Oral Ifetroban in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Overview

About this study

The purpose of this study is to determine if ifetroban prevents and treats lung fibrosis due to multiple causes (bleomycin, genetic, radiation). The safety and efficacy of oral ifetroban will be assessed in patients with IPF.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

1. Male or female age 40 years or older

2. IPF Diagnosis:

1. Satisfying the 2022 American Thoracic Society/European Respiratory Society
/Japanese Respiratory Society/Latin American Thoracic Association
(ATS/ERS/JRS/ALAT) diagnostic criteria (Raghu 2022) confirmed by the investigator

2. UIP or probable UIP based on chest HRCT obtained within 2 months of Day 0, or
historical lung biopsy consistent with UIP.

3. If receiving antifibrotic agents pirfenidone or nintedanib, patients must be receiving
a stable dose for ≥ 2 months prior to Day 0 and planning to stay on stable background
therapy; if not receiving pirfenidone or nintedanib, patients must be naive to both
drugs or not have received either for at least 4 weeks prior to Day 0 and remain off
background therapy with no intention to start or re-start (combination of nintedanib
and pirfenidone not allowed).

4. If receiving monotherapy for the treatment of pulmonary hypertension (e.g.
phosphodiesterase 5 inhibitors, endothelin receptor antagonists or inhaled or oral
prostanoid therapy), patients must be receiving a stable dose for ≥ 4 weeks prior to
Day 0 and planning to remain on a stable dose throughout the study.

5. FVC ≥ 40% of predicted normal according to Global Lung Initiative (GLI)

6. Diffusion Capacity of Carbon Monoxide (DLCO) [corrected for hemoglobin] ≥ 25% to <80%
of predicted normal

Exclusion Criteria:

1. Relevant airways obstruction (pre-bronchodilator Forced Expiratory Volume in one
second to forced vital capacity ratio less than 70% (FEV1/FVC < 0.7))

2. In the opinion of the Investigator, other clinically significant pulmonary
abnormalities.

3. Known significant PAH, defined as previous clinical or echocardiographic evidence of
significant right heart failure, history of right heart catheterization showing a
cardiac index < 2 L/min/m^2, or PAH requiring combination of PAH-specific therapies or
any PAH parenteral therapy.

4. Emphysema ≥ 50% on HRCT assessed by the investigator, or the extent of emphysema is
greater than the extent of fibrosis according to reported results from the most recent
chest HRCT.

5. Acute IPF exacerbation within 6 weeks prior to screening and/or during the screening
period (investigator-determined).

6. ILD associated with other known causes

7. Lower respiratory tract infection requiring antibiotics within 4 weeks prior to Day 0
and/or during the screening period.

8. Major surgery (major according to the investigator's assessment) performed within six
weeks prior to Day 0 or planned during the course of the trial. (Being on a transplant
list is allowed).

9. AST or ALT > 1.5 x ULN, Bilirubin > 1.5 x ULN, Creatinine clearance < 30 mL/min
calculated by Cockcroft-Gault formula.

10. Underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).

11. Cardiovascular diseases, any of the following:

1. Severe hypertension, uncontrolled despite treatment (≥ 160/100 mmHg)

2. Myocardial infarction within 6 months of Day 0

3. Unstable cardiac angina

12. Bleeding risk, any of the following:

a. Known genetic predisposition to bleeding;

b. Patients who require:

i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g., vitamin K antagonists, direct thrombin
inhibitors, direct oral anticoagulants, heparin, hirudin)

ii. High dose antiplatelet therapy (> 325 mg/day of aspirin; > 75 mg/day ticlodipine or clopidogrel; any dose of
other 2b3a anti-platelet agents)

13. History of hemorrhagic central nervous system (CNS) event within 12 months of Day 0

14. Any of the following within 3 months of Day 0:

1. Hemoptysis or hematuria

2. Active gastro-intestinal (GI) bleeding needing hospitalization/intervention or
peptic ulcer disease

15. Coagulation parameters: International normalized ratio (INR) >2, prolongation of
prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x ULN

Note: Prophylactic low dose heparin or heparin flush as needed for maintenance of an
indwelling intravenous device (e.g. less than or equal to enoxaparin 40 mg s.c. per
day or heparin 5000 units s.c. every 8 hours), as well as prophylactic use of
antiplatelet therapy (e.g. acetyl salicylic acid (ASA) up to 325 mg/day, or
clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy) are not
prohibited.

16. History of thrombotic event (including stroke and transient ischemic attack) within 12
months of Day 0

17. Use of disease-modifying antirheumatic drugs, B-cell depleting therapies or
immunosuppressive medications, within 6 months of Day 0.

18. Use of systemic corticosteroids equivalent to prednisone >15mg/day within 2 weeks of
Day 0.

19. Simultaneous use of pirfenidone and nintedanib at screening.

20. Other disease that may interfere with testing procedures or in the judgment of the
Investigator may interfere with trial participation or may put the patient at risk
when participating in this trial.

21. Any documented active or suspected malignancy within 5 years prior to Day 0, except
appropriately treated basal cell carcinoma of the skin, in situ squamous cell
carcinoma of the skin or "under surveillance" prostate cancer.

22. Evidence of active infection (chronic or acute) based on clinical exam or laboratory
findings.

23. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt,
aborted attempt, or preparatory acts or behavior).

24. The patient has a confirmed infection with Severe Acute Respiratory Syndrome-
Coronvirus-2 (SARS-CoV-2) within the 4 weeks prior to Day 0 or during the screening
period.

25. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.

26. Women of childbearing potential* not willing or able to use highly effective methods
of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per
year when used consistently for 28 days prior to and 3 months after IMP
administration.

27. In the opinion of the Investigator, active alcohol or drug abuse.

28. Patients not able to understand or follow trial procedures including completion of
self- administered questionnaires without help.

- A woman is considered of childbearing potential, i.e. fertile, following menarche
and until becoming post-menopausal unless permanently sterile. Permanent
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral
oophorectomy

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/14/23. Questions regarding updates should be directed to the study team contact.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Jacksonville, Fla.

Mayo Clinic principal investigator

Augustine Lee, M.D.

Open for enrollment

Contact information:

Jennifer Singh

(904) 953-5061

Singh.Jennifer@mayo.edu

More information

Publications

  • Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated. On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane-prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling. We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We used TBXA2R-deficient mice and small-molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models. TBXA2R expression was upregulated in fibroblasts in the lungs of patients with IPF and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting that an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes, which are nonenzymatic products of arachidonic acid induced by reactive oxygen species, were persistently elevated during fibrosis. F2-isoprostanes induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-β (transforming growth factor-β) signaling. treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment. TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis. Read More on PubMed