E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic or familial PAH |
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MedDRA Classification |
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 endpoint is to demonstrate that the exposure to bosentan in children with IPAH or familial PAH, using a pediatric formulation, is similar to that in adults with PAH. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to evaluate the tolerability and safety of a pediatric formulation of bosentan in this patient population. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
All patients should start the study drug (bosentan pediatric formulation) at the 2mg/kg b.i.d whether or not they were previously treated with bosentan.
Eligible patients must meet all of the following inclusion criteria during the Screening visit:
· Signed informed consent by the parents or the legal representatives.
· Male or female ≥2 and < 12 years of age. Females who are menstruating must have a negative serum pregnancy test. A reliable method of contraception must be considered, if appropriate. If using hormonal contraception, an additional alternative reliable method of contraception must be used.
- Reliable method of contraception are:
Barrier type devices (e.g., female condom, diaphragm, contraceptive sponge) only in combination with a spermicide.
Intra-uterine devices.
Oral, injectable or implantable contraceptives only in combination with a barrier method.
- Hormone-based contraceptives alone, regardless of the route of administration, are not considered as reliable methods of contraception.
- Abstention, rhythm method, and contraception by the partner alone are not acceptable methods of contraception.
. Idiopathic PAH or familial PAH diagnosed by right heart catheterization (Clinical classification of pulmonary hypertension - Venice 2003).
· WHO functional class II or III. (see Appendix 3 of the protocol).
· Oxygen saturation (SpO2) ≥ 88% (at rest, on room air).
· PAH treatment-naïve patients or Patients already treated with either:
- Bosentan monotherapy
- Intravenous epoprostenol monotherapy
- Intravenous or inhaled iloprost monotherapy
- Combination of bosentan and intravenous epoprostenol
- Combination of bosentan and intravenous or inhaled iloprost.
· PAH therapy must have been stable for at least 3 months prior to Screening.
· Stable treatment with calcium channel blockers, if any, for at least 3 months prior to Screening.
· Patient’s PAH condition must have been stable for at least 3 months prior to Screening. |
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E.4 | Principal exclusion criteria |
Patients will not be included in the study if any of the following exclusion criteria are present at the Screening visit:
· PAH associated with conditions other than idiopathic or familial PAH.
· Non stable patients, e.g., history (in the last 3 months prior to Screening) of recurrent syncope or signs and symptoms of non compensated right heart failure.
· Need or plan to wean patients from intravenous epoprostenol, or intravenous or inhaled iloprost.
· Body weight < 4 kg.
· Systolic blood pressure < 80% the lower limit of normal range, according to age and gender. (See Appendix 1 of the protocol).
· AST and/or ALT values > 3 times the upper limit of normal ranges.
· Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C. (See Appendix 4 of the protocol). · Hemoglobin and/or hematocrit levels < 75% of the lower limit of normal ranges.
· Pregnancy.
· Known intolerance or hypersensitivity to bosentan or any of the excipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The main analysis of the primary endpoint is performed on the PK-evaluable set for this equivalence study. |
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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 | No |
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 | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
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 | 1 |