A Randomized Placebo-Controlled Trial of Sarilumab in Hospitalized Patients with Covid-19

Abstract

BACKGROUND Sarilumab (anti-interleukin-6 receptor-alpha; monoclonal antibody) may attenuate the inflammatory response in Covid-19. METHODS We performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (cohort 1) was patients with critical Covid-19 receiving mechanical ventilation (MV) randomized to sarilumab 400 mg or placebo. The primary end point for phase 3 was the proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS Four-hundred fifty-seven (457) and 1365 patients were randomized and treated in phases 2 and 3, respectively. Among phase 3 critical patients receiving MV (n=289; 34.3% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive not receiving MV) at day 22 was 43.2% in sarilumab 400 mg and 35.5% in placebo (risk difference [RD] +7.5%; 95% confidence interval [CI], − 7.4 to 21.3; P=0.3261), representing a relative risk improvement of 21.7%. Day 29 all-cause mortality was 36.4% in sarilumab 400 mg versus 41.9% in placebo (RD − 5.5%; 95% CI, −20.2 to 8.7; relative risk reduction 13.3%). In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio (HR) for death in sarilumab 400 mg compared with placebo was 0.76 (95% CI, 0.51 to 1.13) overall, improving to 0.49 (95% CI, 0.25 to 0.94) in patients receiving corticosteroids at baseline. CONCLUSION In hospitalized patients with Covid-19 receiving MV, numerical benefits with sarilumab did not achieve statistical significance, but benefit may be greater in patients receiving corticosteroids. A larger study is required to confirm this observed numerical benefit.

Immunotherapy of COVID-19: Inside and Beyond IL-6 Signalling

“…By contrast, critically-ill patients (showing values of PaO2/FIO2 ratio <100 mmHg and requiring IMV) and mild-moderate patients (showing values of PaO2/FIO2 ratio > 200-300 mmHg and requiring low-flow or no oxygen) generally show poor responses to IL-6 inhibitors. Nevertheless, results from a large RCT evaluating sarilumab recently posted as a preprint ( 99 ) seem to suggest that IL-6 inhibitors can reduce the risk of death by up to half even in ICU patients undergoing IMV, in case these are co-treated with steroids and still show relatively low median values of IL-6 and CRP, substantially falling within our proposed response ranges.…”

Efficacy and safety of IL-6 inhibitors in patients with COVID-19 pneumonia: a systematic review and meta-analysis of multicentre, randomized trials

“…All studies were multicentre. Three studies have not yet undergone peer-review as of September 15th 2021 and are available as pre-print only [ 42 , 44 , 47 ]. One study was performed on ICU patients alone [ 48 ], and eight studies also included patients under invasive mechanical ventilation at baseline [ 34 , 40 , 41 , 43 , 45 – 48 ] (Table 2 ).…”

“…Five studies compared IL-6 inhibitors with placebo [ 36 , 38 , 40 , 45 , 47 ], nine studies with standard treatment, [ 35 , 37 , 41 – 44 , 46 , 48 , 49 ] and one study against favipiravir [ 42 ].…”

“…Three trials reported longest follow-up and 28/30-day mortality data stratified by steroids use [ 40 , 43 , 47 ]. In this analysis, we found a significant subgroup interaction, with improved survival in patients receiving steroids together with IL-6 inhibitors ( p for interaction = 0.004) (Additional file 1 ).…”

“…Notably, only five trials were double-blinded [ 36 , 38 , 40 , 45 , 47 ] and only three were judged to carry a low risk of bias [ 36 , 38 , 40 ]. All others RCTs were open-label.…”