Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial
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Abstract
Background
Elevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.
Methods
This was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to ≥2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered with ClinicalTrials.gov ( NCT04327388 ).
Findings
Between March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to ≥2-point improvement between placebo (12·0 [9·0–15·0] days) and sarilumab groups (200 mg: 10·0 [9·0–12·0] days, p=0.96, log-rank test; 400 mg: 10·0 [9·0–13·0] days, p=0.34) or in proportions of patients alive (placebo, 91·7%; sarilumab 200 mg, 89·9%, p=0·63; sarilumab 400 mg, 91·9%, p=0·85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI −7·7 to 25·5, p=0·25) for critical patients. There were no unexpected safety signals.
Interpretation
This trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.
Funding
Sanofi and Regeneron Pharmaceuticals, Inc.
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SciScore for 10.1101/2021.02.01.21250769: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The protocol was approved by the institutional review boards at each participating hospital and by national ethics committees, as required by local and national regulations.
Consent: 17 Patients: This study enrolled patients aged 18 years or older at the time of signing informed consent who had been hospitalised for laboratory-confirmed SARS-CoV-2 infection in any specimen within 2 weeks prior to randomisation and with evidence of pneumonia by chest imaging or chest auscultation and no alternative explanation for current clinical presentation.Randomization not detected. Blinding Because of the uncertainties of assessing treatment efficacy in COVID-19 … SciScore for 10.1101/2021.02.01.21250769: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The protocol was approved by the institutional review boards at each participating hospital and by national ethics committees, as required by local and national regulations.
Consent: 17 Patients: This study enrolled patients aged 18 years or older at the time of signing informed consent who had been hospitalised for laboratory-confirmed SARS-CoV-2 infection in any specimen within 2 weeks prior to randomisation and with evidence of pneumonia by chest imaging or chest auscultation and no alternative explanation for current clinical presentation.Randomization not detected. Blinding Because of the uncertainties of assessing treatment efficacy in COVID-19 pneumonia at the time of study design, the initial protocol allowed adaptations such as modification of the provisional phase 3 endpoints, sample size re-estimation before entering phase 3, or closing a dose group while the study remained blinded. Power Analysis In sample size determination, approximately 400 patients, randomised 2:2:1, were estimated to provide ≥90% power for pairwise comparison between each sarilumab dose (approximately 160 patients each) and placebo (approximately 80 patients) using a log-rank test of superiority at a two-sided significance level of 0·05. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Despite these limitations, survival at day 29 was possibly higher by 9% in the sarilumab arms than in the placebo arm for patients who required noninvasive or invasive mechanical ventilation or ECMO at baseline. Therefore, we think the results of this study do not exclude the possibility of a benefit from targeted immunomodulation in hospitalised patients with COVID-19 pneumonia with critical illness and suggest that subsequent randomised trials of targeted immunomodulatory therapies in this disease focus on critically ill patients and are adequately powered to assess survival as a primary endpoint.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04327388 Completed Sarilumab COVID-19 Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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