A Study of Macitentan in Japanese Pediatric Participants With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of macitentan on hemodynamic measures at Week 24 in pediatric populations.

Official Title
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A Multicenter, Open-label, Phase III Study to Assess the Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients (>=3 Months to <15 Years) With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Macitentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pulmonary arterial hypertension (PAH) belonging to the nice 2013 updated classification group 1 PAH diagnosis confirmed by historical right heart catheterization where in the absence of pulmonary vein obstruction and/or significant lung disease pulmonary artery wedge pressure (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 World Health Organization (WHO) functional class (FC) I to IV PAH-specific treatment-naïve participants or participants on PAH-specific treatment A female of childbearing potential must have a negative highly sensitive serum beta-human chorionic gonadotropin (beta-hCG) test at screening and a negative urine pregnancy test at the first administration of study intervention A female participant must not get pregnant and must agree not to donate eggs during the study and for a period of up to 4 weeks following the end of study Exclusion Criteria: Participants with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn Participants with the following diseases: pulmonary vein stenosis; bronchopulmonary dysplasia Severe hepatic impairment, example, Child-Pugh Class C, at screening Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 4 weeks after the last dose of study intervention Known allergies, hypersensitivity, or intolerance to macitentan or its excipients Participant with PAH associated with open shunts, with congenital cardiac abnormalities such as univentricular heart, with pulmonary hypertension due to lung disease, and renal dysfunction

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Macitentan<br>Participants will receive oral dose of macitentan based on age and weight through Week 52. | Drug: Macitentan<br>* Macitentan will be administered orally as a tablet.<br>* Other names: ZEPENDO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold Change in Pulmonary Vascular Resistance Index (PVRI) | PVRI fold change at Week 24 is calculated as 100*(PVRI at Week 24 divided by PVRI at baseline). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Week 24 in Pulmonary Vascular Resistance (PVR) | Change from baseline at Week 24 in PVR as a part of pulmonary hemodynamic parameter will be reported. | Baseline and Week 24 | 
| Change from Baseline at Week 24 in Mean Right Atrial Pressure (mRAP) | Change from baseline at Week 24 in mRAP as a part of pulmonary hemodynamic parameter will be reported. | Baseline and Week 24 | 
| Change from Baseline at Week 24 in Mean Pulmonary Arterial Pressure (mPAP) | Change from baseline at Week 24 in mPAP as a part of pulmonary hemodynamic parameter will be reported. mPAP is calculated as (2*diastolic pulmonary arterial pressure plus systolic pulmonary arterial pressure) divided by 3. | Baseline and Week 24 | 
| Change from Baseline at Week 24 in Cardiac Index (CI) | Change from baseline at Week 24 in CI will be reported. CI is calculated as cardiac output divided by body surface area. | Baseline and Week 24 | 
| Change from Baseline at Week 24 in Cardiac Output (CO) | The CO was a measured cardiopulmonary hemodynamic parameter. It is the volume of blood expelled by the ventricles of the heart with each beat. It was calculated as the product of stroke volume (output of either ventricle per heartbeat) and the number of beats per minute. | Baseline and Week 24 | 
| Change from Baseline at Week 24 in Total Pulmonary Resistance (TPR) | TPR is a measured hydrodynamic parameter. Change from baseline at Week 24 in TPR will be reported. | Baseline and Week 24 | 
| Change from Baseline at Week 24 in Mixed Venous Oxygen Saturation (SvO2) at Rest | SvO2 is a measured hydrodynamic parameter. Change from baseline at Week 24 in Svo2 at rest will be reported. | Baseline and Week 24 | 
| Improvement in World Health Organization (WHO) Functional Class (FC) from Baseline at Week 24 | Improvement in WHO FC from baseline at Week 24 will be assessed as per the low (I, II), intermediate (III), and high-risk category (IV). | Baseline and Week 24 | 
| Improvement in Panama FC from Baseline at Week 24 | Improvement in Panama FC from baseline at Week 24 will be assessed as per the low (I, II), intermediate (III), and high-risk category (IV). | Baseline and Week 24 | 
| Change from Baseline at Week 24 in Exercise Capacity (6-Minute Walk Distance [6MWD] as Measured by the 6-Minute walk Test [6MWT]). | The 6MWT is a non-encouraged test that measures the distance covered by the participant during a 6-minute walk in developmentally capable children equal or above 6 years of age. | Baseline and Week 24 | 
| Change from Baseline at Week 24 in N-terminal pro-brain natriuretic peptide (NT-proBNP) | The quantitation of NT-proBNP plasma levels will be performed and reported. | Baseline and Week 24 | 
