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    Summary
    EudraCT Number:2023-000984-30
    Sponsor's Protocol Code Number:67896062PAH3001
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2024-01-03
    Trial 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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2023-000984-30
    A.3Full title of the trial
    A Multicenter, Open-label, Phase III Study to Assess the Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients (≥3 months to <15 years) with Pulmonary Arterial Hypertension
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Macitentan in Japanese Pediatric Patients with Pulmonary Arterial Hypertension
    A.4.1Sponsor's protocol code number67896062PAH3001
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/457/2023
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJanssen Pharmaceutical K.K.
    B.1.3.4CountryJapan
    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 supportJanssen Pharmaceutical K.K
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International NV
    B.5.2Functional name of contact pointClinical Registry group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 CM
    B.5.3.4CountryNetherlands
    B.5.6E-mailClinicalTrialsEU@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 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/ JNJ-67896062
    D.3.4Pharmaceutical form Dispersible tablet
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    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
    Pulmonary Arterial Hypertension is a condition in which the pressure in the blood vessels going to the lungs (the pulmonary arteries) is higher
    than normal
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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 hemodynamic measures at Week 24
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of macitentan on pulmonary hemodynamic parameters other than PVRI at Week 24.
    - To evaluate the effect of macitentan on World Health Organization (WHO) Functional Class (FC) at Week 24 (For patients whose age is >4 years of age
    when initial informed consent)
    - To evaluate the effect of macitentan on Panama FC at Week 24#- To evaluate the effect of macitentan on exercise capacity at Week 24 (For patients who are developmentally able to understand and perform the 6-minute walk test [6MWT] and whose age is ≥6 years of age when initial informed consent)
    - To evaluate the effect of macitentan on NT-proBNP at Week 24
    - To evaluate the effect of macitentan on Echocardiography at Week 24
    - To evaluate the effect of macitentan on quality of life at Week 24
    - To evaluate the effect of macitentan on physical activity at Week 24 (For patients whose age is ≥2 years of age when initial informed consent)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Japanese males or females between ≥ 3 months and < 15 years of age at the first administration of study intervention.
    2. PAH belonging to the Nice 2013 Updated Classification Group 1 (including Down syndrome) and of the following etiologies:
    a. Idiopathic PAH (iPAH)
    b. Heritable PAH (hPAH)
    c. PAH associated with CHD:
    i. PAH with co-incidental CHD
    ii. Post-operative PAH (persisting/ recurring/ developing ≥ 6 months after repair of CHD)
    d. Drug or toxin induced PAH
    e. PAH associated with HIV
    f. PAH associated with connective tissue disease (PAH-aCTD)
    3. PAH diagnosis confirmed by historical right heart catheterization (RHC; characterized by mean pulmonary arterial pressure ≥25 mm Hg, and pulmonary arterial wedge pressure ≤15 mm Hg, and pulmonary vascular resistance index (PVRi) >4 Wood Units × m2), where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced by left atrium pressure (LAP) or left ventricular end diastolic pressure (LVEDP) (in absence of mitral stenosis) assessed by heart
    catheterization.
    4. WHO FC I to IV.
    5. PAH-specific treatment-naïve patients or patients on PAH-specific treatment
    6. A woman of childbearing potential must have a negative highly sensitive serum -human chorionic gonadotropin test at Screening and a negative urine pregnancy test at the first administration of study intervention.
    7. A woman must be
    a. Not of childbearing potential
    b. Of childbearing potential and
    o Practicing a highly effective, preferably user-independent method of contraception (failure rate of <1% per year when used consistently and
    correctly) and agrees to remain on a highly effective method while receiving study intervention and until 30 days after last dose - the end of relevant systemic exposure. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in
    relationship to the first dose of study intervention.
    8. A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the purposes of assisted reproduction during the study and for a period of up to 4 weeks following the EOS.
    9. Parent(s) (preferably both if available or as per local requirements) (or their legally acceptable representative) must sign an ICF indicating that they understand the purpose of, and procedures required for, the study and is/are willing to allow the child to participate in the study. Assent is also required of children capable of understanding the nature of the study (typically 7 years of age and older) as described in Informed Consent
    Process in Appendix 3: Regulatory, Ethical, and Study Oversight Considerations.
