+Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.
+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)
+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.
In-Depth [randomized controlled trial]:
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+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.
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