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

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

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

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Macitentan

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Azumino-shi, Japan, 399-8288
    • Nagano Children's Hospital
  • Bunkyō City, Japan, 113 8519
    • Institute of Science Tokyo Hospital
  • Fukuoka, Japan, 813-0017
    • Fukuoka Children's Hospital
  • Okayama, Japan, 700 8558
    • Okayama University Hospital
  • Sapporo, Japan, 060-8648
    • Hokkaido University Hospital
  • Setagaya Ku, Japan, 157 8535
    • National Center for Child Health and Development
  • Shinjuku-ku, Japan, 162-8666
    • Tokyo Women's Medical University Hospital
  • Suita-Shi, Japan, 564-8565
    • National Cerebral and Cardiovascular Center
  • Suita-shi, Japan, 565-0871
    • Osaka University Hospital
  • Tokyo, Japan, 113-8655
    • The University of Tokyo Hospital
  • Ōta-ku, Japan, 143-8541
    • Toho University Medical Center Omori Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 15 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Macitentan; Participants will receive oral dose of macitentan based on age and weight through Week 52.	Drug: Macitentan; Macitentan will be administered orally as a tablet.; Other Names: OPSUMIT; ZEPENDO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fold Change From Baseline at Week 24 in Pulmonary Vascular Resistance Index (PVRI)	PVRI fold change at Week 24 was calculated as 100*(PVRI at Week 24 divided by PVRI at baseline). PVR was determined by right heart catheterization.	Baseline (Day 1), Week 24
Change From Baseline in Hematology Parameter: Neutrophils Band Form (NBF)	Change from baseline in hematology parameters: NBF was reported. Data for each parameters was planned to be reported at specified timepoints only.	Baseline (Day 1), Weeks 8, 16, 20, 40, 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 24 in Hemodynamic Variable: Pulmonary Vascular Resistance (PVR)	Change from baseline to Week 24 in hemodynamic variable: PVR was reported. PVR is calculated as: PVR= (Mean pulmonary artery pressure [mPAP]-Pulmonary artery wedge pressure [PAWP)/ Cardiac output [CO].	Baseline (Day 1), Week 24
Change From Baseline to Week 24 in Hemodynamic Variable: Mean Right Atrial Pressure (mRAP)	Change from baseline to Week 24 in hemodynamic variable: mRAP was reported.	Baseline (Day 1), Week 24
Change From Baseline to Week 24 in Hemodynamic Variable: Mean Pulmonary Arterial Pressure (mPAP)	Change from baseline to Week 24 in hemodynamic variable: mPAP was reported. mPAP is calculated as: 2*diastolic pulmonary arterial pressure (dPAP) + systolic pulmonary arterial pressure (sPAP)/3.	Baseline (Day 1), Week 24
Change From Baseline to Week 24 in Hemodynamic Variable: Cardiac Index (CI)	Change from baseline to Week 24 in hemodynamic variable: CI was reported. CI was calculated as: CO/Body surface area (BSA).	Baseline (Day 1), Week 24
Change From Baseline to Week 24 in Hemodynamic Variable: Cardiac Output (CO)	Change from baseline to Week 24 in hemodynamic variable: CO was reported.	Baseline (Day 1), Week 24
Change From Baseline to Week 24 in Hemodynamic Variable: Total Pulmonary Resistance (TPR)	Change from baseline to Week 24 in hemodynamic variable: TPR was reported. TPR was calculated as: (mPAP/CO)*80.	Baseline (Day 1), Week 24
Percent Change From Baseline to Week 24 in Hemodynamic Variable: Mixed Venous Oxygen Saturation (SvO[2])	Percent change from baseline to Week 24 in hemodynamic variable: SvO(2) was reported.	Baseline (Day 1), Week 24
Number of Participants With Change From Baseline at Weeks 4, 8, 12, 16, 20, 24, 28, 40, and 52 in World Health Organization (WHO) Functional Class (FC)	WHO-FC for participants with pulmonary arterial hypertension (PAH) ranges: Class I (no limitation in physical activity, ordinary physical activity did not cause undue dyspnea or fatigue, chest pain or near syncope), Class II (slight limitation of physical activity, comfortable at rest, ordinary physical activity caused undue dyspnea or fatigue, chest pain, or near syncope), Class III (marked limitation of physical activity, comfortable at rest, less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope) and Class IV (cannot perform a physical activity without any symptoms, signs of right heart failure, dyspnea and/or fatigue may be present even at rest, discomfort is increased by any physical activity). Participants who improve in WHO FC are reported below. Improvement was defined as reduction in FC.	Weeks 4, 8, 12, 16, 20, 24, 28, 40, and 52
