Covid-19 Living Data

Trial NCT02735707
Publication REMAP-CAP - Gordon AC, N Engl J Med (2021) (published paper)
Dates: 2020-04-19 to 2020-11-19
Funding: Mixed (Multiple funders, internationally, with multiple regional sponsors; Roche Products Ltd and Sanofi (drug provision in UK))
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Australia, Ireland, the Netherlands, New Zealand, Saudi Arabia, UK Follow-up duration (days): 90
Inclusion criteria	Adult patients admitted to hospital with either clinically suspected or microbiologically confirmed Covid-19 Severe disease state, defined by receiving respiratory or cardiovascular organ failure support in an intensive care unit: Respiratory organ support is defined as invasive or non-invasive mechanical ventilation including via high flow nasal cannula if flow rate >30 L/min and FIO2 >0.4. If non-invasive ventilation would normally be provided but is being withheld, due to infection control concerns associated with aerosol generating procedures, then the patient still meets the severe disease state criteria. Cardiovascular organ support was defined as the intravenous infusion of any vasopressor or inotrope. Pandemic surge capacity means that provision of advanced organ support may need to occur in locations that do not usually provide ICU-level care. Therefore, an ICU is defined as an area within the hospital that is repurposed so as to be able to deliver one or more of the qualifying organ failure supports (non-invasive ventilation, invasive ventilation, and vasopressor therapy 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-β1a, 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 Tocilizumab 8 mg/kg IV infusion single dose over 1 hour, maximum 800 mg, a second infusion could be administered 12 to 24 hours after the first. Sarilumab 400 mg IV infusion single dose
	Control Standard care
Participants
	Randomized participants : Tocilizumab=366 Sarilumab=48 Standard care=412
	Characteristics of participants N= 826 Mean age : NR 583 males Severity : Mild: n=* / Moderate: n=3 / Severe: n=567 Critical: n=233 Number of vaccinated participants: NR
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 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 published report, the pre-print article, 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: "On the basis of an interim analysis as of October 28, the independent data and safety monitoring board reported that tocilizumab had met the statistical criteria for efficacy (posterior probability, 99.75%; odds ratio, 1.87; 95% credible interval, 1.20 to 2.76). According to the protocol, further assignment to control closed on November 19, with randomization continuing between different active immune modulation interventions... After a subsequent interim analysis, the data and safety monitoring board reported that sarilumab had also met the statistical criteria for efficacy, so these results are also reported." There was some discrepancy between the report and the protocol as it pertains to time to death. The protocol pre-specifies this outcome as "ICU mortality censored at 90 days". There were no important changes from the trial registration in the population, intervention, or control treatments. Quote: "Investigators at each site prespecified at least two interventions, one of which had to be control, to which patients would be randomly assigned...Randomization to the Corticosteroid domain for Covid-19 closed on June 17, 2020. Thereafter, glucocorticoids were allowed according to the recommended standard of care." This study was updated on March 1st, 2021 with data from the published report.