    10. Willing and able to adhere to the lifestyle restrictions specified in the protocol.
    E.4Principal exclusion criteria
    1. Patients with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.
    2. Patients with PAH associated with open shunts, as specified below:
    a. Eisenmenger syndrome
    b. Moderate to large left-to-right shunts as judged by the investigator
    3. Patients with the following congenital cardiac abnormalities:
    a. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, pulmonary atresia with ventricular septal defect, unless operatively repaired and with no residual shunt
    b. Univentricular heart and/or patients with Fontan-palliation
    4. Patients with pulmonary hypertension due to lung disease (eg, bronchopulmonary dysplasia)
    5 Patients with the following diseases:
    a. Patients with pulmonary vein stenosis
    b. Patients with bronchopulmonary dysplasia
    6. Hemoglobin or hematocrit <75% of the lower limit of normal range (LLN) at Screening.
    7. Serum AST and/or ALT >3 × ULN at Screening.
    8. Severe hepatic impairment, eg, Child-Pugh Class C, at Screening.
    9. Clinical signs of hypotension which in the investigator’s judgment would preclude initiation of a PAH-specific therapy at Screening.
    10. Severe renal dysfunction with an estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73 m2 at Screening.
    11. Known concomitant life-threatening disease with a life expectancy <12 months.
    12. Patients receiving PAH-specific treatments (excluding PDE-5 inhibitor) at the first administration of study intervention.
    13. Start or change of dose* with PDE-5 inhibitor within 90 days before RHC at Screening
    (* Dose adjustments are permitted based on patient body-weight change).
    14. Start or change of dose* of Calcium channel blockers and/or diuretics within 7 days before RHC (* Dose adjustments are permitted based on patient body-weight change).
    15 Previous treatment* with macitentan at any time.
    16. Any PAH-related surgical intervention planned, or patients listed for organ transplantation related to PAH.
    17. Treatment with strong inducers of CYP3A4 (eg, rifabutin, rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort), within 4 weeks prior to the first administration of study intervention.
    18. Systemic treatment with strong inhibitors of CYP3A4 (eg, clarithromycin, itraconazole, ketoconazole, nelfinavir, posaconazole, ritonavir, and voriconazole) within 4 weeks prior to the first administration of study intervention.
    19. Systemic treatment with moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole and amiodarone), or administration of a combination of a moderate CYP3A4 inhibitor (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a moderate CYP2C9 inhibitor (eg, miconazole) within 4 weeks prior to the first administration of study intervention.
    20. Taken any disallowed therapies as noted in in the protocol before the planned first dose of study intervention.
    21. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study intervention or is currently enrolled in an investigational study.
    22. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 4 weeks after the last dose of study intervention.
    23. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
    24. Known allergies, hypersensitivity, or intolerance to macitentan or its excipients.
    25. Drug or substance abuse, or any condition that, in the opinion of the investigator, may prevent compliance with the protocol or adherence to study intervention.
    26. Previous RHC assessments associated with serious complications, such as (but not limited to) cardiac arrest, arrhythmia requiring intervention, pulmonary hemorrhage, stroke, thromboembolic event, and pulmonary hypertensive crisis.
    E.5 End points
    E.5.1Primary end point(s)
    Fold change at Week 24 in pulmonary vascular resistance index (PVRI)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    E.5.2Secondary end point(s)
    - Change from baseline to Week 24 in the following hemodynamic variables: pulmonary vascular resistance (PVR), mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), cardiac index (CI), cardiac output (CO), total pulmonary resistance (TPR) and mixed venous oxygen saturation (SvO2) at rest.
    - Improvement in WHO FC from baseline to Week 24 (yes/no).
    - Improvement in Panama FC from baseline to Week 24 (yes/no).
    - Change from baseline to Week 24 in exercise capacity (6-minute walk distance [6MWD], as measured by the 6MWT).
    - Change from baseline to Week 24 in NT-proBNP.
    - Change from baseline to Weeks 24 in tricuspid annularplane systolic excursion (TAPSE) and left ventricular eccentricit y index measured b y echocardiography.
    - Change from baseline to Week 24 in: PedsQL™ 4.0 Generic Core Scales Short Form (SF-15).
    - Change from baseline to Week 24 in physical activity as measured by accelerometry.
    - Macitentan and aprocitentan concentrations in plasma or blood at all assessed timepoints.
    - Changes from baseline to all assessed timepoints in exercise capacity (6MWD, as measured by the 6MWT).
    - Change from baseline to all assessed timepoints indyspnea on exertion assessed by the Borg CR10 Scale®
    - Change from baseline to all assessed timepoints in physical activity as measured by accelerometry
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study
    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 Yes
    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) Yes
    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 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 Yes
    E.8.2.3.1Comparator description
    Standard of Care
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Japan
    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
    E.8.9 Initial estimate of the duration of the trial
    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 Yes
    F.1.1Number of subjects for this age range: 7
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 4
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients who cannot give assent will be included. In general, the majority of patients will not give consent but only assent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 7
    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)
    The patient will take other endothelin receptor antagonist treatment Continuously.
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: Japan
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