Interleukin-6 Receptor Antagonists Improve Outcomes in Severe COVID-19
Multiple observational and ex-vivo laboratory studies have demonstrated that IL-6 is an important cytokine associated with disease severity and mortality.
A recent study published in The New England Journal of Medicine has found that the interleukin-6 receptor antagonists tocilizumab and sarilumab improved both outcomes and survival in patients who were critically ill with COVID-19 and were receiving organ support in an intensive care unit (ICU).
Tocilizumab and sarilumab are both monoclonal antibodies and work by inhibiting membrane-bound and soluble IL-6 receptors. They are used to treat inflammatory conditions including rheumatoid arthritis, and cytokine release syndrome after chimeric antigen receptor T-cell (CAR-T) therapy. Their clinical use has been described in COVID-19; however, no randomized controlled trials so far have been conclusive.
The study was part of the REMAP-CAP trial, an international, adaptive platform designed to determine the best treatment strategies for patients with severe pneumonia in both pandemic and non-pandemic settings.
The 2 therapies were evaluated in an on-going international, multifactorial, adaptive platform trial that included 803 patients. Of those 803, 353 received tocilizumab, 48 received sarilumab and 402 received a control. All of the participants were aged >18 years, were critically ill, had a suspected or confirmed case of COVID-19, were admitted to an ICU and were receiving respiratory or cardiovascular organ support.
Patients were excluded from the study if the threat of death was imminent with the lack of commitment to full support or if they previously participated in the REMAP-CAP trial.
The primary outcome was respiratory and cardiovascular organ support-free days up to day 21, and was measured using a Bayesian cumulative logistic model that calculated the primary outcome based on evidence accumulated in the trial and assumed prior knowledge in the form of a prior distribution.
Findings from the study showed that tocilizumab and sarilumab both met the pre-defined triggers for efficacy. The median number of organ support-free days was 10 for tocilizumab, sarilumab and the control. Compared with the control, the primary outcome was 1.64 for tocilizumab and 1.76 for sarilumab.
The rate of hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for the control. Compared to the control, the median adjusted odds ratio for hospital survival was 1.64 for tocilizumab and 2.01 for sarilumab.
“We saw both an improved time to clinical improvement as well as a reduction in mortality. It is therefore possible that the maximum benefit from IL-6 inhibition is seen in the most severely ill patients with Covid-19,” the authors said. “However, it is important to note that in our trial, patients had to be enrolled within 24 hours after starting organ support. This may be an important factor to maximize effectiveness; treating critically ill patients early, while any developing organ dysfunction may be more reversible.”