Covid-19 Living Data

Trial NCT02735707
Publication REMAP-CAP - Derde L, medRxiv (2021) (preprint)
Dates: 2020-03-25 to 2021-04-10
Funding: Mixed (PREPARE consortium by the European Union; FP7-HEALTH-2013-INNOVATION-1; RECOVER consortium by the European Union Horizon 2020 research and innovation program; Australian National Health and Medical Research Council; Health Research Council of New Zealand; Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant; UK NIHR; NIHR Imperial Biomedical Research Centre; Health Research Board of Ireland; UPMC Learning While Doing Program; Translational Breast Cancer Research Consortium; Global Coalition for Adaptive Research; French Ministry of Health; Minderoo Foundation; Wellcome Trust Innovations Project; Netherlands Organization for Health Research and Development ZonMw; NIHR Research Professorship; NIHR Clinician Scientist Fellowship; Australian National Health and Medical Research Council Career Development Fellowship; Roche Products Ltd; Sanofi (Aventis Pharma Ltd); Swedish Orphan Biovitrum AB (Sobi); Faron Pharmaceuticals (drug provision in some countries) )
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / UK, Netherlands, Ireland, Australia, New Zealand, Canada, Finland, Italy, Saudi-Arabia Follow-up duration (days): 90
Inclusion criteria	Participants aged > 18 years suspected or microbiologically confirmed COVID-19 receiving or not respiratory or cardiovascular organ support within 24 hours in an ICU.
Exclusion criteria	Death deemed to be imminent and inevitable during the next 24 hours one or more of the participant, substitute decision maker or attending physician are not committed to full active treatment more than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection or more than 24 hours elapsed since ICU admission previous participation in this REMAP within the last 90 days patient has already received any dose of one or more of any form of interferon, anakinra, tocilizumab, or sarilumab during this hospitalization long-term therapy with any of these agents prior to this hospital admission patient has been randomized in a trial evaluating an immune modulation agent for proven or suspected COVID-19 infection where the protocol of that trial requires ongoing administration of study drug known condition or treatment resulting in ongoing immune suppression including neutropenia prior to this hospitalization intention to prescribe systemic corticosteroids for any reason, other than participation in the Corticosteroid domain of this platform, is an exclusion criterion to receive IFN-β1a known hypersensitivity to proteins produced by E. coli will result in exclusion criterion to receive anakinra known or suspected pregnancy is an exclusion criterion to receive the anakinra, IFN-β1a, tocilizumab, and sarilumab interventions a baseline alanine aminotransferase or an aspartate aminotransferase that is more than five times the upper limit of normal is an exclusion criterion to receive tocilizumab or sarilumab a baseline platelet count < 50 x 109 / L is an exclusion criterion to receive tocilizumab or sarilumab.
Interventions
	Treatment Anakinra Initial dose: 300 mg intravenously for the first 24 hours - Maintenance dose: 100 mg intravenously 4 times a day for 14 days or until either free from invasive mechanical ventilation for more than 24 hours, or discharge from ICU. Sarilumab 400 mg IV single dose Tocilizumab 8 mg/kg IV infusio single dose, maximum 800 mg, a second infusion could be administered 12 to 24 hours after the first.
	Control Standard care
Participants
	Randomized participants : Standard care=418 Anakinra=378 Sarilumab=485 Tocilizumab=972
	Characteristics of participants N= 2253 Mean age : NR 1536 males Severity : Mild: n=0 / Moderate: n=4 / Severe: n=1482 Critical: n=730 Number of vaccinated participants: NR
Primary outcome
	In the register All-cause mortality [Time Frame: Day 90]; Days alive and not receiving organ support in ICU [Time Frame: Day 21]
	In the report An ordinal scale that is a composite of in-hospital mortality and duration of respiratory and cardiovascular organ support, censored at 21 days, where all deaths within hospital and up to day 90 were assigned the worst outcome
Documents available	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print version of the article, the study registry and protocol were used in data extraction and risk of bias assessment. The report contains definite results of tocilizumab, sarilumab and anakinra from the Immune Modulation Therapy domain of the REMAP-CAP clinical trial (an international, adaptive platform trial). There is no change from the trial registration in the intervention and control treatments. The platform initially included only participants admitted to an intensive care unit and receiving respiratory or cardiovascular organ support, a moderate state enrolling hospitalized participants not receiving respiratory or cardiovascular organ support was added subsequently. A blinded International Trial Steering Committee (ITSC) closed all arms of the domain on April 10, 2021. The primary outcome indicated in the registry reflects the primary outcome reported in the paper. Adverse events are not reported.