Duvelisib Ameliorates Manifestations of Pneumonia in Established Novel Coronavirus Infection (COVID-19)

This randomized placebo-controlled phase 2 study will evaluate whether a two-week exposure to duvelisib, a gamma/delta phosphoinositide 3-kinase (PI3K) inhibitor, reduces inflammation in the lungs in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 who do not require mechanical ventilation at study initiation. The primary objective of the study is to determine the efficacy of duvelisib treatment in preventing death or the need for mechanical ventilation among patients with World Health Organization (WHO)-defined severe COVID-19. Key secondary endpoints will be reductions in oxygen requirements of patients and improvements in their performance status, safety and tolerability of duvelisib in the setting of COVID-19, biomarkers of inflammation, and generation of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody responses to SARS-Cov-2 spike protein. The study will determine if a two-week exposure to duvelisib beginning soon after presentation with severe COVID-19 warrants further evaluation in a larger clinical study.

Inclusion criteria

• Hospitalized in participating facility.
• Documentation of pneumonia with radiographic evidence of infiltrates by imaging (e.g., chest x-ray or CT scan).
• Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other authorized or approved assay in any specimen collected within 72 hours prior to enrollment. Note - An exception must be requested to the Sponsor if ≥72 hours since positive test.
• Symptoms suggestive of severe systemic illness with COVID-19, such as respiratory rate > 30 breaths per minute, heart rate >125 beats per minute, oxygen saturation (O2 sat) in the blood of <93% on room air at sea level or the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2)< 300
• 18 years of age or older
• Patients with hematological parameters at screening consistent with < grade 2 NCI CTCAE v5.0 toxicity: hemoglobin >8 g/dL, platelet count >50,000 K/mcl, an absolute neutrophil count (ANC) >1,000/mm3, and an absolute lymphocyte count (ALC) >500/mm3.
• Patients with laboratory measurements of liver function at screening consistent with < grade 2 NCI CTCAE v5.0 toxicity: alanine aminotransferase (ALT) < 5 times the upper limit of normal (ULN); aspartate aminotransferase (AST) < 5 times ULN; and bilirubin < 3 times ULN.
• The effects of duvelisib on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) must have a negative serum or urine pr5egnancy test prior to starting therapy. WOCBP and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from enrollment into this study until at least 60 days after the first dose of duvelisib. A woman of childbearing potential (WOCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 2 months after completion of duvelisib administration. WOCBP must have a negative pregnancy test within 24 hours of the first dose of duvelisib.
• The patient must be willing to comply with fertility requirements as below:

• Total abstinence (when this is in line with the usual practice and lifestyle of the patient) will be accepted. Periodic abstinence (i.e., calendar, ovulation, post-ovulation methods) and withdrawals are not acceptable forms
• If a female participant is of reproductive potential, the participant (and her partner) must agree to use of one of the following combinations of birth control during the study and for 2 months after the last dose of study drug (or tubal ligation as a single method):

• Use of a double-barrier method of contraception: condoms (male or female) and a diaphragm or cervical cap with spermicide;
• Use of an IUD and a barrier method: condoms (male or female, with or without spermicide) or a diaphragm or cervical cap with spermicide;
• Tubal ligation.
• Women who are post-menopausal, defined as age greater than 45 and no menses for at least 24 consecutive months, or who have had a hysterectomy, are considered not of reproductive potential.
• Males must agree to using contraception during the study and for 2 months after the last dose of study drug or have undergone a male sterilization procedure (at least 6 months prior to screening.
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception, or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of contraception that comparable efficacy (failure rate <1%). In case of oral contraception, the woman should be stable on the same pill for a minimum of 3 months prior to enrollment on the study.
• Patients must agree not to donate blood, sperm/ova or any other organs while taking protocol therapy and for at least 2 weeks after stopping treatment.
• Willingness and ability of the patient to comply with scheduled visits, drug administration plan, protocol specified laboratory tests, other study procedures and study restrictions
• Evidence of personally signed informed consent indicating that the subject is aware of the life-threatening nature of the disease and has been informed on the procedures to be followed, the experimental nature of the therapy, alternative, potential risks and discomforts, potential benefits and other pertinent aspects of study participation.

Exclusion criteria

• Patients requiring mechanical ventilation (intubation or Bi-PAP) at the time randomization.
• Patients receiving any investigational drugs other than drugs or therapies to treat COVID-19, with the exception of investigational immune-modulatory drugs as per section 5.4.
• Pregnant women are excluded from this study because duvelisib is agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with duvelisib, breastfeeding should be discontinued before starting study drug and breastfeeding should not be resumed until at least 1 month after last dose of study drug.
• Clinical suspicion that the etiology of acute illness (acute decompensation) is primarily due to a condition other than COVID-19
• Known contraindication to duvelisib
• Patients with hepatic cirrhosis as defined by symptomatic liver dysfunction; liver fibrosis by biopsy; ALT > 5 times ULN, AST> 5 times ULN, or bilirubin > 3 times ULN.
• Patients with autoimmune diseases or patients on chronic immunosuppressive medications at the time of hospital admission or screening.