Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial

JAMA. 2021 Jul 20;326(3):230-239. doi: 10.1001/jama.2021.9508.

Abstract

Importance: Effective treatments for patients with severe COVID-19 are needed.

Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1β antibody, in patients hospitalized with severe COVID-19.

Design, setting, and participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020.

Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227).

Main outcomes and measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations.

Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, 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 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (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, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo.

Conclusions and relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29.

Trial registration: ClinicalTrials.gov Identifier: NCT04362813.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • C-Reactive Protein / analysis
  • COVID-19 / mortality
  • COVID-19 / therapy
  • COVID-19 Drug Treatment*
  • Combined Modality Therapy
  • Double-Blind Method
  • Female
  • Ferritins / blood
  • Fibrin Fibrinogen Degradation Products / analysis
  • Hospitalization
  • Humans
  • Interleukin-1beta / antagonists & inhibitors*
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Respiration, Artificial / statistics & numerical data*
  • Survival Rate
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Fibrin Fibrinogen Degradation Products
  • Interleukin-1beta
  • fibrin fragment D
  • canakinumab
  • C-Reactive Protein
  • Ferritins

Associated data

  • ClinicalTrials.gov/NCT04362813