Number of Participants With Change From Baseline at Weeks 4, 8, 12, 16, 20, 24, 28, 40, and 52 in Panama Functional Class (FC)	Panama FC for PAH ranges: Class I (asymptomatic, growing normally, attending nursery/school regularly, no limitation of physical activity, playing sports with his/her classmates), Class II (slight limitation of physical activity, unduly dyspnoeic and fatigued when playing with his/her classmates, comfortable at rest, grow along own centiles, nursery/school attendance 75% normal, no chest pain), Class IIIa (marked limitation of physical activity, no attempt at sports, comfortable at rest, less than ordinary activity (example: dressing) causes undue dyspnea, fatigue, syncope and/or presyncope or chest pain, nursery/schooling compromised <50% normal attendance), Class IIIb (growth compromised, poor appetite, supplemental feeding, same as class IIIa) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Participants who improve in Panama FC are reported below. Improvement was defined as reduction in Panama FC.	Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline to Weeks 24 and 52 in 6-minute Walk Distance (6MWD) as Measured by the 6-minute Walk Test (6MWT)	Change from baseline to Weeks 24 and 52 in 6MWD as measured by 6MWT was reported. 6MWD was the distance that a participant could walk in 6 minutes. Rest periods were allowed if the participant could no longer continue. If the participant need to rest, he/she may pause, lean against the wall and continue walking whenever he/she feels able. The timer continued to run even if the participant stopped to rest.	Baseline (Day 1), Weeks 24 and 52
Change From Baseline to Weeks 12, 24, 28, 40, and 52 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)	Change from baseline to Weeks 12, 24, 28, 40, and 52 in NT-proBNP was reported.	Baseline (Day 1), Week 12, 24, 28, 40, and 52
Change From Baseline to Weeks 12, 24, and 52 in Tricuspid Annular Plane Systolic Excursion (TAPSE)	Change from baseline to Weeks 12, 24, and 52 in TAPSE was reported. It was calculated as: original TAPSE value/body surface area (BSA). TAPSE was a dimension used to evaluate Right Ventricle (RV) longitudinal systolic function; it measured the extent of systolic motion of the lateral portion of the tricuspid ring towards the apex.	Baseline (Day 1), Weeks 12, 24, and 52
Change From Baseline to Week 12, 24, and 52 in Left Ventricular Eccentricity Index (LVEI)	Change from baseline to Weeks 12, 24, and 52 in LVEI was reported. It included diastolic (D) LVEI and systolic (S) LVEI. Left ventricular (LV) internal diameters were measured using the parasternal short axis view at the level of the papillary muscles: D1: LV internal diameter perpendicular to interventricular septum at end-diastole; D2: LV internal diameter parallel to interventricular septum, and at right angle from D1, at end-diastole; S1: LV internal diameter perpendicular to interventricular septum at end-systole; S2: LV internal diameter parallel to interventricular septum, and at a right angle from S1, at end-systole. The LVEI was a ratio that was calculated by sponsor as: LVEI diastole = D2/D1; LVEI systole = S2/S1.	Baseline (Day 1), Weeks 12, 24 and 52
Change From Baseline to Week 12, 24, and 52 in Quality of Life (QoL) as Assessed by Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales Short Form (SF-15)	Change from baseline to Weeks 12, 24, and 52 in QoL as assessed by PedsQL 4.0 generic core scales SF-15 was reported. The PedsQL 4.0 questionnaire generic core scales score SF-15 assessed general physical, emotional, social and school functioning on a 5-point Likert scale from 0 to 4 with 0= if it is never a problem, 1= if it is almost never a problem, 2= if it is sometime a problem, 3= if it is often a problem, 4 if it is almost always a problem. Scores were transformed on a scale from 0 to 100. Higher scores indicated better health related QoL. The QoL questionnaire was completed by parent(s)/caregiver(s) and by participants.	Baseline (Day 1), Weeks 12, 24, and 52
Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Number of Hours of Daytime Activity	Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: number of hours of daytime activity was reported.	Baseline (Day 1), Weeks 12, 24, and 52
Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Mean Count Per Minute of Daily Activity	Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: mean count per minute of daily activity was reported.	Baseline (Day 1), Weeks 12, 24, and 52
Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Mean Daily Time Spent in Light Physical Activity	Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: mean daily time spent in light physical activity was reported.	Baseline (Day 1), Weeks 12, 24, and 52
Change From Baseline to Weeks 12, 24, and 52 in Physical Activity as Measured by Accelerometry: Mean Daily Time Spent in Moderate to Vigorous Physical Activity	Change from baseline to Weeks 12, 24, and 52 in physical activity as measured by accelerometry: mean daily time spent in moderate to vigorous physical activity was reported.	Baseline (Day 1), Weeks 12, 24, and 52
