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Is the anti–interleukin-1β antibody canakinumab effective to treat patients hospitalized with COVID-19 and hyperinflammation?
This randomized clinical trial included 454 patients hospitalized with severe COVID-19 not requiring invasive mechanical ventilation (IMV) and with elevated C-reactive protein or ferritin levels. Treatment with intravenous canakinumab vs placebo resulted in survival without IMV at 29 days of 88.8% vs 85.7%, a difference that was not statistically significant.
Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV.
Effective treatments for patients with severe COVID-19 are needed.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT04362813
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Corresponding Author: Roberto Caricchio, MD, Division of Rheumatology, Department of Medicine, Lewis Katz School of Medicine at Temple University, 3322 N Broad St, Philadelphia, PA 19140 (firstname.lastname@example.org).
Accepted for Publication: May 16, 2021.
Author Contributions: Drs Caricchio and Abbate had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Caricchio, Stepanenko, Ruiz-Seco, Li, Whelan, Noviello.
Acquisition, analysis, or interpretation of data: Abbate, Gordeev, Meng, Hsue, Neogi, Arduino, Fomina, Bogdanov, Stepanenko, Ruiz-Seco, González-García, Chen, Li, Whelan, Noviello.
Drafting of the manuscript: Caricchio, Abbate, Gordeev, Neogi, Stepanenko, Ruiz-Seco, González-García, Li, Whelan, Noviello.
Critical revision of the manuscript for important intellectual content: Caricchio, Abbate, Meng, Hsue, Neogi, Arduino, Fomina, Bogdanov, Stepanenko, Ruiz-Seco, González-García, Chen, Li, Whelan, Noviello.
Statistical analysis: Arduino, Stepanenko, Chen, Li.
Obtained funding: Gordeev, Stepanenko, Noviello.
Administrative, technical, or material support: Meng, Neogi, Stepanenko, Ruiz-Seco, Whelan.
Supervision: Meng, Hsue, Arduino, Bogdanov, Stepanenko, González-García, Noviello.
Conflict of Interest Disclosures: All authors received funding from Novartis during the conduct of the study. Dr Caricchio reported receiving grants from Janssen and personal fees from Janssen, GlaxoSmithKline, Bristol Myers Squibb, Eli Lilly, and Siemens outside the submitted work. Dr Abbate reported receiving grants from Kiniksa, Janssen, Olatec, and Serpin Pharma; personal fees from Janssen, Kiniksa, Cromos, Olatec, Serpin Pharma, Eli Lilly, and Merck; and nonfinancial support from Swedish Orphan Biovitrum outside the submitted work. Dr Hsue reported receiving honoraria from Gilead and Merck outside the submitted work. Dr Neogi reported receiving personal fees from Novartis outside the submitted work. Drs Chen, Li, Whelan, and Noviello reported being employees of Novartis. Dr Whelan reported having a patent pending through Novartis. Dr Noviello reported being a former/employee/stockholder of Bristol Myers Squibb and stockholder of Johnson & Johnson; in addition, Dr Noviello reported having a patent pending through Novartis.
Funding/Support: This study was sponsored by Novartis Pharma AG, Basel, Switzerland.
Role of the Funder/Sponsor: The sponsor, in consultation with investigators, designed and conducted the study. Collection of data and management of trial sites were conducted by the sponsor. An independent data monitoring committee reviewed trial safety data weekly. All authors contributed to the interpretation of the data, including sponsor coauthors. A preliminary draft of the manuscript was prepared by a writer contracted by Novartis. All authors reviewed the final version of the manuscript for approval and concurred with the decision to submit the manuscript for publication. The sponsor did not have the right to veto publication nor control the decision to which journal the paper was submitted.
Group Information: The CAN-COVID Investigators are listed in Supplement 4.
Data Sharing Statement: See Supplement 5.
Additional Contributions: We thank the patients who participated in the trial, and Marco Migliaccio, PhD, for medical writing assistance, which was funded by Novartis Pharma AG, Basel, Switzerland.
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