E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension |
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E.1.1.1 | Medical 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 |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate macitentan in comparison to Standard of Care (SoC) with regard to delaying disease progression in children with PAH. |
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E.2.2 | Secondary objectives of the trial |
To assess safety and tolerability of macitentan in children with PAH.
To assess PK of macitentan in children with PAH. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic (PK) Substudy.
Optional for up to 40 subjects.
The analysis of the PK sub-study will be used to select the appropriate daily dose in subjects below 2 years of age. |
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E.3 | Principal inclusion criteria |
1. Signed informed consent by the parent(s) or legally designated representative AND assent from developmentally capable children prior to initiation of any study-mandated procedure.
2. Males or females between ≥ 2 years and < 18 years of age.
3. Subjects with body weight ≥ 10 kg at randomization.
4. PAH diagnosis, confirmed by historical RHC (mPAP ≥ 25 mmHg, and PAWP ≤ 15 mmHg, and PVRi > 3 WUxm2).
5. PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects with Down syndrome) and of following etiologies:
• iPAH
• hPAH
• PAH associated with CHD
• Drug or toxin induced PAH
• PAH associated with HIV
• PAH-aCTD
6. WHO FC I to III.
7. Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to EOS. |
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E.4 | Principal exclusion criteria |
1. Subjects with PAH due to portal hypertension, schistosomiasis, or with pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn.
2. Subjects with PAH associated with Eisenmenger syndrome, or with moderate to large left-to right shunts.
3. Subjects receiving a combination of > 2 PAH-specific treatments at randomization.
4. Treatment with i.v. or s.c. prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing.
5. Hemoglobin or hematocrit <75% of the lower limit of normal range
6. Serum AST and/or ALT > 3 times the upper limit of normal range'
7. Pregnancy (including family planning) or breastfeeding.
8. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time to the first of the following CEC-confirmed disease progression events occurring between randomization and EOS:
• Death (all causes)
• Atrial septostomy or Potts’ anastomosis, or registration on lung transplant list
• Hospitalization due to worsening PAH
• Clinical worsening of PAH |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Between randomization and End-of-Study (EOS) |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are analyzed in the following hierarchical order:
• Time to first CEC-confirmed hospitalization for PAH occurring between randomization and EOS.
• Time to CEC-confirmed death due to PAH occurring between randomization and EOS.
• Time to death (all causes) occurring between randomization and Study Closure. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Between randomization and End-of-Study (EOS) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Canada |
China |
Colombia |
France |
Germany |
Hungary |
Israel |
Korea, Republic of |
Mexico |
Philippines |
Poland |
Portugal |
Russian Federation |
South Africa |
Spain |
Thailand |
Ukraine |
United States |
Vietnam |
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E.8.7 | Trial 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
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The study is considered completed when the last subject completes the study (i.e. last EOS visit or last safety follow-up contact, whichever occurs last) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |