E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065150 |
E.1.2 | Term | Associated with pulmonary arterial hypertension |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065151 |
E.1.2 | Term | Idiopathic pulmonary arterial hypertension |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065152 |
E.1.2 | Term | Familial pulmonary arterial hypertension |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
|
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 is the safety and tolerability of ambrisentan in the paediatric PAH population. |
|
E.2.2 | Secondary objectives of the trial |
Pharmacokinetics in the paediatric population: • Population pharmacokinetic assessment based on one plasma sample per subject at Weeks 4, 8, 12, 16, 20, and 24. • Pharmacokinetic/pharmacodynamic modelling.
To obtain supportive efficacy data: • The change from baseline in the 6 minute walking distance (6MWD) test evaluated after 24 weeks of therapy. • Mean changes from baseline in the 6MWD test at Weeks 4, 8, 12, 16, and 20. • The time to clinical worsening of PAH. • The change from baseline in Subject Global Assessment to Week 24 using the SF-10 health survey for children. • The change from baseline in WHO functional class to Week 24. • Change from baseline in plasma brain natriuretic peptide (BNP or N-Terminal pro-B-type Natriuretic Peptide) concentration at Week 24.
|
|
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 |
Cardiopulmonary Hemodynamic Sub-study: Hemodynamic assessments will be performed at baseline and Week 24 or early withdrawal in a subgroup of subjects enrolled in centres where the collection of hemodynamic data is considered part of the standard of care.
|
|
E.3 | Principal inclusion criteria |
1. Male or female at least 8 years of age and not yet 18 years of age at the time of randomization. 2. A current diagnosis of PAH (WHO Group 1) with WHO class II or III symptoms in one of the following categories: • Idiopathic • Heritable [familial] • Secondary to connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed connective tissue disease (CTD), systemic lupus erythematosus, or overlap syndrome). • Persistent PAH despite surgical repair (at least 6 months prior to the screening visit) of atrial septal defects, ventricular septal defects, atrio-ventricular septal defects, and persistent patent ductus. 3. Have met the following hemodynamic criteria for subjects with right heart catheterization (RHC) when performed as part of the diagnosis or routine care: • mean pulmonary arterial pressure (mPAP) of 25 mmHg • pulmonary vascular resistance (PVR) of 240 dynesec/cm5 • left ventricular end diastolic pressure (LEVDP) or pulmonary capillary wedge pressure (PCWP) of ≤15 mmHg. 4. Subjects must either be treatment naïve, have discontinued treatment with another ERA (e.g., bosentan) at least 1 month previously because of elevated liver function tests (LFTs), or have been on a stable dose of background treatment for PAH (e.g., sildenafil or prostacyclin) for at least one month prior to the Screening Visit. Background treatment for PAH, if any, should not change from the Screening Visit until the end of all Treatment Period assessments. 5. Subjects who discontinued ERA treatment due to elevated LFTs, must have LFTs of <3 x Upper Limit of Normal (ULN). 6. A female is eligible to participate in this study, as assessed by the investigator, if she is of: a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant); or, b. Child-bearing potential - has a negative pregnancy test and is not lactating at the Screening and Baseline/Randomisation Visits and agrees to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of study drug (reliable methods of contraception are listed in Appendix 2. 7. Subject or subject’s legal guardian is able and willing to give written informed consent. As part of the consent, female subjects of childbearing potential will be informed of the risk of teratogenicity and will need to be counselled in a developmentally appropriate manner on the importance of pregnancy prevention; and male subjects will need to be informed of potential risk of testicular tubular atrophy and aspermia.
|
|
E.4 | Principal exclusion criteria |
1. Subjects currently taking an ERA. 2. Subjects currently taking cyclosporine A. 3. Subjects whose body weight is less than 20 Kg. 4. Subjects who have not tolerated PAH therapy due to adverse effects which may be related to their mechanism of action (e.g., prostanoids, ERA, PDE-5 inhibitors) with the exception of liver abnormalities for those subjects who were receiving another ERA. 5. Female subjects who are pregnant or breastfeeding. 6. Subjects with diagnosis of active hepatitis (hepatitis B surface antibody and hepatitis C antibody), or clinically significant hepatic enzyme elevation (i.e., ALT, AST or AP >3xULN) at Screening. 7. Subjects with severe renal impairment (creatinine clearance <30 mL/min) at Screening. 8. Subject has clinically significant fluid retention in the opinion of the investigator. 9. Subject has clinically significant anaemia in the opinion of the investigator. 10. Subject has a known hypersensitivity to the study drug, the metabolites, or formulation excipients. 11. Subjects who have participated in another trial or have taken another investigational product during the previous 30 days. 12. Alcohol abuse, illicit drug use within 1 year. 13. Any concurrent condition or concurrent use of medication that would affect subject safety in the opinion of the investigator.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety as assessed by: • Adverse Events. • Serious Adverse Events. • Clinical laboratory parameters. • Physical examination (Including height, weight, body mass index / body surface area, oxygen saturation, jugular venous pressure, liver size, and presence of peripheral oedema and/or ascites.) • Vital Signs. • Pubertal development (change from baseline in endocrinology assessments at Weeks 12 and 24).
|
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 |
Diferent dose of same IMP |
|
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | 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 |
|
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
|
Not applicable. Note: Patients will be eligible to enrol into a long term follow-up study. |
|
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 |