respiratory Medicine, North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees (B.P.), University Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology and Infection, University of Birmingham, Birmingham (C.G.), the Centre for Clinical Infection, James Cook University Hospital, Middlesbrough (D.C.), the North West Anglia NHS Foundation Trust, Peterborough (K. Rege), the Department of Research and Development, Cardiff and Vale University Health Board, Cardiff (C.F.), the School of Life Course Sciences, King’s
University London (L.C.C.), and the Intensive Care National Audit and Research Centre (K. Rowan), London, the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton (S.N.F.), the Department of Mathematics and Statistics, Lancaster University, Lancaster (T.J.), the MRC Biostatistics Unit, University of Cambridge, Cambridge (T.J.), and Roslin Institute, University of Edinburgh, Edinburgh (J.K.B.) — all in the United Kingdom.

Address reprint requests to Drs. Horby and Landray at RECOVERY Central Coordinating Office, Richard Doll Bldg., Old Road Campus, Roosevelt Dr., Oxford OX3 7LF, United Kingdom, or at .dexamethasone

A complete list of collaborators in the RECOVERY trial is provided in the Supplementary Appendix, available at NEJM.org.

1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727733.

2. Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis 2020;20:669677.dexamethasone

3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:10541062.

4. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507513.

5. Cao J, Tu W-J, Cheng W, et al. Clinical features and short-term outcomes of 102 patients with corona virus disease 2019 in Wuhan, China. Clin Infect Dis 2020;71:748755.dexamethasone

6. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846848.

7. Docherty AB, Harrison EM, Green CA, et al. Features of 20133 UK patients in hospital with covid-19
via the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369:m1985m1985.

8. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 — final report. N Engl J Med 2020;383:18131826.dexamethasone

9. Carsana L, Sonzogni A, Nasr A, et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study. Lancet Infect Dis 2020;20:11351140.

10. de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is
under the name ofsociated with high viral load and hypercytokinemia. Nat Med 2006;12:12031207.

11. Wong CK, Lam CWK, Wu AKL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004;136:95103.dexamethasone

12. Baillie JK, Digard P. Influenza — time to target the host? N Engl J Med 2013;369:191193.

13. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497506.

14. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science 2020;368:473474.dexamethasone

15. Shang L, Zhao J, Hu Y, Du R, Cao B. On the
usage of corticosteroids for 2019-nCoV pneumonia. Lancet 2020;395:683684.

16. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395:473475.

17. Corral-Gudino L, Bahamonde A, Arnaiz-Revillas F, et al. GLUCOCOVID: a controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. June 18, 2020 (https://www.medrxiv.org/content/10.1101/2020.06.17.20133579v1). preprint.dexamethasone

18. Dagens A, Sigfrid L, Cai E, et al. Scope, quality, and inclusivity of clinical guidelines produced early in the covid-19 pandemic: rapid review. BMJ 2020;369:m1936m1936.

19. Zhao JP, Hu Y, Du RH, et al. Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:183184. (In Chinese.)

20. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:10611069.dexamethasone

21. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020;368:m606m606.

22. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA 2020;324:13301341.

23. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984;3:409422.dexamethasone

24. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2:349360.

25. Collins R, Bowman L, Landray M, Peto R. The magic of randomization versus the myth of real-world evidence. N Engl J Med 2020;382:674678.

26. Rojek AM, Horby PW. Modernising epidemic science: enabling patient-centred research during epidemics. BMC Med 2016;14:212212.dexamethasone

27. Whitty C. Dexamethasone in the treatment of COVID-19: implementation and management of supply for treatment in hospitals. London: Medicines and Healthcare Products Regulatory Agency, June 16, 2020 (https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103054).

28. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006;3(9):e343e343.

29. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med 2018;197:757767.dexamethasone

30. Lansbury LE, Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Shen Lim W. Corticosteroids as adjunctive therapy in the treatment of influenza: an updated Cochrane systematic review and meta-analysis. Crit Care Med 2020;48(2):e98e106.

31. Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med 2015;163:519528.

32. Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol 2004;31:304309.dexamethasone

33. Lee N, Chan PKS, Hui DSC, et al. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis 2009;200:492500.

34. Cheng PKC, Wong DA, Tong LKL, et al. Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome. Lancet 2004;363:16991700.

