Clinical trial NCT05571059: Oral Ifetroban in Patients With Idiopathic Pulmonary Fibrosis (IPF)
Official title: A Randomized, Double-Blind, Placebo-Controlled Phase II Study to Determine the Safety and Efficacy of Oral Ifetroban in Patients With Idiopathic Pulmonary Fibrosis (IPF)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Lead sponsor: Cumberland Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2022-10-07
Enrollment: 128
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Double-Blind, Placebo-Controlled
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: This is a multicenter, prospective, randomized, placebo-controlled, phase II study to determine the safety and efficacy of oral ifetroban compared to placebo in subjects with IPF. Patients who meet the inclusion criteria and none of the exclusion criteria will receive oral ifetroban or placebo once daily for 12 months. Subjects will be randomly assigned to one of two oral treatment groups: ifetroban or placebo and block randomized by background therapy. All subjects who receive treatment will be assessed for safety. All subjects with at least one efficacy assessment post-baseline will be evaluated for efficacy. Blood and urine will be collected for standard and novel PPF biomarkers.

Eligibility criteria: 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/m2, 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:

    1. Known genetic predisposition to bleeding.
    2. 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 subcutaneously (SC) per day or heparin 5000 units SC every eight hours), low-dose FXa inhibitors (rivaroxaban/apixaban: 2.5mg twice daily (max 5mg/day), edoxaban: 15mg/day), 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. The patient has a confirmed infection with Severe Acute Respiratory Syndrome- Coronvirus-2 (SARS-CoV-2) within the four weeks prior to Day 0 or during the screening period.
24. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
25. 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 three months after Investigational Medicinal Product (IMP) administration.

    Note: 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
26. In the opinion of the Investigator, active alcohol or drug abuse.
27. Patients not able to understand or follow trial procedures including completion of self- administered questionnaires without help.

Primary outcomes:
measure: Change from baseline in Forced Vital Capacity (FVC) in mL
timeFrame: Baseline through 12 months
Secondary outcomes:
measure: Time to the first occurrence of any of the components of the composite endpoint: time to first acute IPF exacerbation, first hospitalization for respiratory cause, or death
timeFrame: Baseline through 12 months
measure: Time to first acute IPF exacerbation or death
timeFrame: Baseline through 12 months
measure: Proportion of patients with acute exacerbations of lung fibrosis
timeFrame: Baseline through 12 months
measure: Time to hospitalization for respiratory cause or death
timeFrame: Baseline through 12 months
measure: Change from baseline in quality of life (SOBQ)
timeFrame: Baseline through 12 months
measure: Change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea domain score
timeFrame: Baseline through 12 months
measure: Change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Cough domain score
timeFrame: Baseline through 12 months
measure: Change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Fatigue domain score
timeFrame: Baseline through 12 months
measure: Time to death
timeFrame: Baseline through 12 months
measure: Incidence of Treatment Emergent Adverse Events (safety & tolerability)
timeFrame: Baseline through 12 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami
country: United States
facility: Miami VA Health System
state: Florida
city: Chicago
country: United States
facility: Northwestern Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Royal Oak
country: United States
facility: Beaumont Hospital, Royal Oak
state: Michigan
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Bend
country: United States
facility: Bend Memorial Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Research Institute
state: South Dakota
city: Dickson
country: United States
facility: Pulmonary & Sleep Specialists
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Denison
country: United States
facility: Premier Pulmonary Critical Care and Sleep Medicine
state: Texas
Study officials:
affiliation: Cumberland Pharmaceuticals
name: Todd Rice, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Suzuki T, Kropski JA, Chen J, Carrier EJ, Chen X, Sherrill TP, Winters NI, Camarata JE, Polosukhin VV, Han W, Rathinasabapathy A, Gutor S, Gulleman P, Sabusap C, Banovich NE, Tanjore H, Freeman ML, Tada Y, Young LR, Gokey JJ, Blackwell TS, West JD. Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis. Am J Respir Crit Care Med. 2022 Sep 1;206(5):596-607. doi: 10.1164/rccm.202106-1503OC.