| Change from Baseline at 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 and Week 24 | 
| Change from Baseline at 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 and Week 24 | 
| Change from Baseline at 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 and Week 24 | 
| Change from Baseline at Week 24 in Physical Activity as Measured by Accelerometry | The physical activity (counts/minute) of the participant is assessed via accelerometer. It is used as a tool to assess functional capacity, disease severity, and prognosis. | Baseline and Week 24 | 
| Plasma Concentration of Macitentan and Aprocitentan | Plasma concentration of macitentan and active metabolite (aprocitentan) at all assessed timepoints will be reported. | Day 1 and Week 12 | 
| Change from Baseline to all Assessed Timepoints in Exercise Capacity (6MWD, as Measured by the 6MWT) | Change from baseline to all assessed timepoints in exercise capacity (6MWD, as measured by the 6MWT) will be reported. | Baseline up to Week 52 | 
| Change from Baseline to all Assessed Timepoints in Dyspnea on Exertion Assessed by the Borg CR10 Scale | Dyspnea on exertion will be assessed by the Borg CR10 scale. The scale is used to assess how strong participant's perception of dyspnea and level of exertion is. It ranges from Very weak, that is 1, to Extremely strong, that is 10. If perception or feeling is stronger than 10, Maximal - it can vary beyond 10, example, 12 or still higher (that's why Absolute maximum is marked with a dot •). | Baseline up to Week 52 | 
| Change from Baseline to all Assessed Timepoints in Physical Activity as Measured by Accelerometry | Change from baseline to all assessed timepoints in physical activity as measured by accelerometry will be reported. The physical activity (counts/minute) of the participant is assessed via accelerometer. It is used as a tool to assess functional capacity, disease severity, and prognosis. | Baseline up to Week 52 | 
| Improvement in WHO FC from Baseline to all Assessed Timepoints | Improvement in WHO FC from baseline to all assessed timepoints will be reported. | Baseline up to Week 52 | 
| Improvement in Panama FC from Baseline to all Assessed Timepoints | Improvement in Panama FC from baseline to all assessed timepoints will be reported. | Baseline up to Week 52 | 
| Percent Change from Baseline in Plasma NT-proBNP at Each Timepoint of Assessment | Percent change from baseline in plasma NT-proBNP at each timepoint of assessment will be reported. | Baseline up to Week 52 | 
| Percent Change from Baseline in TAPSE Measured by Echocardiography to all Assessed Timepoints | Percent change from baseline in TAPSE measured by echocardiography to all assessed timepoints will be reported. | Baseline up to Week 52 | 
| Percent Change from Baseline in LVEI Measured by Echocardiography to all Assessed Timepoints | Percent change from baseline in LVEI measured by echocardiography to all assessed timepoints will be reported. | Baseline up to Week 52 | 
| Change from Baseline to all Assessed Timepoints in PedsQL 4.0 Generic Core Scales Short Form (SF-15) | Change from baseline to all assessed timepoints in PedsQL 4.0 Generic Core Scales Short Form (SF-15) will be reported. | Baseline up to Week 52 | 
| Number of Participants with Adverse Events (AEs) | An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | Up to 3 years | 
| Number of Participants with Serious Adverse Events (SAEs) | An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a participant, or is an important medical event. | Up to 3 years | 
| Number of Participants with AEs Leading to Premature Discontinuation of Macitentan | Number of participants with AEs leading to premature discontinuation of macitentan will be reported. | Up to 3 years | 
| Number of Participants with AEs of Special Interests (AESIs) | Number of participants with AESIs will be reported. AESI in this study are: anemia/decreased hemoglobin level, edema/fluid retention, hepatic impairment/ alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) increase, and hypotension. | Up to 3 years | 
| Number of Participants with Clinical Safety Laboratory Abnormalities | Number of participants with clinical safety laboratory abnormalities (including serum chemistry, hematology, and urinalysis) will be reported. | Up to 3 years | 
| Number of Participants with Change from Baseline in Laboratory Parameters to all Timepoints of Assessments | Number of participants with change from baseline in laboratory parameters (including serum chemistry, hematology, and urinalysis) to all timepoints of assessments will be reported. | Baseline up to 3 years | 
| Number of Participants with Change from Baseline in Vital Signs to all Timepoints of Assessments | Number of participants with change from baseline in vital signs (including diastolic blood pressure [DBP], systolic blood pressure [SBP], and pulse rate [PR], height, and body weight) to all timepoints of assessments will be reported. | Baseline up to 3 years | 
| Number of Participants with Change from Baseline in Electrocardiogram (ECG) Parameters | Number of participants with change from baseline in ECG parameters will be reported. | Baseline up to 3 years |