Canakinumab fails to improve survival odds without ventilation in severe COVID-19
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Canakinumab fails to significantly increase the likelihood of survival without accompanying invasive mechanical ventilation, compared with placebo, in patients with severe COVID-19, according to data published in JAMA.
“IL-1 is an upstream proinflammatory cytokine that is involved in the pathogenesis of a variety of autoinflammatory conditions and induces the production of secondary inflammatory mediators, including IL-6,” Roberto Caricchio, MD, of the Lewis Katz School of Medicine at Temple University, in Philadelphia, and colleagues wrote. “In vitro experiments have shown that infection with SARS-CoV-2 triggers activation of the inflammasome and the maturation and release of IL-1.”
“Postmortem examination of lungs of patients who died of COVID-19 pneumonia have revealed intense inflammasome formation,” they added. “Immuno-profile studies have shown that IL-1 is one of the inflammatory cytokines that defines the ‘core COVID-19 signature’.”
To examine the efficacy of the IL-1 inhibitor canakinumab (Ilaris, Novartis), in patients who are hospitalized with severe COVID-19, Caricchio and colleagues conducted the CAN-COVID trial. According to the researchers, this randomized, double-blind, placebo-controlled phase 3 study included 454 participants with COVID-19 pneumonia from 39 hospitals in Europe and the United States.
Patients additionally demonstrated hypoxia, not requiring invasive mechanical ventilation, and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin. They were enrolled between April 30, 2020, and Aug. 17, 2020, with the last assessment of the primary endpoint on Sept. 22, 2020.
Participants were randomized 1:1 to receive either a single intravenous infusion of canakinumab, at a dose of 450 mg for those weighing less than 60 kg, 600 mg for those 60-80 kg, and 750 mg for those above 80 kg, or placebo. The primary outcome was survival without invasive mechanical ventilation from day 3 to day 29. Secondary outcomes included mortality related to COVID-19, as well as biomarker measurements of systemic hyperinflammation and safety.
According to the researchers, 88.8% of participants in the canakinumab group survived without requiring ventilation, compared with 85.7% of those who received placebo, 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). Meanwhile, mortality related to COVID-19 occurred in 4.9% of participants in the canakinumab group, compared with 7.2% in the placebo group, with a rate difference of –2.3% (95% CI, –6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.3-1.5).
Serious adverse events were observed in 16% of those treated with canakinumab, compared with 20.6% in the placebo group.
“In this multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 39 hospitals in Europe and the United States, the IL-1 inhibitor canakinumab did not significantly increase the likelihood of survival without [invasive mechanical ventilation] among patients hospitalized with severe COVID-19,” Caricchio and colleagues wrote. “These findings were also consistent for the secondary outcome of COVID19–related mortality.”
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