Efficacy and Safety of Oral Bosentan in Patients With Idiopathic Pulmonary Fibrosis

Inclusion criteria

• Male or female patients over 18 years of age.

• Women must be either postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile.
• Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.
• IPF proven diagnosis < 3 years documented according to ATS/ERS international multidisciplinary consensus, with or without surgical (thoracoscopic or open) chest lung biopsy
• Duration of illness ≥ 3 months.
• Six-minute walk test distance (limited by dyspnea) ≥ 150 meters and < 500 meters
• Patients who have signed the informed consent form prior to initiation of any study procedure.

Exclusion criteria

• Interstitial lung disease due to conditions other than IPF, including but not limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans with organizing pneumonia, and cancer.
• History of clinically significant environmental exposure known to cause pulmonary fibrosis (drugs, asbestos, beryllium, radiation, domestic birds, etc.).
• Severe concomitant illness limiting life expectancy (< 1 year).
• FVC ≥ 90% predicted.
• Severe restrictive lung disease: FVC < 50% predicted or FVC < 1.2 l, or DLco < 30% predicted or residual volume ≥ 120% predicted.
• Severe obstructive lung disease: FEV1/FVC< 0.65.
• Documented improvement of patient's condition within 12 months prior to randomization with or without IPF-specific therapy (e.g., corticosteroids, immunosuppressive, cytotoxic or antifibrotic drugs, TNFa blocker, interferon g).
• Recent pulmonary or upper respiratory track infection (within 4 weeks of randomization).
• PaO2 < 55 mm Hg (sea level) or 50 mm Hg (altitude) at rest on room air.
• Echocardiographic evidence of severe pulmonary hypertension (PH): systolic pulmonary pressure ≥ 50 mm Hg or tricuspid regurgitation velocity ≥ 3.2 m/sec (unless severe PH is invalidated by a right heart catheterization). If the pulmonary pressure is not quantifiable, presence of significant right ventricular enlargement or hypertrophy or right ventricular dysfunction.
• Severe chronic heart failure, e.g., NYHA class III or IV and/or left ventricular ejection fraction < 25%.
• Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements, e.g., the 6MWT or the PFTs.

(e.g., angina pectoris, intermittent claudicating, chronic arthritis).

• Baseline values of liver transaminases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) > 3 times the upper limit of normal ranges.
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
• Serum creatinine ≥ 2.5 mg/dl (221 mmol/l) or dialysis.
• Hemoglobin concentration < 75% the lower limit of normal ranges.
• Systolic blood pressure < 85 mm Hg.
• Pregnancy or breast-feeding.
• Current drug or alcohol dependence.
• Smoker (≥ 5 cigarettes per day) or former smoker (≥ 5 cigarettes per day) having stopped less than 6 months prior to randomization.
• Recently started (< 8 weeks from Screening visit) or planned cardio-pulmonary rehabilitation program based on exercise.
• Treatment with oral corticosteroids (> 15 mg/day prednisone or equivalent), immunosuppressive, cytotoxic or antifibrotic drugs such as TNF alpha blocker, or interferon gamma within 4 weeks of randomization.within 4 weeks of randomization.
• Treatment with glibenclamide (glyburide), cyclosporine A or tacrolimus within 1 weeks of randomization.
• Treatment with an endothelin receptor antagonist within 3 months of randomization.
• Treatment within 3 months of randomization or planned treatment with another investigational drug.
• Known hypersensitivity to bosentan or any of the excipients.