PMID- 37953814
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231201
IS  - 2328-8957 (Print)
IS  - 2328-8957 (Electronic)
IS  - 2328-8957 (Linking)
VI  - 10
IP  - 11
DP  - 2023 Nov
TI  - Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An 
      Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial.
PG  - ofad518
LID - 10.1093/ofid/ofad518 [doi]
LID - ofad518
AB  - 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 PI3Kdeltagamma 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.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of 
      Infectious Diseases Society of America.
FAU - Goldsmith, Scott R
AU  - Goldsmith SR
AUID- ORCID: 0000-0001-9216-2418
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
AD  - City of Hope National Medical Center, Duarte, California, USA.
FAU - Covut, Fahrettin
AU  - Covut F
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Fiala, Mark
AU  - Fiala M
AUID- ORCID: 0000-0002-0208-5023
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Xiang, Zhifu
AU  - Xiang Z
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Iqbal, Zahid
AU  - Iqbal Z
AD  - Division of Critical Care Medicine, Department of Anesthesiology, Washington 
      University School of Medicine in St Louis, St Louis, Missouri, USA.
AD  - Department of Anesthesiology, University of Nebraska Medical Center, Omaha, 
      Nebraska, USA.
FAU - Moore, Nathan
AU  - Moore N
AD  - Barnes Jewish Christian Medical Group, Missouri Baptist Hospital, St Louis, 
      Missouri.
FAU - Bradtke, Elizabeth
AU  - Bradtke E
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Christen, Brandon
AU  - Christen B
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Rettig, Michael P
AU  - Rettig MP
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Christ, Stephanie
AU  - Christ S
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Gehrs, Leah
AU  - Gehrs L
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Street, Emily
AU  - Street E
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Wallace, Nicholas
AU  - Wallace N
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Ritchey, Julie
AU  - Ritchey J
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
FAU - Gao, Feng
AU  - Gao F
AD  - Division of Public Health Sciences, Department of Surgery, Washington University 
      School of Medicine in St Louis, St Louis, Missouri, USA.
FAU - Pachter, Jonathan
AU  - Pachter J
AD  - Verastem Oncology, Needham, Massachusetts, USA.
FAU - Parikh, Bijal
AU  - Parikh B
AD  - Division of Laboratory and Genomic Medicine, Department of Pathology and 
      Immunology, Washington University School of Medicine in St Louis, St Louis, 
      Missouri, USA.
FAU - Dubberke, Erik R
AU  - Dubberke ER
AD  - Division of Infectious Disease, Department of Medicine, Washington University 
      School of Medicine in St Louis, St Louis, Missouri, USA.
FAU - DiPersio, John F
AU  - DiPersio JF
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine in St Louis, St Louis, Missouri, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT04372602
GR  - R35 CA210084/CA/NCI NIH HHS/United States
GR  - R50 CA211466/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20231027
PL  - United States
TA  - Open Forum Infect Dis
JT  - Open forum infectious diseases
JID - 101637045
PMC - PMC10633784
OTO - NOTNLM
OT  - ARDS
OT  - COVID-19
OT  - PI3K inhibition
OT  - cytokine storm
OT  - duvelisib
COIS- Potential conflicts of interest. J. P. reports employment with Verastem Oncology 
      Inc. All other authors report no potential conflicts.
EDAT- 2023/11/13 06:42
MHDA- 2023/11/13 06:43
PMCR- 2023/10/27
CRDT- 2023/11/13 04:17
PHST- 2023/07/21 00:00 [received]
PHST- 2023/10/25 00:00 [accepted]
PHST- 2023/11/13 06:43 [medline]
PHST- 2023/11/13 06:42 [pubmed]
PHST- 2023/11/13 04:17 [entrez]
PHST- 2023/10/27 00:00 [pmc-release]
AID - ofad518 [pii]
AID - 10.1093/ofid/ofad518 [doi]
PST - epublish
SO  - Open Forum Infect Dis. 2023 Oct 27;10(11):ofad518. doi: 10.1093/ofid/ofad518. 
      eCollection 2023 Nov.