Duvelisib to Combat COVID-19

• Duvelisib (Drug), also known as Copiktra: -For patients unable to administer orally, a duvelisib suspension will be administered through a nasogastric/orogastric tube.
• Peripheral blood draw (Procedure): * First 10 patients enrolled * Screening, Day 2, Day 4, Day 8, Day 10, Day 15, and Day 29
• Placebo (Drug): -Provided by Verastem

Primary outcomes

• Overall Survival as Measured by Number of Participants Alive Through 28 Days [Through 28 days]

Secondary outcomes

• Length of Hospital Stay [Through 28 days]
• Length of ICU Stay [Through 28 days]
• Duration of Ventilator Use [Through 28 days]: -For those on a ventilator at the time of randomization
• Duration of Vasopressors Use [Through 28 days]
• Duration on Renal Replacement Therapy [Through 28 days]
• Viral Kinetics as Measured by Virologic Failure [Through 28 days]: -Defined as increase in viral load of >0.5 log on two consecutive days, or >1 log increase in one day, not in keeping with any baseline trend of rising viral loads during the pre-treatment viral testing
• Number of Adverse Events as Measured by CTCAE v. 5.0 [Through 29 days]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* A diagnosis of advanced COVID-19 as defined both of the following:

  * as a positive test for SARS-CoV-2 RNA detected by RT-PCR collected from the upper respiratory tract (e.g. nasopharyngeal, nasal, oropharyngeal swab, or saliva) and, if possible, the lower respiratory tract (sputum, tracheal aspirate, or bronchoalveolar lavage), analyzed by a CLIA certified lab with an FDA approved assay.
  * Critical disease manifested by any of the following:

    * Chest imaging with ≥ 50% lung involvement
    * Respiratory failure requiring invasive mechanical ventilation, non-invasive mechanical ventilation (eg. BiPAPA, OptiFlow), supplementary oxygen with FiO2 ≥ 6 LPM or extracorporeal membrane oxygenation (ECMO)
    * Shock - defined as mean arterial pressure ≤ 65 mmHg unresponsive to 25ml/kg isotonic intravenous fluid resuscitation and/or requiring vasopressor support
    * Cardiac dysfunction defined by:

      * New global systolic dysfunction with ejection fraction ≤ 40%
      * Takotsubo cardiomyopathy
* Patients who have received prior investigational or off-label agents for COVID-19 does not exclude eligibility.
* At least 18 years of age at the time of study registration
* Adequate hematologic function defined as absolute neutrophil count ≥1000/mm3 and platelet count ≥ 50,000/mm3 without growth factor or transfusion support for 7 days prior to screening.
* Creatinine-clearance ≥ 15 mL/minute or receiving renal replacement therapy
* Aminotransferase (AST/ALT) levels <3x the upper limit of normal
* Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)
* Women of childbearing potential (defined as women with regular menses, women with amenorrhea, women with irregular cycles, women using a contraceptive method that precludes withdrawal bleeding, or women who have had a tubal ligation) are required to have a negative pregnancy test and use two forms of acceptable contraception, including one barrier method, during participation in the study treatment period.
* Male patients if engaging in sex with a women of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during participation in the study and throughout the evaluation period.

Exclusion Criteria:

* Known allergy or intolerance to duvelisib or another PI3K inhibitor.
* Known or suspected active viral (including CMV, HIV, hepatitis B, and hepatitis C), bacterial, mycobacterial, or fungal infection other than COVID-19. CMV viral load will be assessed at screening and those with viremia will be excluded. Other virologic testing not required unless infection is suspected.
* Pregnant and/or breastfeeding.
* Any uncontrolled intercurrent illness that would put the patient at greater risk or limit compliance with study requirements in the opinion of the investigator.

Participant flow

Outcome results

• Overall Survival as Measured by Number of Participants Alive Through 28 Days (Primary), Count of participants, Participants: Duvelisib 10; Placebo 8
• Length of Hospital Stay (Secondary), Median, days: Duvelisib 19 (7 to 28); Placebo 24 (7 to 28)
• Length of ICU Stay (Secondary), Median, days: Duvelisib 19 (5 to 28); Placebo 20.50 (7 to 28)
• Duration of Ventilator Use (Secondary), Median, days: Duvelisib 16 (2 to 28); Placebo 20 (11 to 28)
• Duration of Vasopressors Use (Secondary), Median, days: Duvelisib 9 (7 to 28); Placebo 19 (9 to 28)
• Duration on Renal Replacement Therapy (Secondary), Median, days: Duvelisib 28 (28 to 28); Placebo 19 (13 to 28)
• Viral Kinetics as Measured by Virologic Failure (Secondary), Count of participants, Participants: Duvelisib 3; Placebo 5
• Number of Adverse Events as Measured by CTCAE v. 5.0 (Secondary), Count of participants, Participants: Duvelisib 1; Placebo 1

Adverse events

Time frame: Adverse events were collected from start of treatment through Day 29. All-cause mortality was collected from start of treatment through 6 months.

Serious adverse events by term

Other adverse events by term

6 more terms not shown.

• Results publication: Goldsmith SR, Covut F, Fiala M, Xiang Z, Iqbal Z, Moore N, Bradtke E, Christen B, Rettig MP, Christ S, Gehrs L, Street E, Wallace N, Ritchey J, Gao F, Pachter J, Parikh B, Dubberke ER, DiPersio JF. Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial. Open Forum Infect Dis. 2023 Oct 27;10(11):ofad518. doi: 10.1093/ofid/ofad518. eCollection 2023 Nov. PMID 37953814

• Study Protocol and Statistical Analysis Plan (PDF, 2020-11-30)

• John DiPersio, M.D., Ph.D., Principal investigator, Washington University School of Medicine