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

Inclusion Criteria:

1. Male or female patients over 18 years of age.

• Women must be either postmenopausal (i.e., amenorrhea for at least 1 year), orsurgically or naturally sterile.

• Women of childbearing potential must have a negative pre-treatment pregnancy testand use a reliable method of contraception during study treatment and for atleast 3 months after study treatment termination.

2. IPF proven diagnosis < 3 years documented according to ATS/ERS internationalmultidisciplinary consensus, with or without surgical (thoracoscopic or open) chestlung biopsy

3. Duration of illness ≥ 3 months.

4. Six-minute walk test distance (limited by dyspnea) ≥ 150 meters and < 500 meters

5. Patients who have signed the informed consent form prior to initiation of any studyprocedure.

Exclusion Criteria:

1. Interstitial lung disease due to conditions other than IPF, including but not limitedto radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans withorganizing pneumonia, and cancer.

2. History of clinically significant environmental exposure known to cause pulmonaryfibrosis (drugs, asbestos, beryllium, radiation, domestic birds, etc.).

3. Severe concomitant illness limiting life expectancy (< 1 year).

4. FVC ≥ 90% predicted.

5. Severe restrictive lung disease: FVC < 50% predicted or FVC < 1.2 l, or DLco < 30%predicted or residual volume ≥ 120% predicted.

6. Severe obstructive lung disease: FEV1/FVC< 0.65.

7. Documented improvement of patient's condition within 12 months prior to randomizationwith or without IPF-specific therapy (e.g., corticosteroids, immunosuppressive,cytotoxic or antifibrotic drugs, TNFa blocker, interferon g).

8. Recent pulmonary or upper respiratory track infection (within 4 weeks ofrandomization).

9. PaO2 < 55 mm Hg (sea level) or 50 mm Hg (altitude) at rest on room air.

10. Echocardiographic evidence of severe pulmonary hypertension (PH): systolic pulmonarypressure ≥ 50 mm Hg or tricuspid regurgitation velocity ≥ 3.2 m/sec (unless severe PHis invalidated by a right heart catheterization). If the pulmonary pressure is notquantifiable, presence of significant right ventricular enlargement or hypertrophy orright ventricular dysfunction.

11. Severe chronic heart failure, e.g., NYHA class III or IV and/or left ventricularejection fraction < 25%.

12. Acute or chronic impairment (other than dyspnea) limiting the ability to comply withstudy requirements, e.g., the 6MWT or the PFTs.

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

13. Baseline values of liver transaminases, i.e., aspartate aminotransferases (AST) and/oralanine aminotransferases (ALT) > 3 times the upper limit of normal ranges.

14. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.

15. Serum creatinine ≥ 2.5 mg/dl (221 mmol/l) or dialysis.

16. Hemoglobin concentration < 75% the lower limit of normal ranges.

17. Systolic blood pressure < 85 mm Hg.

18. Pregnancy or breast-feeding.

19. Current drug or alcohol dependence.

20. Smoker (≥ 5 cigarettes per day) or former smoker (≥ 5 cigarettes per day) havingstopped less than 6 months prior to randomization.

21. Recently started (< 8 weeks from Screening visit) or planned cardio-pulmonaryrehabilitation program based on exercise.

22. Treatment with oral corticosteroids (> 15 mg/day prednisone or equivalent),immunosuppressive, cytotoxic or antifibrotic drugs such as TNF alpha blocker, orinterferon gamma within 4 weeks of randomization.within 4 weeks of randomization.

23. Treatment with glibenclamide (glyburide), cyclosporine A or tacrolimus within 1 weeksof randomization.

24. Treatment with an endothelin receptor antagonist within 3 months of randomization.

25. Treatment within 3 months of randomization or planned treatment with anotherinvestigational drug.

26. Known hypersensitivity to bosentan or any of the excipients.