Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

Abstract

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, setting, and participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main outcomes and measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions and relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial registration: ClinicalTrials.gov Identifier: NCT02735707.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Angus reported receiving personal fees from Ferring Pharmaceuticals Inc, Bristol-Myers Squibb, Bayer AG, and ALung Technologies Inc outside the submitted work; in addition, Dr Angus had a patent to selepressin—compounds, compositions, and methods for treating sepsis pending and a patent to proteomic biomarkers of sepsis in elderly patients pending. Dr Annane reported receiving grants from French Ministry of Health during the conduct of the study. Dr Bentum-Puijk reported receiving European Union FP7-Health-2013-INNOVATION-1 grant No. 602525 and H2020 RECOVER grant agreement No. 101003589 during the conduct of the study. Dr L. Berry reported receiving grants for PREPARE Network from the European Commission; Australia funding grants for OPTIMISE-CAP; and New Zealand funding grants for REMAP-CAP during the conduct of the study. Dr S. Berry reported receiving grants for PREPARE Network from the European Commission, Australia funding grants for OPTIMISE-CAP, and New Zealand funding grants for REMAP-CAP during the conduct of the study. Dr Mouncey reported receiving grants from European Commission FP7 and the National Institute for Health Research (NIHR) during the conduct of the study. Dr Bhimani reported receiving grants from the Canadian Institutes of Health Research during the conduct of the study. Dr Bradbury reported receiving personal fees from Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Novartis, Portola, Bayer, and Ablynx outside the submitted work. Dr Brunkhorst reported receiving grants from the European Union during the conduct of the study. Dr Buxton reported receiving grants from the Breast Cancer Research Foundation during the conduct of the study and grants from Bayer, Amgen, Eli Lilly and Company, Janssen, Kazia Therapeutics, DelMar Pharma, Eisai, the National Brain Tumor Society, the National Foundation for Cancer Research, and the Asian Foundation for Cancer Research; gifts from the Yousefzadeh Family Foundation and Jeffrey Tarrant; and personal fees from Berry Consultants LLC outside the submitted work. Dr Cheng reported receiving grants from the National Health and Medical Research Council (NHMRC) during the conduct of the study. Dr de Jong reported receiving personal fees from Roche, Janssen, Vertex, and Visterra outside the submitted work. Dr Derde reported receiving European Union FP7-HEALTH-2013-INNOVATION-1 grant 602525 and H2020 RECOVER grant agreement No. 101003589 during the conduct of the study and being a member of the COVID-19 guideline committee for the Society of Critical Care Medicine/European Society of Intensive Care Medicine (ESICM)/Surviving Sepsis Campaign, member of the ESICM COVID-19 taskforce, and chair of the Dutch intensivists (NVIC) taskforce on infectious threats. Dr Detry reported receiving grants for the PREPARE Network from the European Commission, Australia funding grants for OPTIMISE-CAP, and New Zealand funding grants for REMAP-CAP during the conduct of the study. Dr Estcourt reported receiving grants from the NIHR during the conduct of the study. Dr Fitzgerald reported receiving grants for PREPARE Network from the European Commission, Australian funding grants for OPTIMISE-CAP, and New Zealand funding grants for REMAP-CAP during the conduct of the study. Dr Gordon reported receiving grants from the NIHR and the NIHR Research Professorship; nonfinancial support from the NIHR Clinical Research Network and the NIHR Imperial Biomedical Research Centre during the conduct of the study; and personal fees from GlaxoSmithKline and Bristol-Myers Squibb outside the submitted work. Dr Haniffa reported the Critical Care Asia project, where he is co-coordinator, is supported by the Wellcome Trust through the University of Oxford. Dr Higgins reported receiving grants from the NHMRC, the Health Research Council of New Zealand, and the Minderoo Foundation during the conduct of the study. Dr Horvat reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study. Dr Hullegie reported receiving grants from the European Commission during the conduct of the study. Dr Kruger reported receiving personal fees from Smiths Medical outside the submitted work. Dr Lamontagne reported serving as methodological chair (nonvoting) for the World Health Organization (WHO) guideline on corticosteroids for COVID-19. The WHO guideline was initiated before any data from REMAP-CAP was made available. The first guideline panel meeting only reviewed data from the RECOVERY trial and the GLUCOCOVID trial. At a subsequent guideline panel meeting, the panel reviewed a meta-analysis commissioned by the WHO that included data from REMAP-CAP. Both the WHO-led meta-analysis and the guideline document are under review at the time of writing. Dr Lewis reported being the senior medical scientist at Berry Consultants LLC during the conduct of the study. Dr Lorenzi reported receiving grants from the European Commission for the PREPARE Network, Australia funding grants for OPTIMISE-CAP, and New Zealand funding grants for REMAP-CAP during the conduct of the study. Dr Marshall reported receiving personal fees from AM Pharma outside the submitted work and being a member of the international trial steering committee for REMAP-CAP; Canadian principal investigator for REMAP-CAP; chair of the International Forum for Acute Care Trialists; and co-chair of the WHO Working Group on Clinical Characterization and Management. Dr McArthur reported receiving grants from the Health Research Council of New Zealand during the conduct of the study. Dr McAuley reported receiving personal fees from GlaxoSmithKline, Boehringer Ingelheim, and Bayer for consultancy outside the submitted work; in addition, Dr McAuley reported a patent for a novel treatment for acute respiratory distress syndrome issued to his institution. Dr McGlothlin reported receiving grants from the European Commission for the PREPARE Network, Australian funding grants for OPTIMISE-CAP, and New Zealand funding grants for REMAP-CAP during the conduct of the study. Dr McVerry reported receiving salary support from UPMC Learning While Doing Program and the Translational Breast Cancer Research Foundation during the conduct of the study and grants from Bayer Pharmaceuticals Inc and the NIH/National Heart, Lung, and Blood Institute outside the submitted work. Dr Murthy reported receiving grants from the Canadian Institutes of Health Research during the conduct of the study. Dr Nichol reported receiving grants from the Health Research Board of Ireland during the conduct of the study. Dr Parke reported that research in the CVICU Auckland City Hospital is supported in part by an unrestricted grant from Fisher and Paykel Healthcare Limited, New Zealand. Dr Sanil reported receiving grants from the European Commission for PREPARE Network, Australia funding grants for OPTIMISE-CAP, and New Zealand funding grants for REMAP-CAP during the conduct of the study. Dr Saunders reported receiving grants from the European Commission for PREPARE Network, Australia funding grants for OPTIMISE-CAP, and New Zealand funding grants from REMAP-CAP during the conduct of the study. Dr Seymour reported receiving grants from the NIH’s National Institute of General Medical Sciences and personal fees from Beckman Coulter Inc and Edwards Lifesciences Inc outside the submitted work. Dr Turner reported receiving grants from the Health Research Council of New Zealand during the conduct of the study. Dr Venkatesh reported receiving institutional research support from Baxter outside the submitted work. Dr Webb reported receiving grants from the NHMRC and the Minderoo Foundation during the conduct of the study. Dr Zarychanski reported receiving research operating support from the Canadian Institutes of Health Research and the Lyonel G. Professorship of Hematology at the University of Manitoba. No other disclosures were reported.

