E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension (PAH) in children |
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E.1.1.1 | Medical condition in easily understood language |
PAH is a deadly disease that causes narrowing of the pulmonary artery, which requires more effort from the heart to pump blood into the lungs, eventually leading to right heart failure. |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064908 |
E.1.2 | Term | Associated with (APAH) |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064909 |
E.1.2 | Term | Idiopathic (IPAH) |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064910 |
E.1.2 | Term | Familial (FPAH) |
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 |
to investigate the pharmacokinetics (PK) of the pediatric formulation of bosentan at doses of 2 mg/kg b.i.d. and 2 mg/kg t.i.d. in children with pulmonary arterial hypertension (PAH) from ≥ 3 months to < 12 years of age. |
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E.2.2 | Secondary objectives of the trial |
to evaluate efficacy, tolerability, and safety of bosentan in children with PAH from ≥ 3 months to < 12 years of age. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. PAH diagnosis confirmed with RHC: - Idiopathic or heritable PAH, or - Associated PAH persisting after complete repair of a congenital heart defect (PAH has to be persistent for at least 6 months after surgery)
2. WHO Functional Class I, II or III
3. Male or female ≥ 3 months and < 12 years of age (maximum age at randomization is 11.5 years)
4. Body weight ≥3,5 kg
5. Peripheral oxygen saturation (SpO2) ≥ 88% (at rest, on room air)
6. Baseline PAH-therapy (calcium channel blocker, bosentan, intravenous or inhaled prostanoid, oral PDE-5 inhibitor) if present, has to be stable for at least 3 months prior to screening. During the study, all background treatments should remain stable.
7. Signed informed consent by the parents or legal representatives |
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E.4 | Principal exclusion criteria |
1. PAH etiologies other than listed above
2. Non-stable disease status
3. Need or plan to wean patient from intravenous epoprostenol or intravenous or inhaled iloprost.
4. Systolic blood pressure < 80% of the lower limit of normal range.
5. AST and/or ALT values > 1.5 times the upper limit of normal range.
6. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
7. Hemoglobin and/or hematocrit levels < 75% of the lower limit of normal range.
8. Known intolerance or hypersensitivity to bosentan or any of the excipients of the dispersible Tracleer tablet.
9. Treatment with forbidden medication within 2 weeks or at least 5 times the half-life prior to randomization, whichever is the longest: - Glibenclamide (glyburide) - Cyclosporin A - Sirolimus - Tacrolimus - Fluconazole - Rifampicin (rifampin) - Ritonavir - Co-administration of CYP2C9 inhibitors (e.g., amiodarone, voriconazole) and moderate/strong CYP3A4 inhibitors (e.g., amprenavir, erythromycin, ketoconazole, diltiazem, itraconazole) - Endothelin receptor antagonists (ERAs) other than bosentan
10. Treatment with another investigational drug within 1 month prior to randomization or planned treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The main PK endpoint is defined as the daily exposure to bosentan, i.e., AUC over a period of 24 h (AUC(0-24h)), and calculated as a multiple of the exposure over a dosing interval (AUCτ), 3×AUCτ and 2xAUCτ for three times and two times daily dosing, respectively.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Per protocol, the pharmacokinetic assessment is performed once at week 4 (Visit 3). If deemed needed by the investigator, deviations are possible as long as patients received stable treatment of bosentan for at least 2 weeks, to ensure steady state bosentan plasma concentrations. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
Belarus |
China |
Czech Republic |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Mexico |
Netherlands |
Poland |
Russian Federation |
Serbia |
South Africa |
Spain |
Ukraine |
United States |
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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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End of Study is defined as the date on which the last randomized patient, not prematurely withdrawn, completes the 24-week treatment and the 7-day AE follow-up period. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |