Macitentan Use in an Idiopathic Pulmonary Fibrosis Clinical Study

Phase 2

Completed

• Conditions: Idiopathic Pulmonary Fibrosis
• Interventions: Drug: ACT-064992 (macitentan); Drug: Placebo

• Registration Number: NCT00903331
• Lead Sponsor: Actelion

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2009-05
• Study First Submitted: 2009-05-14
• Study First Submitted QC: 2009-05-15
• Study First Posted: 2009-05-18
• Primary Completion: 2011-06
• Study Completion: 2011-08
• Disposition First Submitted: 2012-09-27
• Disposition First Submitted QC: 2012-09-27
• Disposition First Posted: 2012-10-01
• Results First Submitted: 2013-10-29
• Status Verified: 2014-01
• Results First Submitted QC: 2014-01-02
• Last Update Submitted: 2014-01-02
• Results First Posted: 2014-02-17
• Last Update Posted: 2014-02-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 178

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ACT-064922	ACT-064992 (macitentan)	ACT-064922 tablet (macitentan), 10 mg, once daily
Placebo	Placebo	Matching placebo, once daily

Primary Outcome Measures

Name	Time	Method
Forced Vital Capacity (FVC) at Baseline and End of Period 1	12 months	FVC was measured at baseline and at the end of Period 1. The same equipment and tester were used during the course of the study. The equipment was calibrated and the calibration documented prior to each patient's measurement. The person responsible for conducting the pulmonary function tests was required to comply with the study guidelines and the American Thoracic Society/European Respiratory Society joint criteria on lung function testing.

Secondary Outcome Measures

Name	Time	Method
Number of Patients at Risk of Event of Disease Worsening or Death up to the End of Study	Up to end of study (Up to 24 months)	Disease worsening was indicated by pulmonary function test/idiopathic pulmonary fibrosis worsening (PFT/IPF) or acute respiratory decompensation of IPF.; PFT/IPF worsening was indicated by the occurrence of both of the following: confirmed by two tests at least 4 weeks apart, as defined by the occurrence of both of the following: decrease from baseline ≥ 10% in forced vital capacity and decrease from baseline ≥ 15% in corrected diffusing capacity of the lung for carbon monoxide.; Acute respiratory decompensation of IPF was defined as an unexplained rapid deterioration (over a period of less than 4 weeks) of the patient's condition with increasing shortness of breath requiring oxygen supplementation ≥ 5 L/min to maintain a resting oxygen saturation ≥ 90% or arterial oxygen pressure ≥ 55 mmHg (sea level) or 50 mmHg (high altitude).

Trial Locations

Locations (53)

St. Paul's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

Stanford University Medical Center - Chest Clinic; 🇺🇸 Stanford, California, United States

The Alfred Hospital; 🇦🇺 Melbourne, Australia

St. Vincent's Public Hospital; 🇦🇺 Darlinghurst, Australia

Hopital Avicenne; 🇫🇷 Bobigny, France

Prince Charles Hospital Lung Transplant; 🇦🇺 Chermside, Australia

Baylor College of Medicine - Baylor Clinic; 🇺🇸 Houston, Texas, United States

Ospedale di Cattinara; 🇮🇹 Trieste, Italy

Rabin Medical Center, Beilinson Hospital; 🇮🇱 Petach Tikvah, Israel

Kaplan Medical Center; 🇮🇱 Rehovot, Israel

Justus-Liebig-Universität Gießen; 🇩🇪 Giessen, Germany

Yale University School of Medicine; 🇺🇸 New Haven, Connecticut, United States

U.C. Davis University of California; 🇺🇸 Sacramento, California, United States

St. Luke's Medical Group; 🇺🇸 Chesterfield, Missouri, United States

Helios Klinikum Emil von Behring; 🇩🇪 Berlin, Germany

University of Alberta - Health Sciences Center; 🇨🇦 Edmonton, Alberta, Canada

Ludwig-Maximilian-Universität München; 🇩🇪 Munchen, Germany

Hospital Notre-Dame du CHUM; 🇨🇦 Montreal, Quebec, Canada

Tel-Aviv Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

Hôpital Cardiologique et Pneumologique Louis Pradel; 🇫🇷 Bron, France

Kelowna General Hospital; 🇨🇦 Kelowna, British Columbia, Canada

Ospedale San Giuseppe Milanocuore; 🇮🇹 Milan, Italy

Università degli Studi di Torino Clinica di Malattie dell'Apparato Respiratorio; 🇮🇹 Orbassano, Italy

A.O.U Policlinico Tor Vergata; 🇮🇹 Roma, Italy

Mayo Clinic - Arizona; 🇺🇸 Scottsdale, Arizona, United States

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Pulmonary Associates, P.A.; 🇺🇸 Phoenix, Arizona, United States

UCSD Pulmonary Critical Care; 🇺🇸 San Diego, California, United States

University of California - San Francisco; 🇺🇸 San Francisco, California, United States

The Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

Temple University Hospital - Lung Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Royal Perth Hospital; 🇦🇺 Perth, Australia

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada

St. Joseph's Healthcare; 🇨🇦 Hamilton, Ontario, Canada

CHRU - Hopital Calmette Clinique des Maladies Respiratoires; 🇫🇷 Lille, France

Universität zu Köln; 🇩🇪 Koln, Germany

Fachklinik fur Lungenerkrankungen; 🇩🇪 Immenhausen, Germany

Bolnišnica Golnik; 🇸🇮 Golnik, Slovenia

Hadassah Ein Kerem Medical Center; 🇮🇱 Jerusalem, Israel

The Chaim Sheba Medical Center; 🇮🇱 Tel Hashomer, Israel

Centre for Chest Diseases, Milpark Hospital; 🇿🇦 Johannesburg, South Africa

Hospital Clinic I Provincial de Barcelona; 🇪🇸 Barcelona, Spain

Pretoria East Hospital; 🇿🇦 Pretoria, South Africa

Hospital General Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Clinico San Carlos; 🇪🇸 Madrid, Spain

Ege University School of Medicine; 🇹🇷 Izmir, Turkey

Hospital Universitario Ramón y Cajal; 🇪🇸 Madrid, Spain

Karolinska Universitetssjukhuset Lung Allergi kliniken; 🇸🇪 Stockholm, Sweden

Ankara University School of Medicine; 🇹🇷 Ankara, Turkey

Fundación Hospital Alcorcón; 🇪🇸 Madrid, Spain

Wichita Clinic P.A; 🇺🇸 Wichita, Kansas, United States

National Jewish Medical & Research Center; 🇺🇸 Denver, Colorado, United States

University of Wisconsin - Madison; 🇺🇸 Madison, Wisconsin, United States