A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension (PAH)

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multicenter, open-label, randomized, controlled, parallel Phase 3 study with an open-label single-arm extension period to evaluate pharmacokinetics (PK), safety and efficacy of macitentan in children with pulmonary arterial hypertension (PAH).

Official Title
-----------------
A Multicenter, Open-label, Randomized, Study With Single-arm Extension Period to Assess the Pharmacokinetics, Safety and Efficacy of Macitentan Versus Standard of Care in Children With Pulmonary Arterial Hypertension

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: Macitentan
* Other: Standard-of-care


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Signed informed consent by the parent(s) or legally designated representative and assent from developmentally capable children prior to initiation of any study-mandated procedure Males or females between greater than or equal to (>=) 1 month and less than (<) 18 years of age Participants with body weight >= 3.5 kilograms (kg) at randomization Pulmonary arterial hypertension (PAH) diagnosis confirmed by historical RHC (mPAP greater than or equal to [>=] 25 millimeters of mercury [mmHg], and Pulmonary artery wedge pressure [PAWP] less than or equal to [<=] 15 mmHg, and Pulmonary vascular resistance index [PVRi] greater than [>] 3 WU × m2), where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced by Left atrium pressure [LAP] or Left ventricular end diastolic pressure [LVEDP] (in absence of mitral stenosis) assessed by heart catheterization PAH belonging to the Nice 2013 Updated Classification Group 1 (including participants with Down Syndrome) and of following etiologies: idiopathic PAH; heritable PAH; PAH associated with congenital heart disease (CHD); Drug or toxin induced PAH; PAH associated with HIV; PAH associated with connective tissue diseases (PAH-aCTD); and World health organization (WHO) Functional class I to III Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to the end of study (EOS) Key Exclusion Criteria: Participants with PAH due to portal hypertension, schistosomiasis, or with pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn Participants with PAH associated with Eisenmenger syndrome, or with moderate to large left-to-right shunts Participants receiving a combination of > 2 PAH-specific treatments at randomization. Treatment with intravenous (IV) or subcutaneous (SC) prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing Hemoglobin or hematocrit <75 percent (%) of the lower limit of normal range Serum Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) greater than (>) 3 times the upper limit of normal range Pregnancy (including family planning) or breastfeeding. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol Severe hepatic impairment, for example Child-Pugh Class C Clinical signs of hypotension which in the investigator's judgment would preclude initiation of a PAH-specific therapy Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 micro-moles per liter [micro-mol/L]) Participants with known diagnosis of bronchopulmonary dysplasia

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Macitentan<br>Macitentan is administered once daily via oral route. Children less than (<) 2 years old (y.o.) will be assigned as a cohort to the macitentan group without randomization. The dose will be adjusted to the participant's age (for those < 2 y.o.) or to the participant's body weight (for those greater than or equal to (>=) 2 y.o.). single-arm extension period (SAEP) will start at end of core period (EOCP) visit and ends at end of study (EOS) visit. | Drug: Macitentan<br>* Dispersible tablet; Oral use<br>* Other names: ACT-064992;|
| Other: Standard-of-care<br>Standard-of-care as per site's clinical practice which may comprise treatment with pulmonary arterial hypertension (PAH) non-specific treatment and/or up to two PAH-specific medications excluding macitentan and intravenous/subcutaneous (IV/SC) prostanoids. | Other: Standard-of-care<br>* Standard-of-care as per site's clinical practice which may comprise treatment with PAH non-specific treatment and/or up to two PAH-specific medications excluding macitentan and IV/SC prostanoids.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Greater than or Equal to (>=) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 12 | Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported. | Week 12 | 
| Participants Less than (<) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 4 | Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first CEC-confirmed Disease Progression Event | Time to the first of the following CEC-confirmed disease progression events: • Death (all causes) • Atrial septostomy or Potts' anastomosis, or registration on lung transplant list • Hospitalization due to worsening PAH • Clinical worsening of PAH. | Between randomization/visit 2 and end of core study period (EOCP); up to 7 years | 
| Time to First CEC-confirmed Hospitalization for PAH | Time to first CEC-confirmed hospitalization for PAH occurring between randomization/visit 2 and EOCP. | Between randomization/visit 2 and EOCP/; up to 7 years | 
| Time to CEC-confirmed death due to PAH | Time to CEC-confirmed death due to PAH occurring between randomization/visit 2 and EOCP. | Between randomization/visit 2 and EOCP; up to 7 years | 
| Time to death (all causes) | Time to death (all causes) occurring between randomization/visit 2 and EOCP. | Between randomization/visit 2 and EOCP; up to 7 years | 
| The Percentage of Participants with World Health Organization (WHO) Functional Class (FC) I or II versus III or IV | Percentage of participants with WHO FC I or II versus III or IV will be reported. | Week 24 | 
| Change from Baseline to Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | The quantitation of NT-proBNP plasma levels will be performed and reported. | Baseline to Week 24 | 
| Change from Baseline to Week 48 in Moderate to Vigorous Physical Activity as Measured by Accelerometry | Change from baseline to Week 48 in moderate to vigorous physical activity as measured by accelerometry will be reported. | Baseline to Week 48 | 
| Change from Baseline to Week 24 in Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography | TAPSE is a dimension used to evaluate right ventricle (RV) longitudinal systolic function; it measures the extent of systolic motion of the lateral portion of the tricuspid ring towards the apex. | Baseline to Week 24 | 
| Change from Baseline to Week 24 in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography | For LVEI, left ventricle (LV) internal diameters will be measured and recorded in millimeter (mm) with up to 1 decimal place, using the parasternal short axis view at the level of the papillary muscles. | Baseline to Week 24 | 
| Change from Baseline to Week 24 in Pediatric Quality of Life Inventory version 4.0 (PedsQL 4.0) Generic Core Scales Short Form (SF-15) | The PedsQL 4.0 SF-15 is a questionnaire for quality of life assessment which will assess the general physical, emotional, social and school functioning (15 questions). The questionnaires are adapted for different age groups: toddlers (2-4 years of age), young children (5-7 years of age), children (8-12 years of age), and adolescents (13-14 years of age). It is rated on the scale of 0 to 4 where 0=never, 1=almost never, 2=sometimes, 3=often, and 4=almost always. | Baseline to Week 24 |