Safety and Efficacy of Venetoclax in Idiopathic Pulmonary Fibrosis

March 27, 2024 updated by: A. Brent Carter, MD, University of Alabama at Birmingham
Based on preclinical data, investigators hypothesize that apoptosis resistance in monocyte-derived macrophages (MDMs) have a decisive role in the development of idiopathic pulmonary fibrosis (IPF). Specifically, macrophages from subjects with IPF have increased expression of Bcl-2 in mitochondria. In preclinical models of IPF, a conditional deletion of Bcl-2 in MDMs reverses established fibrosis by inducing apoptosis. Additional evidence to suggest that Bcl-2 expression in MDM mitochondria is a therapeutic target for IPF as administration of the Bcl-2 inhibitor, ABT-199 (Venetoclax), showed marked efficacy in preclinical models of IPF by inducing apoptosis of MDMs and reversing established fibrosis. ABT-199 is an orally available mimetic of the BH3 domain of Bcl-2, which is the domain the anchors Bcl-2 in the mitochondria to inhibit apoptosis. ABT-199 has shown therapeutic efficacy and good safety and tolerability in patients with chronic lymphocytic leukemia. Investigators anticipate that treatment with ABT-199 could result in significant benefit for IPF patients that have a life expectancy of 3-5 years. As there is no curative therapy for IPF, this clinical trial has the potential to substantially alter treatment approaches in patients with IPF.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

3

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: A. Brent Carter, MD
  • Phone Number: (205) 934-5018
  • Email: BCARTER1@UAB.EDU

Study Contact Backup

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • UAB
      • Birmingham, Alabama, United States, 35214
        • TKC

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age between 40-85 years old, male and female.
  2. A diagnosis of IPF that fulfills current ATS/ERS Consensus Criteria (1).
  3. IPF duration <5 years, based on the date of definitive diagnosis.
  4. Ability and willingness to give informed consent and adhere to study requirements.
  5. Forced Vital Capacity (FVC) > 50% predicted values.

Exclusion Criteria:

  1. Diagnosis of major comorbidities expected to interfere with study participation.
  2. History of malignancy within the last 5 years, excluding basal or squamous cell skin cancer.
  3. The occurrence of any acute infection requiring systemic antibiotic therapy within 2 weeks prior to Screening (Visit 1).
  4. Treatment for >14 days within the preceding month with >20 mg. prednisone (or equivalent) or any treatment during the last month with a cellular immunosuppressant (e.g., cyclophosphamide, methotrexate, calcineurin inhibitors, azathioprine, etc.), given increased risks of opportunistic infections.
  5. Concurrent participation in other experimental trials.
  6. Fertile women who do not agree to abstinence or an effective form of contraception (as approved by the investigator), or who are breast feeding, for 4 weeks before randomization until 90 days after the last administration of study medication (or placebo).
  7. Men who are not surgically sterile and do not agree to remain abstinent from heterosexual intercourse or use effective contraception (as approved by the investigator), and refrain from donating sperm, from the time of giving informed consent until 90 days after the last administration of study medication (or placebo).
  8. Subjects with known hypersensitivity to capsule "bulking" agents.
  9. A history of bone marrow disorder including aplastic anemia, or marked anemia defined as hemoglobin < 10.0 g/dL (or 6.2 mmol/L).
  10. Severe cardiovascular disease, defined as any of the following within the preceding 12 weeks: acute myocardial infarction or unstable angina, a coronary revascularization procedure, congestive heart failure (NYHA Class III or IV), or stroke, including a transient ischemic attack.
  11. Evidence of cardiac conducting abnormalities, defined as second- or third-degree AV block not successfully treated with a pacemaker, or a personal or family history of long QT syndrome (QTc interval >450 msec for males or 470 msec for females).
  12. End-stage renal disease requiring dialysis.
  13. Undergoing transplantation evaluation or listed with the United Network for Organ Sharing (UNOS) as a lung transplantation candidate at the time of enrollment in this trial.
  14. Liver function tests (transaminases, alkaline phosphatase, direct and total bilirubin) >2x upper limit of normal values.
  15. Systemically administered potent CYP3A4 inhibitors or inducers are prohibited during the 24-week treatment period.

Inhibitors include: pirfenidone, boceprevir, cobicistat, conivaptan, ritonavir, itraconazole, ketoconazole, telaprevir, troleandomycin, voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir.

Inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: treatment
Venetoclax 100 mg daily for 3 weeks
Drug: Venetoclax
100 mg daily by mouth for 3 weeks This drug inhibits a protein (Bcl-2) that protects cells from undergoing programmed cell death.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with treatment-related adverse events as assessed by measuring liver function.
Time Frame: 3 weeks
complete metabolic panel
3 weeks
Number of participants with treatment-related adverse events as assessed by measuring blood counts.
Time Frame: 3 weeks
complete blood count
3 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of monocyte-derived macrophages that undergoing apoptosis.
Time Frame: 3 weeks
flow cytometry
3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Alabama at Birmingham

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2023

Primary Completion (Actual)

March 18, 2024

Study Completion (Actual)

March 20, 2024

Study Registration Dates

First Submitted

July 26, 2023

First Submitted That Met QC Criteria

August 3, 2023

First Posted (Actual)

August 4, 2023

Study Record Updates

Last Update Posted (Actual)

March 28, 2024

Last Update Submitted That Met QC Criteria

March 27, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB-300010757

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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