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    Summary
    EudraCT Number:2008-006054-17
    Sponsor's Protocol Code Number:AC-055B201
    National Competent Authority:Slovenia - JAZMP
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-04-06
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSlovenia - JAZMP
    A.2EudraCT number2008-006054-17
    A.3Full title of the trial
    A double-blind, randomized, placebo-controlled, multicenter, parallel group study to evaluate the efficacy, safety, and tolerability of macitentan in patients with idiopathic pulmonary fibrosis
    A.3.2Name or abbreviated title of the trial where available
    MUSIC
    A.4.1Sponsor's protocol code numberAC-055B201
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorActelion Pharmaceuticals Ltd.
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMacitentan
    D.3.2Product code ACT-064992
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMacitentan
    D.3.9.1CAS number 441798-33-0
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    To evaluate the efficacy, safety, and tolerabilitiy of macitentan in patients with idiopathic pulmonary fibrosis.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10021240
    E.1.2Term Idiopathic pulmonary fibrosis
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective
    To demonstrate that macitentan positively affects the Forced Vital Capacity (FVC) in comparison with placebo in patients with idiopathic pulmonary fibrosis (IPF).
    E.2.2Secondary objectives of the trial
    Secondary Objectives
    • To evaluate the effect of macitentan on the time to disease worsening or death in patients with IPF.
    • To evaluate the safety and tolerability of macitentan in this patient population.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent.
    2. Male or female patients over 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 ATS/ERS consensus statement, with surgical lung biopsy.
    E.4Principal exclusion criteria
    1. Interstitial lung disease due to conditions other than IPF.
    2. Presence of extensive honeycombing (HC) on Baseline high-resolution computed tomography (HRCT) scan performed within 3 months prior to randomization.
    The patient is not allowed in the study if HC involves more than 5 % of the parenchyma in 3 or more of the 6 zones (i.e., right and left lung, viewed at the levels of tracheal carina, inferior pulmonary veins, and 1 cm above the dome of the diaphragm), whether the involvement is unilateral or bilateral.
    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/forced vital capacity (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 NYHA 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. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the 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, TNFα blocker, imatinib and interferon γ,
    - Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day).
    20. Oral anticoagulants other than those indicated for a venous or
    arterial thrombotic disease within 4 weeks prior to randomization.
    21. Treatment with endothelin receptor antagonists (ERAs) within 4 weeks prior to randomization.
    22. Previous participation in the BUILD-3 (Bosentan Use in Interstitial Lung Disease) study within 6 months prior to randomization.
    23. Systemic treatment within 4 weeks prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mTOR inhibitors).
    24. Treatment with CYP3A inducers within 4 weeks prior to randomization.
    25. Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
    26. Planned treatment, or treatment, with another investigational drug within 4 weeks prior to randomization.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint
    Change from baseline to end of Period 1 in Forced Vital Capacity (FVC).
    A mean difference from placebo of at least 0.1 liter is to be detected. This parameter is expected to be normally distributed with a standard deviation of 0.2 liter.
    Secondary Endpoint
    Time to occurrence of disease worsening or death up to EOS.
    Disease worsening is defined as (i) worsening of PFTs or (ii) acute respiratory decompensation of IPF.
    (i) Worsening of PFTs (confirmed by two tests at least 4 weeks apart) is defined as the occurrence of both:
     Decrease from baseline ≥ 10% in FVC (absolute values, i.e., liters)
    and
     Decrease from baseline ≥ 15% in DLCO (absolute values, i.e., ml•mmHg-1•min-1)
    A patient unable to perform PFTs at a planned visit due to worsening of IPF will be considered as having a worsening of PFTs if this is not invalidated by a test at a follow-up visit.
    (ii) Acute respiratory decompensation of IPF is defined as:
    An unexplained rapid deterioration of patient’s condition within 4 weeks with an increasing shortness of breath requiring oxygen supplementation ≥ 5 liters/min to maintain a resting SaO2 ≥ 90% or PaO2 ≥ 55 mmHg (sea level) or 50 mmHg (high altitude).
    A documented acute respiratory decompensation of IPF will be considered to be an event, irrespective of the results of any follow-up PFTs or fatal outcome.
    Patients who are transplanted (without a prior documented disease worsening), or who withdraw their consent, or those lost to follow-up before the EOS will be censored.
    Patients starting forbidden IPF medications (without prior documented disease worsening as defined above) will not be considered as having IPF worsening.
    Exploratory endpoints
    • Time to death (all causes) up to End-of-Study.
    • Time to occurrence of disease worsening up to EOS.
    • Proportion of patients who experienced either disease worsening or death at End-of-Period 1.
    • Transition dyspnea index (TDI) at End-of-Period 1 and EOS.
    • Proportion of patients who improve in TDI with at least 1 unit at End-of-Period 1 and EOS.
    • Change from baseline to 4 months, 8 months, End-of-Period 1, EOT and EOS in PFTs (FEV1, FVC, DLCO).
    • Change from Baseline to Month 4, End-of-Period 1, EOT and EOS in Quality of Life assessed by the SF-36 questionnaire (individual domains and summary component scores).
    • Change from Baseline to Month 4, End-of-Period 1, EOT and EOS in the Composite Physiologic Index (CPI)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The EOS will occur when the last randomized patient, not prematurely withdrawn, will have completed the
    Period 1 plus 1 year.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 64
    F.4.2.2In the whole clinical trial 156
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    For patients who complete the study as scheduled and for whom treatment with macitentan could be beneficial, participation in an open-label extension study (independent protocol) will be considered.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-03-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-05-31
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