Ruxolitinib in addition to standard of care for the treatment of patients admitted to hospital with COVID-19 (RUXCOVID): a randomised, double-blind, placebo-controlled, phase 3 trial

Abstract

Background: COVID-19 is associated with acute respiratory distress and cytokine release syndrome. The Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib reduces inflammatory cytokine concentrations in disorders characterised by cytokine dysregulation, including graft-versus-host disease, myelofibrosis, and secondary hemophagocytic lymphohistiocytosis. We assessed whether treatment with the JAK1/JAK2 inhibitor ruxolitinib would be beneficial in patients with COVID-19 admitted to hospital.

Methods: RUXCOVID was an international, randomised, double-blind, phase 3 trial of ruxolitinib plus standard of care versus placebo plus standard of care in patients with COVID-19. Patients who were hospitalised but not on mechanical ventilation or in the intensive care unit [ICU] were randomly assigned (2:1) to oral ruxolitinib 5 mg twice per day or placebo for 14 days (14 additional days were allowed if no improvement). The primary endpoint was a composite of death, respiratory failure (invasive ventilation), or ICU care by day 29, analysed by logistic regression including region, treatment, baseline clinical status, age, and sex as covariates. This trial is registered with ClinicalTrials.gov, NCT04362137.

Findings: Between May 4 and Sept 19, 2020, 432 patients were randomly assigned to ruxolitinib (n=287) or placebo (n=145) plus standard of care; the mean age was 56·5 years (SD 13·3), 197 (46%) were female, and 235 (54%) were male. The primary objective was not met: the composite endpoint occurred in 34 (12%) of 284 ruxolitinib-treated patients versus 17 (12%) of 144 placebo-treated patients (odds ratio 0·91, 95% CI 0·48-1·73; p=0·77). By day 29, nine (3%) of 286 ruxolitinib-treated patients had died compared with three (2%) of 145 placebo-treated patients; 22 (8%) of 286 ruxolitinib-treated patients had received invasive ventilation compared with ten (7%) of 145 placebo-treated patients; and 30 (11%) of 284 ruxolitinib-treated patients had received ICU care compared with 17 (12%) of 144 placebo-treated patients. In an exploratory analysis, median time to recovery was 1 day faster with ruxolitinib versus placebo (8 days vs 9 days; hazard ratio 1·10, 95% CI 0·89-1·36). Adverse events included headache (23 [8%] of 281 on ruxolitinib vs 11 [8%] of 143 on placebo) and diarrhoea (21 [7%] vs 12 [8%]).

Interpretation: Ruxolitinib 5 mg twice per day showed no benefit in the overall study population. A larger sample is required to determine the clinical importance of trends for increased efficacy in patient subgroups.

Funding: Novartis and Incyte.

Conflict of interest statement

IG, AG, ALB, AR, JS-O, FT, RT, and SS have no competing interests. MKH reports personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Cipla, Chiesi, Novartis, Pulmonx, Teva, Verona, Merck, Mylan, Sanofi, DevPro, Aerogen, Polarian, Regeneron, United Therapeutics, UpToDate, Altesa Biopharma, Medscape, and Integrity. MKH has received either in kind research support or funds paid to the institution from the National Institutes of Health, Novartis, Sunovion, Nuvaira, Sanofi, AstraZeneca, Boehringer Ingelheim, Gala Therapeutics, Biodesix, the COPD Foundation, and the American Lung Association. MKH has participated in Data Safety Monitoring Boards for Novartis and Medtronic with funds paid to their institution. MKH has received stock options from Meissa Vaccines and Altesa Biopharma. MA has participated in clinical studies funded by AbbVie, AstraZeneca, EMS, Eurofarma, GSK, Humanigen, Janssen, Novartis, Sanofi Genzyme, Angion Biomedica Corporation, and Beigene; has received honoraria from Aché, AstraZeneca, Chiesi, Eurofarma, IPI ASAC Brasil, and Sanofi; has received meeting or travel support from AstraZeneca, GSK, Novartis, and Sanofi Genzyme; and has participated in data safety monitor boards or advisory boards, or both, for Sanofi Genzyme, Chiesi, AstraZeneca, Abbott, and Zambom. JHF has received research funding from Novartis; grants from Boehringer Ingelheim and CSL-Behring; consulting fees from Novartis, Boehringer Ingelheim, and CSL-Behring; honoraria from AstraZeneca, Boehringer Ingelheim, CSL-Behring, GSK, MSD, and Novartis; meeting or travel support from AstraZeneca, Boehringer Ingelheim, CSL-Behring, and Novartis; and materials from CSL-Behring; and has participated in data safety monitor boards or advisory boards, or both, for Boehringer Ingelheim and AstraZeneca. LB, DSB, JMF, BK, WC, TL, and ML are employees and stockholders of Novartis. XS was an employee of Novartis during the conduct of the study. PL is an employee of Incyte.

Published by Elsevier Ltd.

Figures

Figure 1

Trial profile ICU=intensive care unit. *Eight patients were randomly assigned but did not receive treatment due to consent withdrawal (n=4), patient decision (n=3), and misrandomisation (n=1). †Includes patients who completed first course of 14-day treatment, but discontinued from second course of 14-day treatment.

Figure 2

Primary endpoint (death, respiratory failure, or ICU care by day 29) according to subgroup analysis ICU=intensive care unit. M=total number of patients included in the analysis. CRP=C-reactive protein. FEU=fibrinogen equivalent units.