Effectiveness of Tocilizumab, Sarilumab, and Anakinra for critically ill patients with COVID-19 The REMAP-CAP COVID-19 Immune Modulation Therapy Domain Randomized Clinical Trial

Abstract

BACKGROUND: The interleukin-6 receptor antagonist tocilizumab improves outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). However, the effectiveness of other immune modulating agents is unclear. METHODS: We evaluated four immunomodulatory agents in an ongoing international, multifactorial, adaptive platform trial. Adult participants with COVID-19 were randomized to receive tocilizumab, sarilumab, anakinra, or standard care (control). In addition, a small group (n=21) of participants were randomized to interferon-beta1a. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial used a Bayesian statistical model with pre-defined triggers for superiority, equivalence or futility. RESULTS: Statistical triggers for equivalence between tocilizumab and sarilumab; and for inferiority of anakinra to the other active interventions were met at a planned adaptive analysis. Of the 2274 critically ill participants enrolled, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (interquartile range [IQR] -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted odds ratios were 1.46 (95%CrI 1.13, 1.87), 1.50 (95%CrI 1.13, 2.00), and 0.99 (95%CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared to control. Median adjusted odds ratios for hospital survival were 1.42 (95%CrI 1.05,1.93), 1.51 (95%CrI 1.06, 2.20) and 0.97 (95%CrI 0.66, 1.40) for tocilizumab, sarilumab and anakinra respectively, compared to control, yielding 98.8%, 98.8% and 43.6% posterior probabilities of superiority, respectively, compared to control. All treatments appeared safe. CONCLUSIONS: In patients with severe COVID-19 receiving organ support, tocilizumab and sarilumab are similarly effective at improving survival and reducing duration of organ support. Anakinra is not effective in this population.

A guide to immunotherapy for COVID-19

“…49 ). In line with this, anakinra had no effect on survival or release from organ support in the REMAP-CAP trial, in which 378 patients with COVID-19 needing organ support (without further immunological stratification) in the intensive-care unit (ICU) were treated with anakinra and compared with 418 controls 50 . By contrast, patient stratification based on immunological profiles did identify patients likely to benefit from IL-1 blockade.…”

Corona Virus Disease 2019 (COVID-19) as a System-Level Infectious Disease With Distinct Sex Disparities

“…Despite the poorly defined pathophysiology of cytokine storm, widespread acceptance of the term in COVID-19 has motivated to apply potent immunomodulatory therapies such as IL-6 inhibitors and high-dose corticosteroids. Nevertheless,in comparison with the other causes of ARDS (median IL-6 level is 10- to 200-fold higher than COVID-19) the lower levels of circulating cytokines in COVID-19 may not be representative of lung inflammation and need to be determined whether COVID-19 related ARDS phenotype is associated with the cytokine storm ( 73 , 75 ).…”

Clinical Evidence Generation During a Pandemic

“…Similar to RECOVERY, REMAP-CAP has produced several important findings. [8][9][10][11][12][13][14] REMAP-CAP has also integrated with other platform trials under a "multiplatform randomized" design, to speed up knowledge generation. 11,12 These multiplatform designs have spurred innovative solutions around integration of study procedures and oversight across disparate clinical coordination centers.…”

“…Such strategies have been used by the platform trial, Randomized, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), which has focused in particular on patients with severe COVID-19. Similar to RECOVERY, REMAP-CAP has produced several important findings 8–14 . REMAP-CAP has also integrated with other platform trials under a “multiplatform randomized” design, to speed up knowledge generation 11,12 .…”