Figures

Figure 1.. Screening, Randomization, and Follow-up of Participants in the REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

COVID-19 indicates coronavirus disease 2019; ICU, intensive care unit; and REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia. aPatients could meet more than 1 ineligibility criterion. bThe primary analysis of alternative interventions within the corticosteroid domain is estimated from a model that adjusts for patient factors and for assignment to interventions in other domains. To obtain the most reliable estimation of the effect of these patient factors and of other interventions on the primary outcome, all patients enrolled in the severe COVID-19 cohort (for whom there is consent and follow-up) are included. Importantly, however, the model also factors eligibility for the corticosteroid domain and its interventions, such that the final estimate of a corticosteroid domain intervention’s effectiveness relative to any other within that domain is generated from those patients that might have been randomized to either.

Figure 2.. Organ Support–Free Days

A, Distributions of organ support–free days (see the Methods section for definition) by study group as the cumulative proportion (y-axis) for each study group by day (x-axis), with death listed first. Curves that rise more slowly are more favorable. B, Organ support–free days as horizontally stacked proportions by study group. Red represents worse values and blue represents better values. The median adjusted odds ratios from the primary analysis, using a bayesian cumulative logistic model, were 1.43 (95% credible interval, 0.91-2.27) and 1.22 (95% credible interval, 0.76-1.94) for the fixed-dose and shock-dependent hydrocortisone groups compared with the no hydrocortisone group, yielding 93% and 80% probabilities of superiority over the no hydrocortisone group, respectively.