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

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

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.

Adrenal Cortex Hormones/therapeutic use, Adult, Anti-Inflammatory Agents/administration & dosage, Betacoronavirus, COVID-19, Coronavirus Infections/drug therapy, Early Termination of Clinical Trials, Female, Humans, Hydrocortisone/administration & dosage, Intensive Care Units, Male, Middle Aged, Pandemics, Pneumonia, Viral/drug therapy, Respiration, Artificial/statistics & numerical data, SARS-CoV-2, Shock/drug therapy, Treatment Outcome
0098-7484
1317-1329
Angus, Derek C
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Derde, Lennie
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Al-Beidh, Farah
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Beane, Abigail
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van Bentum-Puijk, Wilma
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Berry, Lindsay
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Bhimani, Zahra
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King, Andrew
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Pearson, Karen
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Williams, Hannah
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Smith, Margaret
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Casey, Siobhan
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Butler, M
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Ward, Kathryn
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Stevenson, Hannah
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Pugh, Richard
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Hall, Kathryn
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Lowe, Benjamin
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Thomson, Nicola
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Clark, Sarah
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Williams, Karen
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Jackson, Susan
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Zhao, Xiao Bei
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Thomas, Amy
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Yates, David
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Writing Committee for the REMAP-CAP Investigators
Angus, Derek C
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Derde, Lennie
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Al-Beidh, Farah
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Annane, Djillali
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Arabi, Yaseen
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Beane, Abigail
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van Bentum-Puijk, Wilma
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Berry, Lindsay
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Bhimani, Zahra
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Bonten, Marc
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Marshall, John
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King, Andrew
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Pearson, Karen
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Williams, Hannah
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Butler, M
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Pugh, Richard
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Writing Committee for the REMAP-CAP Investigators (2020) Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA, 324 (13), 1317-1329. (doi:10.1001/jama.2020.17022).

Record type: Article

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.

Full text not available from this repository.

More information

Published date: 6 October 2020
Keywords: Adrenal Cortex Hormones/therapeutic use, Adult, Anti-Inflammatory Agents/administration & dosage, Betacoronavirus, COVID-19, Coronavirus Infections/drug therapy, Early Termination of Clinical Trials, Female, Humans, Hydrocortisone/administration & dosage, Intensive Care Units, Male, Middle Aged, Pandemics, Pneumonia, Viral/drug therapy, Respiration, Artificial/statistics & numerical data, SARS-CoV-2, Shock/drug therapy, Treatment Outcome

Identifiers

Local EPrints ID: 447794
URI: http://eprints.soton.ac.uk/id/eprint/447794
ISSN: 0098-7484
PURE UUID: 23cc6a5d-bccf-4119-b579-0962994c1f75
ORCID for John Marshall: ORCID iD orcid.org/0000-0002-9242-3646
ORCID for John Marshall: ORCID iD orcid.org/0000-0002-9242-3646
ORCID for M Butler: ORCID iD orcid.org/0000-0003-4642-5373
ORCID for Kathryn Ward: ORCID iD orcid.org/0000-0001-7034-6750
ORCID for Ahilanandan Dushianthan: ORCID iD orcid.org/0000-0002-0165-3359
ORCID for Xiao Bei Zhao: ORCID iD orcid.org/0000-0002-9714-3176

Catalogue record

Date deposited: 22 Mar 2021 17:43
Last modified: 16 Apr 2021 01:58

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Contributors

Author: Derek C Angus
Author: Lennie Derde
Author: Farah Al-Beidh
Author: Djillali Annane
Author: Yaseen Arabi
Author: Abigail Beane
Author: Wilma van Bentum-Puijk
Author: Lindsay Berry
Author: Zahra Bhimani
Author: Marc Bonten
Author: Charlotte Bradbury
Author: Frank Brunkhorst
Author: Meredith Buxton
Author: Adrian Buzgau
Author: Allen C Cheng
Author: Menno de Jong
Author: Michelle Detry
Author: John Marshall ORCID iD
Author: Jane Parker
Author: John Marshall ORCID iD
Author: John Reynolds
Author: Andrew King
Author: Karen Pearson
Author: Hannah Williams
Author: Margaret Smith
Author: Siobhan Casey
Author: M Butler ORCID iD
Author: Yvonne Robertson
Author: Kathryn Ward ORCID iD
Author: Hannah Stevenson
Author: Richard Pugh
Author: Jane Woods
Author: John Smith
Author: Andrew Hall
Author: Kathryn Hall
Author: Benjamin Lowe
Author: Nicola Thomson
Author: Sarah Clark
Author: Karen Williams
Author: David Shaw
Author: Ian White
Author: David Johnson
Author: Ahilanandan Dushianthan ORCID iD
Author: Rebecca Cusack
Author: Simon Smith
Author: Susan Jackson
Author: Xiao Bei Zhao ORCID iD
Author: Amy Thomas
Author: David Yates
Corporate Author: Writing Committee for the REMAP-CAP Investigators

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