35. To KK-W, Tsang OT-T, Leung W-S, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020;20:565574.dexamethasone

36. Zhou R, Li F, Chen F, et al. Viral dynamics in asymptomatic patients with COVID-19. Int J Infect Dis 2020;96:288290.

37. He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med 2020;26:672675.

38. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020;581:465469.dexamethasone

39. COVID-19 treatment guidelines: corticosteroids. Bethesda, MD: National Institutes of Health, 2020 (https://www.covid19treatmentguidelines.nih.gov/dexamethasone/).

40. Siemieniuk R, Rochwerg B, Agoritsas T, et al. A living WHO guideline on drugs for Covid-19. BMJ 2020;370:m3379m3379.

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Only the 1000 most recent citing articles are listed here.

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10.1056/NEJMoa2021436-t1

Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support.*

Plus–minus values are methods ±SD. HIV denotes human immunodeficiency virus, IQR interquartile range, NA not applicable, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.dexamethasone

There was a significant (P=0.01) difference in the mean age between patients in the dexamethasone group and those in the usual automotivee group, but there were no significant differences between the groups in any other baseline characteristic.

Among the women, 1 in the dexamethasone group and 3 in the usual automobilee group were pregnant.

Race or ethnic group was recorded in the patient’s electronic
well-being record.dexamethasone

Data regarding the number of days since symptom onset were missing for 4 patients in the dexamethasone group and 13 patients in the usual care group; these patients were excluded from estimates of the median number of days since onset.

Severe liver disease was defined as requiring ongoing specialist
vehiculare.

Severe kidney impairment was defined
under the name of an estimated glomerular filtration rate of less than 30 ml per minute per 1.73 m2.dexamethasone

10.1056/NEJMoa2021436-t2

Primary and Secondary Outcomes and Prespecified Subsidiary Clinical Outcomes.dexamethasone

Rate ratios have been adjusted for age with respect to the outcomes of 28-day mortality, hospital discharge, and successful cessation of invasive mechanical ventilation. Risk ratios have been adjusted for age with respect to the outcomes of invasive mechanical ventilation or death (and its subcomponents),
usage of ventilation, and renal-replacement therapy.

Excluded from this category are patients who were receiving invasive mechanical ventilation at randomization.

Excluded from this category are patients who were receiving oxygen (since some patients in this category were receiving noninvasive ventilation) or invasive mechanical ventilation at randomization.dexamethasone

Excluded from this category are patients who were not receiving invasive mechanical ventilation at randomization.

Excluded from this category are patients who were receiving renal-replacement
treatment at randomization.

Digital Object ThumbnailQUICK TAKE
Dexamethasone and Covid-19
 02:20
dexamethasone

Completed follow-up forms were available for 2095 of 2104 patients (99.6%) in the dexamethasone group and 4306 of 4321 patients (99.7%) in the usual care group. The subgroup of patients who later went through a second randomization to tocilizumab versus usual care in the RECOVERY trial included 95 of 2104 patients (4.5%) in the dexamethasone group and 276 of 4321 patients (6.4%) in the usual care group. In addition, 14 patients were randomly assigned to receive either convalescent plasma or usual care alone (5 [0.2%] in the dexamethasone group and 9 [0.2%] in the usual care group).

Shown are Kaplan–Meier survival curves for 28-day mortality among all the patients in the trial (primary outcome) (Panel A) and in three respiratory-support subgroups according to whether the patients were undergoing invasive mechanical ventilation (Panel B), receiving oxygen (with or without noninvasive ventilation) and without invasive mechanical ventilation (Panel C), or receiving no supplemental oxygen (Panel D) at the time of randomization. The Kaplan–Meier curves have not been adjusted for age. The rate ratios have been adjusted for the age of the patients in three categories (<70 years, 70 to 79 years, and ≥80 years). Estimates of the rate ratios and 95% confidence intervals in Panels B, C, and D were derived from a single age-adjusted regression model involving an interaction term between treatment assignment and level of respiratory support at randomization.

Shown are subgroup-specific rate ratios for all the patients and for those who were receiving no oxygen, receiving oxygen with or without noninvasive ventilation, or undergoing invasive mechanical ventilation at the time of randomization. Rate ratios are plotted as squares, with the size of each square proportional to the amount of statistical information
who was available; the horizontal lines represent 95% confidence intervals.dexamethasone

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