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    Summary
    EudraCT Number:2014-004066-20
    Sponsor's Protocol Code Number:AC-055-403
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-03-09
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-004066-20
    A.3Full title of the trial
    A prospective, multicenter, single-arm, open-label, phase 4 study to evaluate the effects of macitentan on Right vEntricular remodeling in Pulmonary ArterIal hypeRtension assessed by cardiac magnetic resonance imaging
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of the effects of macitentan on the heart in patients with elevated blood pressure in blood vessels of the lungs.
    A.3.2Name or abbreviated title of the trial where available
    REPAIR: Right vEntricular remodeling in Pulmonary ArterIal hypeRtension
    A.4.1Sponsor's protocol code numberAC-055-403
    A.7Trial is part of a Paediatric Investigation Plan No
    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 supportActelion Pharmaceuticals Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationActelion Pharmaceuticals Ltd.
    B.5.2Functional name of contact pointGlobal Medical Affairs
    B.5.3 Address:
    B.5.3.1Street AddressGewerbestrasse 16
    B.5.3.2Town/ cityAllschwil
    B.5.3.3Post code4123
    B.5.3.4CountrySwitzerland
    B.5.6E-maillperchen@its.jnj.com
    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 Yes
    D.2.1.1.1Trade name Opsumit
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/11/909
    D.3 Description of the IMP
    D.3.1Product namemacitentan
    D.3.2Product code ACT-064992
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    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.3.9.2Current sponsor codeACT-064992
    D.3.9.4EV Substance CodeSUB89247
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary Arterial Hypertension
    E.1.1.1Medical condition in easily understood language
    Elevated blood pressure in blood vessels in the lungs.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension.
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of macitentan in patients with symptomatic pulmonary arterial hypertension.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Three sub-studies are planned and described under the same protocol:
    1. Metabolism sub-study, in the US only
    Objectives: To assess the effect of macitentan on cardiac and arterial metabolism in patients with symptomatic pulmonary arterial hypertension by Positron Emission Tomography (PET) -Magnetic Resonance (MR) imaging.
    To further investigate the effect of macitentan on right ventricular function in patients with symptomatic pulmonary arterial hypertension.

    2. Biopsy sub-study
    Objectives: To assess the histological and biochemical effects of macitentan on the endomyocardium of the interventricular septum in patients with symptomatic pulmonary arterial hypertension.
    To assess the biochemical effects of macitentan on peripheral blood mononuclear cells (PBMC) in patients with symptomatic pulmonary arterial hypertension.

