tetano
Editor, Senior Moderator
Open Forum Infect Dis
. 2023 Oct 27;10(11)
fad518.
doi: 10.1093/ofid/ofad518. eCollection 2023 Nov. Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial
Scott R Goldsmith[SUP] 1 2 [/SUP], Fahrettin Covut[SUP] 1 [/SUP], Mark Fiala[SUP] 1 [/SUP], Zhifu Xiang[SUP] 1 [/SUP], Zahid Iqbal[SUP] 3 4 [/SUP], Nathan Moore[SUP] 5 [/SUP], Elizabeth Bradtke[SUP] 1 [/SUP], Brandon Christen[SUP] 1 [/SUP], Michael P Rettig[SUP] 1 [/SUP], Stephanie Christ[SUP] 1 [/SUP], Leah Gehrs[SUP] 1 [/SUP], Emily Street[SUP] 1 [/SUP], Nicholas Wallace[SUP] 1 [/SUP], Julie Ritchey[SUP] 1 [/SUP], Feng Gao[SUP] 6 [/SUP], Jonathan Pachter[SUP] 7 [/SUP], Bijal Parikh[SUP] 8 [/SUP], Erik R Dubberke[SUP] 9 [/SUP], John F DiPersio[SUP] 1 [/SUP]
Affiliations
Background: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (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 aged ≥18 years 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 adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis.
Results: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .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 acute respiratory distress syndrome, supporting further investigation.
Clinical trials registration: NCT04372602.
Keywords: ARDS; COVID-19; PI3K inhibition; cytokine storm; duvelisib.
. 2023 Oct 27;10(11)
fad518.doi: 10.1093/ofid/ofad518. eCollection 2023 Nov. Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial
Scott R Goldsmith[SUP] 1 2 [/SUP], Fahrettin Covut[SUP] 1 [/SUP], Mark Fiala[SUP] 1 [/SUP], Zhifu Xiang[SUP] 1 [/SUP], Zahid Iqbal[SUP] 3 4 [/SUP], Nathan Moore[SUP] 5 [/SUP], Elizabeth Bradtke[SUP] 1 [/SUP], Brandon Christen[SUP] 1 [/SUP], Michael P Rettig[SUP] 1 [/SUP], Stephanie Christ[SUP] 1 [/SUP], Leah Gehrs[SUP] 1 [/SUP], Emily Street[SUP] 1 [/SUP], Nicholas Wallace[SUP] 1 [/SUP], Julie Ritchey[SUP] 1 [/SUP], Feng Gao[SUP] 6 [/SUP], Jonathan Pachter[SUP] 7 [/SUP], Bijal Parikh[SUP] 8 [/SUP], Erik R Dubberke[SUP] 9 [/SUP], John F DiPersio[SUP] 1 [/SUP]
Affiliations
- PMID: 37953814
- PMCID: PMC10633784
- DOI: 10.1093/ofid/ofad518
Background: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (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 aged ≥18 years 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 adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis.
Results: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .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 acute respiratory distress syndrome, supporting further investigation.
Clinical trials registration: NCT04372602.
Keywords: ARDS; COVID-19; PI3K inhibition; cytokine storm; duvelisib.