| 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 (PAH) is a disease of the small pulmonary arteries that is characterized by vascular proliferation and remodeling. |
|
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate whether the addition of selexipag to Standard of Care treatment delays disease progression in children with PAH in comparison to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of selexipag in children with PAH.
To evaluate whether selexipag can delay hospitalization and death due to PAH worsening in children.
To assess the trough plasma concentrations of selexipag and its active metabolite at steady-state in children with PAH.
To explore the following safety and efficacy variables.
To explore the Quality of Life (QoL).
To explore the long-term safety, tolerability and efficacy of selexipag in children with PAH. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Parent(s) (preferably both, if available, or as per local requirements, or their legally authorized representatives [LARs]) must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to allow the child to participate in the study. Assent is also required of children capable of understanding the nature of the study (typically 7 years of age and older) as described in Informed Consent Process in Section 10.4, Regulatory, Ethical, and Study Oversight Considerations.
2. Male and female participants between ≥2 and <18 years of age weighing ≥9 kg at Randomization.
3. PAH diagnosis confirmed by documented historical RHC performed at any time before participant’s screening, and characterized by:
• mPAP ≥25 mmHg,
AND
• Pulmonary arterial wedge pressure (PAWP) ≤15 mmHg (in the absence of pulmonary vein obstruction and/or significant lung disease, PAWP can be replaced by left atrial pressure or, in absence of mitral stenosis, by left ventricular end diastolic pressure)
AND
• Indexed PVR index (PVRi) >3 Wood units × m2.
4. PAH (WHO Group 1), including patients with Down syndrome, of the following etiologies:
• Idiopathic PAH (IPAH).
• Heritable PAH (HPAH).
• PAH associated with congenital heart disease (PAH-aCHD):
– PAH with coincidental CHD (ie, a small atrial septal defect, ventricular septal defect, or patent ductus arteriosus that does not itself account for the development of elevated PVR) and if approved by the BCAC, refer to Section 10.4).
– Post-operative PAH (persisting / recurring/ developing ≥6 months after repair
of CHD).
• Drug or toxin-induced.
• PAH associated with HIV.
5. WHO FC II and III.
6. Participants treated with at least 1 PAH-specific treatment, eg, an ERA and/or a PDE-5 inhibitor/soluble guanylate cyclase stimulator, provided that the treatment dose(s) has been stable for at least 3 months prior to first dose of study intervention.
7. A female participant of childbearing potential (for a definition refer to section 10.6) is eligible only if the following apply:
Has a negative highly sensitive serum pregnancy test (β-human chorionic gonadotropin) at screening and a negative urine pregnancy test at randomization.
Agrees to undertake monthly urine pregnancy tests every 4 weeks (+-3 days) during the study and up to at least 30 days after study treatment discontinuation.
If sexually active, practicing an effective method of birth control consistent with local regulations regarding the use of birth control methods for participants participating in clinical studies until 30 days after last dose of study intervention. Examples of acceptable methods of contraception are located in Section 10.6. It is the responsibility of the investigator to ensure appropriate counselling, including consultation with a specialist (if needed), to the subject and/or parent(s) / LAR(s) on the acceptable method of contraception. To ensure compliance, the study personnel must remind female participants of childbearing potential who are sexually active and their parent(s) / LAR(s) at each visit to use the methods of contraception defined for this study. These reminders must be documented in the source documents. |
|
| E.4 | Principal exclusion criteria |
Etiology
1. PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, and/or pulmonary capillary hemangiomatosis.
2. PAH associated with Eisenmenger syndrome.
3. Moderate to large left-to-right shuntsa.
4. 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. Participants with PH due to lung disease and/or hypoxia history of bronchopulmonary dysplasia. For participants with Down syndrome, exclusion of lung disease and hypoxia causing PH must be documented (eg, normal oxygen saturation in absence of history of lung disease, computed tomography scan, polysomnography, lung function tests).
Treatment and intervention
6. Previous exposure to Uptravi® (selexipag).
7. Treatment with prostacyclin (epoprostenol) or prostacyclin analogsa (ie, treprostinil, iloprost, beraprost) within 2 months prior to randomization or scheduled to receive any of these treatments during the study.
8. Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study intervention or is currently enrolled in an investigational study
9. Treatment with strong and moderate inhibitors of CYP2C8 (eg, gemfibrozil, clopidogrel, deferasirox, teriflunomide) from 2 weeks prior to randomization until the last dose of study intervention +3 days
10. Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) from 2 weeks prior to randomization until the last dose of study intervention + 3 days
11. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH.
Medical history and co-morbidities
12. Known concomitant life-threatening disease with a life expectancy <12 months
13. History or current suspicion of intussusception or ileus or gastrointestinal obstruction, per the investigator’s judgment
14. Uncontrolled thyroid disease, per the investigator’s judgment
15. Hemoglobin or hematocrit <75% of the lower limit of normal range
16. Known severe or moderate hepatic impairment, ie, Child-Pugh Class B or C
17. Clinical signs of hypotension that, in the investigator’s judgment, would preclude initiation of a PAH-specific therapy
18. 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 (eg, transient ischemic attack, stroke) within the last 3 months prior to first dose of study intervention.
24. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to PH
Pregnancy and breastfeeding
25. Pregnant, planning to become pregnant, or lactating
Other categories
26. Known allergies, hypersensitivity, or intolerance to selexipag or its excipients (Selexipag IB)
27. Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease
28. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the child (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to disease progression from randomization up to 7 days after study treatment discontinuation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Randomization up to 7 days after EOT. |
|
| E.5.2 | Secondary end point(s) |
• Treatment-emergent adverse events and serious adverse events.
• Adverse events leading to premature discontinuation of study treatment
• Treatment-emergent change in vital signs (systolic and diastolic arterial blood pressure and pulse rate) and body weight from baseline to all assessed time points
• Growth: Treatment-emergent change in body weight and height from baseline to all assessed time points
• Sexual maturation (Tanner stage) from baseline to all assessed time points up to 3 days after study treatment discontinuation
• Treatment-emergent electrocardiogram abnormalities.
• Treatment-emergent marked laboratory abnormalities at each time point of assessment.
• Treatment emergent change from baseline in thyroid stimulating hormone over time.
• Treatment emergent change in selected laboratory variables from baseline to all assessed time points.
• Time to first Clinical Event Committee-confirmed hospitalization or death due to pulmonary arterial hypertension occurring from Randomization until 7 days after study treatment discontinuation.
• Trough plasma concentration at steady-state of Selexipag and its metabolite ACT-333679 collected during the maintenance period.
Exploratory
• Time to death (all causes) occurring between Randomization and the Analysis Visit for each Analysis.
• Time to first Clinical Event Committee-confirmed death due to pulmonary arterial hypertension occurring from randomization until 7 days after study treatment discontinuation.
• Time to Clinical Event Committee-confirmed disease progression up to the Analysis Visit for each Analysis.
• World Health Organization functional class III (yes/no) at each time point of assessment up to 7 days after study treatment discontinuation.
• Change in World Health Organization functional class from baseline/enrollment to each time point of assessment up to 7 days after study treatment discontinuation.
• Change from baseline to each time point of assessment in exercise capacity up to 7 days after study treatment discontinuation as measured by the 6-minute walk distance in children ≥6 years of age who are developmentally able to understand and perform the test.
• Change in physical activity (measured by accelerometry) from baseline to 1 year (48 weeks) after Randomization.
• Change in Panama functional class from baseline to each time point of assessment up to 7 days after study treatment discontinuation.
• Percent of baseline in plasma N-terminal pro-brain natriuretic peptide at each time point of assessment up to 7 days after study treatment discontinuation.
• Change from baseline in echocardiographic variables (imaging and Doppler evaluation) such as right ventricular systolic pressure, tricuspid annular plane systolic excursion, etc, at each time point of assessment up to 7 days after study treatment discontinuation.
• Time to disease progression from randomization up 7 days after study treatment discontinuation defined as:
1. All-cause death.
2. Time to non-planned pulmonary arterial hypertension related hospitalization.
3. Time to pulmonary arterial hypertension related deterioration identified by at least one of the following parameters:
i. increase in World Health Organization functional class,
ii. deterioration in exercise testing (15% decrease from baseline of 6-minute walk distance),
iii. signs or symptoms of right-sided heart failure.
• Quality of Life as measured by the PedsQL™ 4.0 Generic Core Scales Short Form.Quality of Life as measured by the disease-specific PedsQL™ 3.0 Cardiac Module using the “heart problems and treatment” component only.
• Quality of Life as measured by the PedsQL™ Multidimensional Fatigue Scale standard version using the “general fatigue” component only.
• Palatability of the study intervention at Day 1, Week 12, and End of Treatment, assessed using a 5-point facial hedonic scale.
• Acceptability of the study intervention at Day 1, Week 12, and End of Treatment, as assessed through a 3-point categorical scale as to whether the child swallowed the medication. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease progression is defined as the first occurrence of either of the following components:
− Death (all causes)
− Atrial septostomy or Potts’ anastomosis, or registration on lung transplant list
− Hospitalization due to worsening pulmonary arterial hypertensiona
− Clinical worsening of pulmonary arterial hypertension. |
|
| 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 |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Event-Driven and Group-Sequential. Open label extension. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| Brazil |
| Canada |
| China |
| Colombia |
| Israel |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Taiwan |
| Thailand |
| United States |
| Viet Nam |
| Finland |
| France |
| Lithuania |
| Poland |
| Sweden |
| Bulgaria |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Belarus |
| Belgium |
| Hungary |
| Portugal |
| Russian Federation |
| Serbia |
| Turkey |
| Ukraine |
|
| 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
|
| The end of study is considered as the last scheduled study assessment shown in the Schedule of Activities for the last participant in the study (LVLS). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 8 |
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