    3. Echo sub-study
    Objective: To assess the effect of macitentan on right and left ventricular function by echocardiography in patients with symptomatic pulmonary arterial hypertension.
    E.3Principal inclusion criteria
    The full list of inclusion criteria is provided in Section 4.3 of the Protocol and all patients must fulfill all criteria. The main inclusion criteria are:
    1. Signed informed consent prior to any study-mandated procedure
    2. Symptomatic pulmonary arterial hypertension (PAH)
    3. World Health Organization (WHO) Functional Class (FC) I to III
    4. PAH etiology belonging to one of the following groups according to Nice classification:
    1.1 Idiopathic PAH
    1.2 Heritable PAH
    1.3 Drug- and toxin-induced PAH
    1.4.1 PAH associated with connective tissue disease
    1.4.4 PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair
    5. Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) performed between Day −28 and Day 1 (inclusion RHC; RHC data obtained at study site within this time frame, prior to obtaining signed informed consent, are acceptable) showing:
    - mPAP ≥ 25 mmHg and
    -- PCWP or LVEDP ≤ 12 mmHg and PVR ≥ 4 Wood Units (WU) (320 dyn.sec.cm-5) or
    --12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg and PVR ≥ 6WU (480 dyn.sec.cm-5)
    6. 6-minute walk distance (6MWD) ≥ 150 m during screening
    7. For patients treated with oral loop diuretics, treatment dose must be stable since at least 1 month prior to RHC
    8. For patients treated with PDE-5 inhibitors, treatment dose must be stable since at least 3 months prior to RHC (initiation of
    PDE-5 inhibitors during screening is allowed after all screening assessments have been performed).
    9. For patients treated with beta blockers, treatment dose must be stable since at least 1 month prior to the RHC
    10. Men or women ≥18 and < 75 years. For patients aged ≥ 65 and < 75 years, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
    11. Women of childbearing potential must:
    a. Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
    b. Agree to use reliable methods of contraception from screening up to 30 days after study treatment discontinuation, and
    c. Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation
    E.4Principal exclusion criteria
    The full list of exclusion criteria is provided in Section 4.4 of the Protocol and all patients must not fulfill any exclusion criterion. The main exclusion criteria are:
    1. Body weight < 40 kg
    2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
    3. Pregnancy, breastfeeding or intention to become pregnant during the study
    4. Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program
    5. Known concomitant life-threatening disease with a life expectancy < 12 months
    6. Any condition likely to affect protocol or treatment compliance
    7. Hospitalization for PAH (exept for diagnosis of PAH) within 3 months prior to informed consent signature
    8. Left atrial volume indexed for body surface area (BSA) ≥ 43mL/m2 by echocardiography or cardiac MRI
    9. Moderate to severe left-heart valvular disease
    10. History of pulmonary embolism or deep vein thrombosis
    11. Presence of one or more of the following signs of relevant lung disease at any time up to screening:
    - Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
    - FVC < 60% of predicted.
    - Forced expiratory volume in one second (FEV1) < 60% of predicted.
    12. Moderate to severe restrictive lung disease (i.e., total lung capacity < 60% of predicted value) at any time prior to enrollment.
    13. Historical evidence of significant coronary artery disease established by:
    - History of myocardial infarction or
    - More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
    - Elevation of the ST segment on electrocardiogram or
    - History of coronary artery bypass grafting or
    - Stable angina
    14. Known uncontrolled diabetes mellitus (in the opinion of the investigator)
    15. Severe renal insufficiency (calculated creatinine clearance < 30 mL/min)
    16. Cancer
    17. Systolic blood pressure < 90 mmHg
    18. Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × ULN accompanied by an AST elevation > ULN at Screening.
    19. Hemoglobin < 100g/L
    20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal range
    21. Need for dialysis
    22. Responders to acute vasoreactivity test based on medical history
    23. Prior use of endothelin receptor antagonists, stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogs
    24. Treatment with strong inducers of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John’s Wort)
    25. Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)
    26. Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).
    27. Hypersensitivity to any endothelin receptor antagonist or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya)
    28. Claustrophobia
    29. MRI-incompatible permanent cardiac pacemaker, automatic internal cardioverter
    30. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device)
    31. Atrial fibrillation, multiple premature ventricular or atrial contractions (PVCs/PACs), or any other condition that would interfere with proper cardiac gating during magnetic resonance imaging (MRI)
    32. For patients enrolling in the metabolism sub-study only: glucose intolerance
    33. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases or 1.4.1: PAH associated with connective tissue disease
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint
    The study has two primary efficacy endpoints:
    -Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume (RVSV) assessed by cardiac MRI from pulmonary artery flow.
    -Ratio of Week 26 to baseline Pulmonary Vascular Resistance (PVR) assessed by RHC.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 26
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints
    Change from baseline to Week 26 in:
    -RV End Diastolic Volume (RVEDV)
    -RV End Systolic Volume (RVESV)
    -RV Ejection Fraction (RVEF)
    -RV mass
    -six-minute walk distance (6MWD)
    -World Health Organization (WHO) Functional Class (FC)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 26
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    France
    Germany
    Hong Kong
    Israel
    Italy
    Malaysia
    Netherlands
    Russian Federation
    Singapore
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    LVLS

    An interim analysis will be conducted when 42 patients have available assessment data for both primary endpoints. If the interim analysis concludes that the study is positive on both primary endpoints, enrollment may stop. Otherwise, the study will continue until 100 patients are enrolled. The decision to stop or continue the study will be taken jointly by the Steering Committee and the sponsor, considering statistical analysis results as well as clinical expertise.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 No
    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 60
    F.4.2.2In the whole clinical trial 100
    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)
    After the patient's study completion or premature withdrawal from the study, whichever applies, the investigator/delegate will explain to patients what treatment(s)/medical care is necessary and available according to local regulations.
    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 Decision2015-04-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-25
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