Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial
Study (n=420) found sarilumab did not reduce time to clinical improvement of ≥2 points on a 7-point scale (1 [death] to 7 [discharged from hospital]), with a median of 10 days for sarilumab (both doses) versus 12 days with placebo, in those with severe or critical Covid-19.
Source:
The Lancet Respiratory Medicine
SPS commentary:
The authors discuss the potential reasons behind the observed lack of benefit of sarilumab in this population, including that IL-6 suppression alone may not be sufficient to quell the inflammatory phase of the disease; patients were not selected on the basis of markers of inflammation; and the optimal time in the disease course for its administration may not have been chosen. In addition, use of systemic corticosteroids (which was high and varied during the study) may have reduced differences between sarilumab groups and placebo, and the study may have been underpowered to detect any statistically significant differences. Finally the chosen efficacy endpoints may not have been sensitive enough for the wide range of disease severity studied in this trial.
The authors also postulate that immunomodulation may only be beneficial for the most serious cases. Their results showed a numerical advantage for sarilumab in those who required intensive respiratory support or treatment in an intensive care unit. Indeed the preliminary results from the REMAP-CAP adaptive-platform trial (n=803), which enrolled a more critically ill population, suggest that sarilumab and tocilizumab increased the number of respiratory or cardiovascular organ support-free days and improved the odds of hospital survival. They conclude that a benefit of sarilumab in patients admitted to hospital with COVID-19 pneumonia with critical illness cannot be excluded, and suggest that subsequent randomised trials focus on patients who are critically ill and are adequately powered to assess survival as a primary endpoint.
A related Comment discusses the data available on IL-6 blockade as a whole, and the value of this study and another on tocilizumab published alongside, which were both conducted in settings outside of the regions where the bulk of the other IL-6 data is emerging. They call for all trial teams to urgently participate in a carefully planned meta-analysis, incorporating analyses for heterogeneous treatment effects and standardised subgroups, and focusing on the important clinical outcome of mortality.