Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Abstract

Background: Accumulating evidence proposed Janus-associated kinase (JAK) inhibitors as therapeutic targets warranting rapid investigation.

Objective: This study evaluated the efficacy and safety of ruxolitinib, a JAK1/2 inhibitor, for coronavirus disease 2019.

Methods: We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe coronavirus disease 2019.

Results: Forty-three patients were randomly assigned (1:1) to receive ruxolitinib plus standard-of-care treatment (22 patients) or placebo based on standard-of-care treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in the intervention group and 21 patients in the control group were included in the study. Treatment with ruxolitinib plus standard-of-care was not associated with significantly accelerated clinical improvement in severe patients with coronavirus disease 2019, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed computed tomography improvement at day 14 compared with 13 (61.9%) patients from the control group (P = .0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at day 28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group.

Conclusions: Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest computed tomography improvement, a faster recovery from lymphopenia, and favorable side-effect profile in the ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population.

Keywords: COVID-19; Ruxolitinib; cytokine storm; efficacy; randomized controlled trial; safety.

Fig 1

Randomization and trial profile. CAR, Chimeric antigen receptor.

Fig 2

Primary and secondary outcomes. A, The cumulative improvement rate in modified intention-to-treat analysis patients. B, Cumulative 28 days incidence of death. C, Cumulative incidence of virus clearance rate in analyzed patients. D, Comparison of blood viral loads of the control group and the ruxolitinib group at D₁. E, Comparison of blood viral loads of the control group and the ruxolitinib group at discharge. F and G, The peak levels of SARS-CoV-2–specific IgM and IgG. H, Cumulative incidence of lymphocyte recovery rate in analyzed patients.

Fig 3

Serial cytokine assessment of 48 cytokines and hsCRP was performed in the ruxolitinib group and the control group. A, The ratio of the mean value of each cytokine at D₃ and D₁ after randomization. B-H, Stacked scatter plots demonstrated cytokines, which were significantly decreased in the ruxolitinib group. I, hsCRP was significantly decreased in the ruxolitinib group. hsCRP, High-sensitivity C-reactive protein; MIF, migration inhibitory factor. All data represent mean ± SEM.

Fig E1

The dynamic change in lymphocytes, IFN-α2, and IFN-γ after treatment with ruxolitinib. A, Dynamic changes in lymphocytes in the patient who developed grade 3 lymphocytopenia after ruxolitinib treatment. The dotted line indicates absolute lymphocyte of 0.5 × 10⁹/L. (B) IFN-α2 and (C) IFN-γ were assessed on D₁ and D₃ in the ruxolitinib group and the control group. Scatter plots represent the levels of IFN-α2 or IFN-γ.