Globally, there have been over 79 million reported cases of Coronavirus Infectious Disease 2019 (COVID-19) with over 1.75 million deaths. Only corticosteroids are known to improve survival for severely ill patients. The benefit from corticosteroids in critically ill patients supports the concept that an excessive host inflammatory response is responsible for much of the morbidity and mortality from COVID-19.
Interleukin-6 receptor antagonists tocilizumab and sarilumab, both used in the treatment of rheumatoid arthritis, may improve outcomes in critically ill patients with COVID-19, according to a study.
Interleukin-6 (IL-6) is released in response to infection and stimulates inflammatory pathways as part of the acute phase response. Tocilizumab and sarilumab are monoclonal antibodies that inhibit both membrane-bound and soluble IL-6 receptors and are used to treat inflammatory conditions, such as rheumatoid arthritis, and cytokine release syndrome after chimeric antigen receptor T-cell (CAR-T) therapy (tocilizumab).
REMAP-CAP Trial: Tocilizumab and Sarilumab
The study, which appeared in medRxiv and is a preprint that has not yet been peer reviewed, reported outcomes of the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP).
Patients with COVID-19 who were in the intensive care unit (ICU) and had started organ support within 24 hours were randomized to receive either tocilizumab (8mg/kg), sarilumab (400mg), or standard care (control). The main outcomes were in-hospital mortality and days free of organ support to day 21, which were determined by a combined ordinal scale.
When the analysis was conducted, there were 353 tocilizumab patients, 48 sarilumab group, and 402 control patients. The median number of organ support-free days was higher in both the tocilizumab (10 [interquartile range (IQR), –1 to 16]) and sarilumab groups (11 [IQR, 0-16) than the control group (0 [IQR, –1 to 15).
When compared to the control group, the median adjusted odds ratio (aOR) for tocilizumab was 1.64 (95% credible intervals [CrI], 1.25-2.14) and for sarilumab, 1.76 (95% CrI, 1.17-2.91).
For patients with available data at the time of analysis, the in-hospital mortality rates were: tocilizumab, 28.0%; sarilumab, 22.2%; and control, 35.8%. The pooled mortality rate for the two treatment groups was 27.3%.
When compared to the control group, the aOR for tocilizumab was 1.64 (95% CrI, 1.14-2.35) and for sarilumab, 2.01 (95% CrI, 1.18-4.71).
Adverse events (AEs) in the tocilizumab group (n=9) included secondary bacterial infection (n=1), bleeds (n=5), cardiac events (n=2), and deterioration in vision (n=1).
AEs in the control group (n=11) included bleeds (n=4) and thromboses (n=7). No AEs were reported in the sarilumab group.
REMAP-CAP is an ongoing international COVID-19 trial for which findings have been previously published. In September, a study published in JAMA investigated the effect of hydrocortisone on mortality and organ support in patients with COVID-19 admitted to the ICU.
As more is learned about COVID-19 and studies are ongoing, new data and studies continue to come out, some with different results than others.
Three studies published in JAMA Internal Medicine in October evaluated the use of tocilizumab to treat COVID-19 patients with mixed results. In July a phase 3 study found that sarilumab was not effective in severely ill patients with COVID-19.
- Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. The REMAP-CAP Randomized, Embedded, Multifactorial Adaptive Platform Trial. Anthony C. Gordon et al. medRxiv.org
- Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. The Writing Committee for the REMAP-CAP Investigators. JAMA. 2020;324(13):1317-1329.