Canakinumab not associated with increased survival without invasive mechanical ventilation among patients hospitalized with severe COVID-19

1. Among patients hospitalized with severe COVID-19 and hyperinflammation, treatment using the anti-interleukin-1β antibody canakinumab, compared with placebo, did not significantly increase the likelihood of survival without invasive mechanical ventilation at day 29.

2. These findings for canakinumab vs placebo were also consistent for the secondary outcome of COVID-19-related mortality where canakinumab did not show improved mortality.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Due to the rapid spread of COVID-19 and unequal access to treatments across regions, data on effective management of the respiratory virus has been limited. More recently, preliminary data from the RECOVERY trial, a platform study with adequate statistical power and large patient populations, has shown that the use of tocilizumab, an IL-6 inhibitor, among patients hospitalized with COVID-19, hypoxia, and systemic inflammation led to improved survival and other clinical outcomes. As such, researchers of the CAN-COVID trial, a phase 3 randomized clinical trial, sought to similarly evaluate the efficacy of canakinumab, an anti-interleukin-1β antibody, in patients hospitalized with severe COVID-19 and hyperinflammation. The main outcome and measure of the analysis was survival without invasive mechanical ventilation (IMV) from day 3 to day 29 where secondary outcomes included COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. From 454 patients hospitalized with COVID-19 with elevated C-reactive protein (CRP) or ferritin levels not requiring IMV, treatment using intravenous canakinumab vs placebo resulted in survival without IMV at 29 days of 88.8% vs 85.7% respectively, a difference that was not statistically significant (rate difference, 3.1%; OR, 1.39; 95%CI -3.1% to 9.3%). These results suggested that among patients hospitalized with severe COVID-19 and hyperinflammation assessed via biomarkers, treatment using the anti-interleukin-1β antibody canakinumab did not significantly increase the likelihood of survival without IMV at day 29 compared with placebo. A limitation of this study was the evolution in the standard of care for COVID-19 management that shifted from more patients receiving dexamethasone (or equivalent) in the canakinumab group prior to study therapy, to more patients receiving placebo-initiated dexamethasone (or equivalent) afterwards, effectively reversing the glucocorticoid usage trends between the two cohorts and potentially resulting in post-study therapy confounding of outcomes.

Click to read the study in JAMA

Relevant Reading: Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

In-Depth [randomized controlled trial]: This randomized, double-blind, placebo-controlled phase 3 trial was conducted across 39 centers in Europe and the US where 454 patients (median age, 59 years; 187 women [41.2%]) hospitalized with COVID-19 were randomly assigned in 1:1 ratio to receive a single intravenous infusion of canakinumab (n = 227; 450mg for body weight of 40-<60 kg, 600mg for 60-80 kg, and 750mg for >80 kg) or placebo (n = 227). Data was collected between April and August 2020, with the final assessment of the primary end point completed in September 2020. Eligible patients included those hospitalized with COVID-19 pneumonia, hypoxia (not requiring IMV) and systemic hyperinflammation defined by increased blood concentrations of CRP or ferritin. In total, 417 (91.9%) patients completed the trial where 198 of 223 (88.8%) vs 191 of 223 (85.7%) patients survived without requiring IMV in the canakinumab vs placebo cohorts respectively, with a rate difference of 3.1% (95%CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95%CI, 0.76-2.54; P = .29). Furthermore, COVID-19-related mortality occurred in 11 of 223 (4.9%) vs 16 of 222 (7.2%) patients in the canakinumab vs placebo cohorts respectively, with a rate difference of -2.3% (95%CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95%CI, 0.30-1.50). Lastly, 36 of 225 (16%) vs 46 of 223 (20.6%) patients experienced serious adverse effects in the canakinumab vs placebo cohorts respectively.

Image: PD

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