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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Patient Disposition and Outcomes

aThese 3 patients were randomized in error because they did not meet all of the eligibility criteria. bThe primary analysis set included randomized patients who received canakinumab or placebo and had at least 1 assessment of clinical status between days 3 and 29. cThe full analysis set included all randomized patients. dThe safety analysis set included all patients who received canakinumab or placebo.

Figure 2.. Use of IMV or Death and Discharge From Hospital

Kaplan-Meier estimates are for patients with COVID-19 and hyperinflammation (N = 454, 227 in each group) treated with the standard care plus 1 single dose of canakinumab or placebo on day 1. Data markers represent censoring times. A and B, Patients were censored after day 29 or at the last follow-up if they discontinued the study; C, patients who died were not censored up to day 29. By day 29, 12 patients died in the canakinumab group and 16 in the placebo group. Most patients completed the observation period of 29 days, and therefore the median observation time was 29 days. Of note, 14 patients were readmitted to the hospital after discharge: 8 in the canakinumab group and 6 in the placebo group. The median time to hospital discharge was 10 days (95% CI, 9-12) for the canakinumab group and 11 days (95% CI, 10-12) for the placebo group.

Figure 3.. Evolution of Clinical Status Over Time

The graphics and table present the clinical status according to the World Health Organization’s 9-point ordinal scale at baseline and days 15 and 29 of patients with COVID-19 and hyperinflammation (full analysis set, N = 454, which includes 3 patients in the placebo arm who were misrandomized and had no assessments available) treated with the standard care as per local practice plus 1 single dose of canakinumab or placebo on day 1. In the table, n is the number of patients with assessment of clinical status performed at each visit, with last observation carried forward imputation for missing data at days 15 and 29, and No. is the number of patients with a given score at each visit. Percentages were calculated as No./n × 100. ECMO indicates extracorporeal membrane oxygenation; and KRT, kidney replacement therapy.

Figure 4.. Blood Concentrations of Inflammatory Markers Over Time

Plots present ratios to baseline of blood concentrations of C-reactive protein (A), D-dimer (B), and ferritin (C) from baseline until day 29, using logarithmic scales. Boxes represent interquartile ranges (IQRs); horizontal lines in the boxes indicate median values, with whiskers indicating 1.5 × IQR below the first quartile and above the third quartile; and dots outside the boxes are potential outliers. Dots in the boxes, which are linked by lines between time points, represent geometric means. For each time interval, only 1 value per patient is presented; if there was more than 1 value available, the value obtained at a time closer to the midpoint of the interval was selected. Results were obtained in the full analysis set, the number of patients with measurements available at each time point for the placebo and canakinumab groups are presented in the table under the graphic. FEU indicates fibrinogen equivalent units.