Duvelisib for Critically-Ill Patients with COVID-19 Disease: An Investigator-Initiated, Randomized, Placebo-Controlled Double-Blind Pilot Trial

Abstract Background Despite improvements in prevention and treatment, severe COVID-19 is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness. Methods We enrolled adults age ≥18 with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to AEs or logarithmic change in viral load. The primary endpoint was 28-day OS. Secondary endpoints included hospital and ICU length of stay, 60-day OS, duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis. Results Fifteen were treated in the duvelisib cohort, 13 in the placebo cohort. 28-day OS was 67% (95% CI, 38-88%) compared to 62% (95% CI, 32-86%) for placebo (p = 0.544), respectively. 60-day OS was 60% versus 46%, respectively, HR 0.66 (95% CI 0.22-1.96; p = 0.454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines. Conclusions In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically-ill population, and was associated with reduction in cytokines implicated in COVID-19 and ARDS, supporting further investigation. Trial Registration Clinicaltrials.gov (NCT04372602)