Gordon REMAP‐CAP 2021.

Study characteristics
Methods	RCT‐ adaptive platform trial Blinding: unblinded Date of study: from 19 April 2020 to 19 November 2020 Location: multicentre: Australia, Ireland, the Netherlands, New Zealand, Saudi Arabia, UK Follow‐up duration (days): 90
Participants	Population: patients with confirmed or suspected COVID‐19 (severe‐critical) Randomised: 826 participants (n1 tocilizumab arm = 366/ n2 sarilumab arm = n2 = 48/ n3 control arm = 412) Characteristics of participants N = 826 randomised; baseline data reported for 803 participants Mean age: 61.4 to 63.4 years 583 (73%) Males Admitted to ICU: n = 826 (100%) Severity: mild: n = 0 / moderate: n = 3/ severe: n = 567 / critical: n = 233 Patients on oxygen without intubation: n = 570 (71%); Intubated: n = 233 (29%) C‐reactive protein (median): 130 to 150 mg/L 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 ICU 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 1 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 randomised 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 baselineALT or an ASP 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 109 / L will result in exclusion from receiving tocilizumab or sarilumab Dropouts and withdrawals: n = 34/826 (4%); withdrawal due to adverse events: NR
Interventions	Interventions: tocilizumab (8 mg/kg infusion, maximum 800 mg), a 2nd infusion could be administered 12 to 24 hours after the 1st at the discretion of the treating clinician. 29% received a 2nd dose. Treatment initiated within 24 hours after starting organ support in the ICU. Sarilumab (400 mg, IV). 90% received the drug. Control: standard care Definition of standard care: other aspects of patient management were provided per each site's standard of care. Overall, > 80% of participants received corticosteroids. Remdesivir use was recorded in 33% (265/807) of patients. Co‐interventions: steroid use at baseline or any time during the study in > 80% of participants
Outcomes	Primary outcome of the trial: respiratory and cardiovascular organ support‐free days up to day 21 Note: the definition of clinical improvement extracted is hospital discharge
Notes	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 New Zealand, and the Canadian Institute of Health Research, the UK National, the Health Research Board of Ireland, the UPMC Learning While Doing Program, the Breast Cancer Research Foundation, the French Ministry of Health, the Minderoo Foundation and the Wellcome Trust Innovations Project.) Conflict of interest: yes. (Quote:) “Dr. Gordon reports grants from NIHR, grants from NIHR Research Professorship (RP‐2015‐06‐18), non‐financial support from NIHR Clinical Research Network, non‐financial support from Roche Products Ltd, non‐financial support from Sanofi (Aventis Pharma)” Protocol: yes, available. Statistical plan: yes, available Data‐sharing stated: yes, after submission of proposal to info@remapcap.org Overall comment: in addition to the pre‐print article, the study registry and protocol were used in data extraction and 'Risk of bias' assessment. Appendices were not available. 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." This trial was updated on 1 March 2021 after publication of the study report.