| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypertension |
|
| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to confirm the selexipag starting dose(s), selected based on pharmacokinetic (PK) extrapolation from adults, that leads to similar exposures as adult doses in children from ≥ 2 to < 18 years of age, with pulmonary arterial hypertension (PAH), by investigating the PK of selexipag and its active metabolite ACT-333679 in this population. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of selexipag in children from ≥ 2 to < 18 years of age with PAH. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated informed consent by the parent(s) or Legally authorized representative(s) AND assent from developmentally capable children.
2. Males or females between ≥ 2 and < 18 years of age at Baseline / Enrollment / Visit 2 weighing ≥ 9 kg.
3. PAH diagnosis confirmed by documented historical right heart catheterization (RHC) performed at any time before the subject’s enrollment
4. PAH with one of the following etiologies:
• idiopathic (iPAH),
• heritable (hPAH),
• associated with congenital heart disease (CHD):
– PAH with co-incidental CHD
– Post-operative PAH (persisting/ recurring/ developing ≥ 6 months after repair of CHD)
• Drug or toxin-induced PAH
• PAH associated with HIV
• PAH associated with connective tissue disease
5. Word Health Organizaition functional class (WHO FC) II to III.
6. Subjects treated with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, provided that the treatment dose(s) has been stable for at least 3 months prior to enrollment, or patients who are not candidates for these therapies.
7. Females of childbearing potential must have a negative pregnancy test at Screening and at Enrollment, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) from screening up to study drug discontinuation + 30 days (EOS). |
|
| E.4 | Principal exclusion criteria |
Etiology
1. Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis.
2. Subjects with PAH associated with Eisenmenger syndrome.
3. Subjects with moderate to large left-to-right shunts.
4. Subjects with cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, univentricular heart, or pulmonary atresia with ventricular septal defect, as well as subjects with Fontan palliation.
5. Subjects with PH due to lung disease and/or hypoxia. For subjects with Down syndrome, exclusion of lung disease and hypoxia causing PH should be documented (e.g., computed tomography scan,
polysomnography, lung function tests).
Treatment and intervention
6. Previous treatment with Uptravi® (selexipag) within 2 weeks prior to enrollment.
7. Subjects having received prostacyclin (epoprostenol) or prostacyclin analogs2 (i.e., treprostinil, iloprost, beraprost) within 2 months prior to enrollment or who are scheduled to receive any of these compounds during the trial.
8. Treatment with another investigational drug within 4 weeks prior to enrollment.
9. Treatment with strong and moderate inhibitors of CYP2C8 (e.g., gemfibrozil, clopidogrel, deferasirox, teriflunomide) within 2 weeks prior to enrollment until the last dose of selexipag + 3 days.
10. Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) are prohibited from 2 weeks prior to enrollment and until the last dose of selexipag + 3 days.
11. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH.
12. History or current suspicion of intussusception or ileus or gastrointestinal obstruction, per investigator’s judgment.
Baseline abnormalities
13. Known concomitant life-threatening disease with a life expectancy < 12 months.
14. Uncontrolled thyroid disease, per investigator’s judgment.
15. Hemoglobin or hematocrit < 75% of the lower limit of normal range.
16. Known severe or moderate hepatic impairment, i.e., Child-Pugh Class B or C [see Appendix 4].
17. Clinical signs of hypotension that, in the investigator’s judgment, would preclude the initiation of a PAH-specific therapy.
18. Subjects with severe renal insufficiency (estimated creatinine clearance < 30 mL/min or serum creatinine > 221 μmol/L).
19. Severe coronary heart disease or unstable angina as assessed by the investigator.
20. Myocardial infarction within the last 6 months prior to enrollment.
21. Decompensated cardiac failure if not under close supervision.
22. Severe arrhythmias as assessed by the investigator.
23. Cerebrovascular events (e.g., transient ischemic attack, stroke) within the last 3 months prior to enrollment.
24. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to PH.
Pregnancy and breastfeeding
25. Pregnancy (including family planning) or breastfeeding.
Other categories
26. Known hypersensitivity to the investigational treatment or to any of the excipients of the drug formulations.
27. Drug or substance abuse, or any condition that, in the opinion of the investigator, may prevent compliance with the protocol or adherence to study treatment.
28. Loss of 250 mL or more of blood within 3 months prior to screening.
29. History or clinical evidence of any disease and/or existence of any surgical or medical condition that might interfere with the absorption, distribution, metabolism, or excretion of the study treatment(s) (e.g., cholecystectomy).
30. Inability to swallow tablets whole. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary pharmacokinetic (PK) endpoint:
- Model-based exposure (AUCτ,ss, combined) of selexipag and ACT-333679 corrected for their potency, determined during the 12 weeks up-titration period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| - PK sampling at Weeks 1, 2, 4, 6 and 12 |
|
| E.5.2 | Secondary end point(s) |
Secondary PK endpoints:
- Area under the plasma concentration-time curve over one dosing interval at steady state (AUCτ,ss), maximum plasma concentration at steady state (Cmax,ss), and the time at which Cmax,ss is observed
(tmax,ss) for selexipag and ACT-333679, based on non-compartmental analysis (NCA).
-Ttrough concentration at steady state (Ctrough, ss) for selexipag and ACT-333679.
Safety endpoints
• Treatment-emergent AEs (TEAEs), treatment-emergent serious adverse events (TESAEs) and treatment-emergent deaths (all causes), AEs leading to permanent discontinuation of study drug.
• Treatment-emergent marked laboratory abnormalities and ECG abnormalities up to EOT+ 3 days.
• Change from baseline up to EOT + 3 days in:
- selected hematology and blood chemistry laboratory variables.
- TSH
- Vital signs (blood pressure, heart rate)
- Height and body mass index
- Sexual maturation (Tanner stage) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- AUCτ,ss, cmax,ss, tmax,ss: PK sampling at Weeks 1, 2, 4, 6 and 12
- Ctrough: PK sampling at Weeks 2, 4,and 6
- TEAEs, TESAEs,treatment emergent deaths and AEs leading to permanent discontinuation: continuously from Day 1 up to 3 days after the end of treatment
- Tanner stage: at screening, Week 16, Month 22 and every 6 months afterwards
- Other safety endpoints: on Day 1 (baseline), Week 12 and Week 16, then every 3 months during the first 12 months and every 6 months thereafter up to the end of treatment visit, with additional timepoints for vital signs (Week 4), ECG (Weeks 1 & 4), laboratory tests (Week 4), TSH (Weeks 4 & 8)
|
|
| 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 | 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 |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Belarus |
| Canada |
| China |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Malaysia |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
| Vietnam |
|
| 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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| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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