Oral Ifetroban in Patients With Idiopathic Pulmonary Fibrosis (IPF)

This is an interventional treatment trial for Idiopathic Pulmonary Fibrosis Read More

Inclusion Criteria:

1. Male or female age 18 years or older

2. Patients with physician diagnosed ILD of known or unknown etiology other than IPF who have radiological evidence of progressive pulmonary fibrosis (PPF). PPF is defined as at least two of the following three criteria occurring within the past year with no alternative explanation, as assessed by the investigator despite approved/unapproved* medications used in clinical practice to treat ILD:

   1. Worsening respiratory symptoms
   2. Physiological evidence of disease progression (either of the following):

   i. Absolute decline in FVC ⩾5% predicted within 1 year of follow-up ii. Absolute decline in DLCO (corrected for Hb) ⩾10% predicted within 1 year of follow-up c. Radiological evidence of disease progression (one or more of the following): i. Increased extent or severity of traction bronchiectasis and bronchiolectasis ii. New ground-glass opacity with traction bronchiectasis iii. New fine reticulation iv. Increased extent or increased coarseness of reticular abnormality v. New or increased honeycombing vi. Increased lobar volume loss Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Although it is critical to exclude alternative explanations of worsening features for all patients with suspected progression, this is particularly important in patients with worsening respiratory symptoms and/or decline in DLCO given the lower specificity of these features for PPF compared with FVC and chest CT.

   *Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus.

   OR

   Idiopathic Pulmonary Fibrosis (IPF) satisfying the 2022 American Thoracic Society/European Respiratory Society /Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) diagnostic criteria (Raghu 2022);

3. For patients with underlying Connective Tissue Disease (CTD): stable CTD defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to Day 0
4. If receiving antifibrotic agents pirfenidone or nintedanib, patients must be receiving a stable dosage for ≥ 3 months prior to screening and Day 0; if not receiving pirfenidone or nintedanib, patients must be naive to both drugs or not have received either 4 weeks prior to Day 0.
5. If receiving immunosuppressive therapy (ie, mycophenolate mofetil, mycophenolic acid, azathioprine and/or tacrolimus), dosage must be stable 6 months prior to screening; these immunosuppressive medications cannot be initiated nor modified during the main study.
6. FVC ≥ 40% of predicted normal according to Global Lung Initiative (GLI) (Appendix 15.1)
7. Diffusion Capacity of Carbon Monoxide (DLCO) [corrected for hemoglobin] ≥ 25% (Appendix 15.1)

Exclusion Criteria:

1. Relevant airways obstruction (pre-bronchodilator Forced Expiratory Volume in one second (FEV1)/Forced Vital Capacity (FVC) < 0.7) (GLI 2012)
2. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
3. Other investigational therapy received within 4 weeks or 6 half-lives (whichever is greater) before Day 0
4. AST or ALT > 1.5 x ULN, Bilirubin > 1.5 x ULN, Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula (Appendix 15.2)
5. Underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).

6. Cardiovascular diseases, any of the following:

   1. Severe hypertension, uncontrolled despite treatment (≥160/100 mmHg), within 6 months of Day 0
   2. Myocardial infarction within 6 months of Day 0
   3. Unstable cardiac angina within 6 months of Day 0

7. Bleeding risk, any of the following:

   a. Known genetic predisposition to bleeding. b. Patients who require c. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, direct oral anticoagulants, heparin, hirudin) d. High dose antiplatelet therapy (> 325 mg/day of aspirin; > 75 mg/day ticlodipine or clopidogrel; any dose of other 2b3a anti-platelet agents) e. History of hemorrhagic central nervous system (CNS) event within 12 months of Day 0 f. Any of the following within 3 months of Day 0: i. Hemoptysis or hematuria ii. Active gastro-intestinal (GI) bleeding or GI - ulcers iii. Major injury or surgery (Investigator's judgment). g. Coagulation parameters: International normalized ratio (INR) >2, prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x ULN

8. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Day 0
9. Use of systemic corticosteroids equivalent to prednisone >15mg/day within 2 weeks of Day 0.
10. Use of cyclophosphamide, cyclosporine, methotrexate and/or leflunomide within 4 weeks of Day 0.
11. Use of rituximab or other specific B-cell depleting therapies within 6 months of Day 0.
12. Initiation or change in dosing of mycophenolate mofetil, mycophenolic acid, azathioprine and/or tacrolimus within 6 months of screening; immunosuppressive medications cannot be initiated during the main study.
13. Initiation or change in dosing of disease-modifying antirheumatic drugs, including but not limited to hydroxychloroquine, sulfasalazine, anti-TNF alpha antagonists, interleukin antagonists, abatacept, tofacitinib and/or baricitinib within 6 months of screening.
14. Long-acting phosphodiesterase five inhibitors.
15. Simultaneous use of pirfenidone and nintedanib at screening.
16. Acute IPF/ILD exacerbation within 6 weeks prior to screening and/or during the screening period (investigator-determined).

17. Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:

    1. Previous clinical or echocardiographic evidence of right heart failure
    2. History of right heart catheterization showing a cardiac index ≤ 2 L/min/m²
    3. PAH requiring parenteral or inhaled therapy with epoprostenol/treprostinil
18. Lower respiratory tract infection requiring antibiotics within 4 weeks prior to Day 0 and/or during the screening period.
19. Major surgery (major according to the investigator's assessment) performed within 3 months prior to Day 0 or planned during the course of the trial. (Being on a transplant list is allowed).
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 or history of malignancy within 5 years prior to Day 0, except appropriately treated basal cell carcinoma of the skin, "under surveillance" prostate cancer or in situ carcinoma of uterine cervix.
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 SARS-CoV-2 within the 4 weeks prior to Day 0 and/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