A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR)
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Abstract
Granulocyte–macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19.
Methods
In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18–79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care ( NCT04376684 ). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28.
Results
In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI −0.8–11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2–33.1%, p=0.009) was observed in the predefined 70–79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI −9.3–11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19.
Conclusions
There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.
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SciScore for 10.1101/2021.04.14.21255475: (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 relevant institutional review boards (IRB/IEC).
Consent: Before patient enrollment, informed consent was obtained written/orally from the patient or written/orally from the patient’s legally authorized representative.Randomization Study treatments: Patients were centrally randomized 1:1 by interactive response technology in a blinded manner to either a single one-hour intravenous (IV) infusion of otilimab 90 mg (aiming to achieve serum otilimab concentrations through to Day 7 similar to steady-state trough in patients with RA) or placebo (saline). Blinding Study treatments: Patients were centrally randomized 1:1 by interactive … SciScore for 10.1101/2021.04.14.21255475: (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 relevant institutional review boards (IRB/IEC).
Consent: Before patient enrollment, informed consent was obtained written/orally from the patient or written/orally from the patient’s legally authorized representative.Randomization Study treatments: Patients were centrally randomized 1:1 by interactive response technology in a blinded manner to either a single one-hour intravenous (IV) infusion of otilimab 90 mg (aiming to achieve serum otilimab concentrations through to Day 7 similar to steady-state trough in patients with RA) or placebo (saline). Blinding Study treatments: Patients were centrally randomized 1:1 by interactive response technology in a blinded manner to either a single one-hour intravenous (IV) infusion of otilimab 90 mg (aiming to achieve serum otilimab concentrations through to Day 7 similar to steady-state trough in patients with RA) or placebo (saline). Power Analysis A sample size of 800 patients provided approximately 90% power to detect a difference of 12% in the proportion of patients alive and free of respiratory failure at a one-sided 2.5% significance level and an assumed placebo response rate of 45%. 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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04376684 Recruiting Investigating Otilimab in Patients With Severe Pulmonary COV… 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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