Macitentan Use in an Idiopathic Pulmonary Fibrosis Clinical Study

The AC-055B201/MUSIC study is a Phase II study, comparing one dose of ACT-064922 (macitentan) 10 mg with placebo in patients with idiopathic pulmonary fibrosis (IPF). The main study objective is to demonstrate that macitentan positively affects the forced vital capacity (FVC) in comparison with placebo in patients with idiopathic pulmonary fibrosis (IPF).

The secondary objectives are to evaluate the effect of macitentan on the time to disease worsening or death in patients with IPF, and to evaluate the benefit/risk profile of macitentan in the treatment of patients with IPF.

The study included two treatment periods: Period 1 (fixed duration) from randomization up to the primary endpoint evaluation (Month 12 or earlier in case of premature discontinuation of study drug) and Period 2 (variable duration) from the primary endpoint evaluation visit up to the end of study (EOS). EOS occurred when the last patient randomized and not prematurely discontinued completed Period 1.

Eligibility Criteria:
Inclusion Criteria:

1. Signed informed consent.
2. Male or female patients of at least 18 years of age (females of child-bearing potential must use a reliable method of contraception).
3. IPF diagnosis within 3 years prior to randomization, proven according to the American Thoracic Society/European Respiratory Society consensus conference criteria, with surgical lung biopsy.

Exclusion Criteria:

1. Interstitial lung disease due to conditions other than IPF.
2. Presence of extensive honeycombing on Baseline high-resolution computed tomography (HRCT) scan performed within 3 months prior to randomization.
3. Severe concomitant illness limiting life expectancy (\< 1 year).
4. Severe restrictive lung disease: forced vital capacity (FVC) \< 50% predicted, or FVC \< 1.2 liter.
5. Diffusing capacity of the lung for carbon monoxide (DLCO) \< 30% predicted.
6. Residual volume ≥ 120% predicted.
7. Obstructive lung disease: forced expiratory volume in 1 second (FEV1)/FVC) \< 0.70.
8. Documented sustained improvement of the patient's IPF condition up to 12 months prior to randomization with or without IPF-specific therapy.
9. Recent pulmonary or upper respiratory tract infection (up to 4 weeks prior to randomization).
10. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests).
11. Chronic heart failure with New York Heart Association class III/IV or known left ventricular ejection fraction \< 25%.
12. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
13. Estimated creatinine clearance \< 30 mL/min.
14. Aspartate aminotransferase (AST) and/or alanine aminotransferase \> 1.5 x upper limit of normal.
15. Hemoglobin \< 75% of the lower limit of the normal range.
16. Systolic blood pressure \< 100 mmHg.
17. Pregnant or breast-feeding.
18. Current drug or alcohol dependence.
19. Chronic treatment with the following drugs (within 4 weeks of randomization):

    * Oral corticosteroids (\> 20 mg/day of prednisone or equivalent),
    * Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine,
    * Antifibrotic drugs including pirfenidone, D penicillamine, colchicine, tumor necrosis factor α blockers, imatinib and interferon γ,
    * Chronic use of N-acetylcysteine prescribed for IPF (\> 600 mg/day).
    * Oral anticoagulants prescribed for IPF.
20. Treatment with endothelin receptor antagonists within 4 weeks prior to randomization.
21. Systemic treatment within 4 weeks prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).
22. Treatment with Cytochrome P450 3A inducers within 4 weeks prior to randomization.
23. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
24. Planned treatment, or treatment with another investigational drug within 4 weeks prior to randomization.