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

• ClinicalTrials.gov Identifier: NCT04487886
• Recruitment Status: Completed
• First Posted: July 27, 2020
• Last Update Posted: June 14, 2022
• Sponsor: Emory University
• Collaborators: Verastem, Inc.; University of Pennsylvania
• Information provided by (Responsible Party): Edmund Waller, Emory University

Study Description

Brief Summary:

In this study, a total of 80 patients with severe coronavirus disease 2019 (COVID-19) infection will be randomized to receive Duvelisib or a placebo. Participants will be enrolled at Emory University Hospital and at the University of Pennsylvania and will be identified and recruited by their treating physician and research team.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Duvelisib; Drug: Placebo	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Duvelisib Ameliorates Manifestations of Pneumonia in Established Novel Coronavirus Infection
• Actual Study Start Date: November 18, 2020
• Actual Primary Completion Date: June 10, 2021
• Actual Study Completion Date: June 10, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Duvelisib; Participants with severe COVID-19 who do not require mechanical ventilation randomized to receive duvelisib for 14 days.	Drug: Duvelisib; Duvelisib will be taken orally at an initial dose of 25 milligrams (mg) twice per day for 14 days. The dose will be de-escalated to 15 mg, twice per day, under certain clinical circumstances.; Other Name: Copiktra
Placebo Comparator: Placebo; Participants with severe COVID-19 who do not require mechanical ventilation randomized to receive a placebo to match duvelisib for 14 days.	Drug: Placebo; A placebo to match duvelisib will be taken orally twice per day for 14 days.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Requiring Mechanical Ventilation or Dying [ Time Frame: Up to Day 29 ]
   This is a composite endpoint of the number of participants who require mechanical ventilation or who die within four weeks of randomization.

Secondary Outcome Measures :

1. Days to Recovery [ Time Frame: Up to Day 29 ]
   Time to recovery (in days) is defined as a score of greater than 5 from the following eight categories from the NIAID ordinal scale. The scale is as follows: 1. Death; 2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7. Not hospitalized, limitation on activities and/or requiring home oxygen; 8. Not hospitalized, no limitations on activities.
2. Duration of Hospitalization [ Time Frame: Up to Day 29 ]
   The number of days spent hospitalized will be compared between study arms.
3. Incidence of Death [ Time Frame: Up to Day 29 ]
   The incidence of death within 29 days of randomization will be compared between study arms.
4. Proportion of Participants Transferred to ICU [ Time Frame: Up to Day 29 ]
   Comparing the proportion of subjects in each group requiring ICU transfer within 29 days of randomization
5. Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score [ Time Frame: Day 15, Day 29 ]
   The ECOG Performance Status instrument includes a single item assessing overall physical status. Health status is rated on a scale of 0 to 5 where 0 = fully active and 5 = dead. Median ECOG performance will be compared between study arms.
6. Incidence of Grade III-V Adverse Events [ Time Frame: Up to Day 29 ]
   The incidence of grade III-V adverse events or Serious Adverse Events (SAEs), as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5, will be compared between study arms.
7. Incidence of Secondary Bacterial or Viral Infections [ Time Frame: Up to Day 29 ]
   The incidence of documented secondary bacterial or viral infections among participants will be compared between study arms.
8. Change in Th1 T Cell Frequency [ Time Frame: Weeks 1, 2, and 4 ]
   The mean frequency of Th1 T cells in blood mononuclear cells will be compared between study arms.
9. Change in Th17 T Cell Frequency [ Time Frame: Weeks 1, 2, and 4 ]
   The mean frequency of Th17 T cells in blood mononuclear cells will be compared between study arms.
10. Change in Interleukin-2 (IL-2) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker IL-2 will be compared between study arms.
11. Change in Interleukin-2 receptor (IL-2R) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker IL-2R will be compared between study arms.
12. Change in Interleukin-6 (IL-6) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker IL-6 will be compared between study arms.
13. Change in Interleukin-7 (IL-7) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker IL-7 will be compared between study arms.
14. Change in Interleukin-8 (IL-8) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker IL-8 will be compared between study arms.
15. Change in Interleukin-10 (IL-10) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker IL-10 will be compared between study arms.
16. Change in Interferon gamma-induced Protein 10 (IP-10) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker IP-10 will be compared between study arms.
17. Change in Macrophage Inflammatory Protein 1alpha (MIP-1a) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker MIP-1a will be compared between study arms.
18. Change in Monocyte Chemoattractant Protein-1 (MCP-1) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker MCP-1 will be compared between study arms.
19. Change in Granulocyte Colony-stimulating Factor (G-CSF) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker G-CSF will be compared between study arms.
20. Change in Tumor Necrosis Factor (TNF)-alpha [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the inflammatory serum biomarker TNF-alpha will be compared between study arms.
21. Change in Vasoactive Intestinal Peptide (VIP) [ Time Frame: Weeks 1, 2, and 4 ]
    VIP is a peptide hormone with immunosuppressive properties. Mean levels VIP will be compared between study arms.
22. Change in Gene Expression Profile of Regulatory T Cells (Tregs) [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of the Tregs will be compared between study arms.
23. Change in Gene Expression Profile of cluster of differentiation 8 (CD8)+Interferon Gamma (IFNg)+ Granulocyte-macrophage colony-stimulating factor (GM-CSF)+ [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of CD8+IFNg+GM-CSF+ will be compared between study arms.
24. Change in Gene Expression Profile of CD8+ T cell immunoglobulin and mucin domain-containing protein 3 (Tim3)+ Programmed cell death protein 1 (PD-1)+ [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of CD8+Tim3+PD-1+ will be compared between study arms.
25. Change in Gene Expression Profile of cluster of differentiation 14 (CD14)+ cluster of differentiation (CD16)+ monocytes [ Time Frame: Weeks 1, 2, and 4 ]
    Mean levels of CD14+CD16+ monocytes will be compared between study arms.
26. Change in Immunoglobulin G (IgG) Antibodies [ Time Frame: Week 4 ]
    Median titers of IgG antibodies to SARS-CoV-2 will be compared between study arms.
27. Overall Survival [ Time Frame: Up to Day 60 ]
    Overall survival is defined as days from randomization to death and censored at last follow up.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Georgia

Emory Saint Joseph's Hospital

Atlanta, Georgia, United States, 30308

Emory University Hospital Midtown

Atlanta, Georgia, United States, 30308

Emory University Hospital

Atlanta, Georgia, United States, 30322

Sponsors and Collaborators

Emory University

Verastem, Inc.

University of Pennsylvania

Investigators

• Principal Investigator: Edmund Waller, MD, PhD; Emory University

More Information

• Responsible Party: Edmund Waller, Professor, Emory University
• ClinicalTrials.gov Identifier: NCT04487886
• Other Study ID Numbers: STUDY00000701
• First Posted: July 27, 2020
• Last Update Posted: June 14, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The researchers plan to share individual participant data including participant status ordinal score at baseline and end of treatment, study drug allocation, duration of treatment, and survival status at Day 60.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Data will be made available for sharing at the conclusion of the study and will be available for one year.
• Access Criteria: Data will be available for sharing with academic or pharmaceutical investigators for analyses including comparison of DAMPEN-CI results with those from other drug trials in similar patient cohorts. Researchers wishing to use data should email the investigators of DAMPEN-Cl. A summary of the research plan will be required prior to release of the DAMPEN-CI data.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Edmund Waller, Emory University:

SARS-CoV-2

Additional relevant MeSH terms:

COVID-19; Pneumonia; Coronavirus Infections; Infections; Respiratory Tract Infections; Pneumonia, Viral; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases