Covid-19 Living Data

Trial NCT02735707
Publication Gordon AC, REMAP-CAP, medRxiv, 2021 (Unblinded)
Dates: 4/19/2020 to 11/19/2020
Funding: Mixed (PREPARE consortium by the EU; FP7-HEALTH-2013-INNOVATION-1; RECOVER consortium by the EU's Horizon 2020 research & innovation programme; Australian National Health & Medical Research Council; Health Research Council of )
Conflict of interest: Yes

Methods
	RCT Blinding: preprint
	Location : Multicenter / Australia, Ireland, the Netherlands, New Zealand, Saudi Arabia, UK Follow-up duration (days): 90
Inclusion criteria	Adult patient admitted to hospital with acute illness due to suspected or proven pandemic (Covid-19) infection; Severe disease state, defined by receiving respiratory or cardiovascular organ failure support in an intensive care unit; Microbiological testing for SARS-CoV-2 of upper or lower respiratory tract secretions or both has occurred or is intended to occur
Exclusion criteria	Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker or attending physician are not committed to full active treatment; Patient is expected to be discharged from hospital today or tomorrow; More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection; Previous participation in this REMAP within the last 90 days; More than 24 hours has elapsed since ICU admission; Patient has already received any dose of one or more of any form of interferon, anakinra, tocilizumab, or sarilumab during this hospitalization or is on long-term therapy with any of these agents prior to this hospital admission; Known condition or treatment resulting in ongoing immune suppression including neutropenia prior to this hospitalization; 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; The treating clinician believes that participation in the domain would not be in the best interests of the patient; Known hypersensitivity to an agent specified as an intervention in this domain will exclude a patient from receiving that agent; Known or suspected pregnancy will result in exclusion from the anakinra, IFN-Î²1a, tocilizumab, and sarilumab interventions. It is normal clinical practice that women admitted who are in an age group in which pregnancy is possible will have a pregnancy test conducted. The results of such tests will be used to determine interpretation of this exclusion criteria; A baseline alanine aminotransferase or an aspartate aminotransferase that is more than five times the upper limit of normal will result in exclusion from receiving tocilizumab or sarilumab; A baseline platelet count < 50 x 10^9 / L will result in exclusion from receiving tocilizumab or sarilumab
Interventions

	Treatment 1 Tocilizumab (8 mg/kg) Co-Intervention: Standard care Duration : 1 day
	Control Standard care
Treatment 3 Sarilumab (400 mg) Co-Intervention: Standard care Duration : 1 day
Participants
	Randomized 826 participants n₁=366/ n₂=412n₃=48
	Characteristics of participants N=826 Mean age : 61.4 583 males Severity : Mild: n=* / Moderate: n=*/ Severe: n=577 Critical: n=233
Primary outcome
	In the register 1. All-cause mortality [ Time Frame: Day 90 ]; 2. Days alive and not receiving organ support in ICU [ Time Frame: Day 21 ]
	In the report Respiratory and cardiovascular organ support-free days up to day 21
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing stated 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 article, the study registry and protocol were used in data extraction and risk of bias assessment. The report contains early, preliminary results of tocilizumab and sarilumab from the Immune Modulation Therapy domain of the REMAP-CAP clinical trial (an international, adaptive platform trial); further follow-up and analysis are ongoing. As a result, long-term outcomes were not reported. Quote: "At a scheduled interim analysis, the independent DSMB reported that tocilizumab had met the statistical trigger for efficacy (posterior probability 99.75%, odds ratio 1.87, 95%CrI 1.20, 2.76) based on an interim analysis of patients as of October 28. As per protocol, further assignment to control closed on November 19 with randomization continuing between different active immune modulation interventions... Following a subsequent interim analysis, the DSMB reported that sarilumab had also met the statistical trigger for efficacy and so these results are also reported" There were no important changes from the trial registration in the population, intervention, or control treatments. Quote: "Investigators at each site selected a priori at least two interventions, one of which had to be control, to which patients would be randomized...Randomization to the Corticosteroid domain for Covid-19 closed on June 17, 2020.12 Thereafter, corticosteroids were allowed as per recommended standard of care."