Change From Baseline to Week 24 and Week 52 in Borg Dyspnea Index (BDI)	Change from baseline to Weeks 24 and 52 in BDI was reported. BDI was a 10-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores ranged from 0 (no shortness of breath) to 10 (worst shortness of breath you have ever had). Higher score indicated worse outcome.	Baseline (Day 1), Weeks 24 and 52
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Number of participants with TEAEs was reported. An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs are defined as any AE occurring at or after the initial administration of study intervention through the day of last dose plus 30 days.	From Baseline (Day 1) up to Week 56
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)	Number of participants with TESAEs was reported. An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TESAEs are defined as any SAE occurring at or after the initial administration of study intervention through the day of last dose plus 30 days.	From Baseline (Day 1) up to Week 56
Number of Participants With AEs Leading to Premature Discontinuation of Study Drug	Number of participants with AEs leading to premature discontinuation of study drug was reported. An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention.	From Baseline (Day 1) up to Week 52
Number of Participants With TEAEs of Special Interest	Number of participants with TEAEs of special interest was reported. It included anemia/decreased hemoglobin level, oedema/fluid retention, hepatic impairment and hypotension. TEAEs are defined as any AE occurring at or after the initial administration of study intervention through the day of last dose plus 30 days.	From Baseline (Day 1) up to Week 56
Number of Participants With Postbaseline Markedly Abnormal Hematology Laboratory Values	Number of participants with postbaseline markedly abnormal hematology laboratory values was reported. It included Hematocrit:<0.28% of blood cells (<0.32M[%]), Hemoglobin: < 100 grams per liter (g/L), Leukocytes: <3.0 10^9 cells per Liter (L), and Leukocytes: <3.0 10^9 cells/L. Abnormality was judged at the discretion of investigator. Data is reported for categories where at least one participant had abnormality.	Weeks 20, 40, 52
Number of Participants With Postbaseline Markedly Abnormal Clinical Chemistry Laboratory Values: Potassium and Calcium	Number of participants with postbaseline markedly abnormal clinical chemistry laboratory values was reported. It included Potassium: >6.0 millimoles per liter (mmol/L) and Calcium: <1.75 mmol/L. Abnormality was judged at the discretion of investigator. Data is reported for categories where at least one participant had abnormality.	Week 4
Number of Participants With Postbaseline Markedly Abnormal Clinical Chemistry Laboratory Values: Alkaline Phosphatase (ALP)	Number of participants with postbaseline markedly abnormal clinical chemistry laboratory values (ALP) was reported. It included Alkaline Phosphatase (ALP): > 2.5 * Upper Limit of Normal (ULN). Abnormality was judged at the discretion of investigator. Participants were assessed at Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52. Data is reported for categories where at least one participant had abnormality at any time point: Weeks 20, 40, and 52 reported.	Week 28
Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Lymphocytes, Monocytes, Eosinophils, and Basophils	Change from baseline in hematology parameters: platelets, leukocytes, lymphocytes, monocytes, eosinophils, and basophils was reported. Data for each parameters was planned to be reported at specified timepoints only.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Hematology Parameter: Hematocrit	Change from baseline in hematology parameter: hematocrit was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Hematology Parameters: Hemoglobin	Change from baseline in hematology parameter: hemoglobin was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Hematology Parameter: Erythrocytes	Change from baseline in hematology parameter: erythrocytes was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Chemistry Parameters: Sodium, Potassium, Urea Nitrogen, Glucose, and Calcium	Change from baseline in chemistry parameters: sodium, potassium, urea nitrogen, glucose, and calcium was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Chemistry Parameters: Creatinine (Jaffe Reaction), Bilirubin, and Direct Bilirubin	Change from baseline in chemistry parameters: Creatinine, bilirubin, and direct bilirubin was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Chemistry Parameter: Creatinine Clearance	Change from baseline in chemistry parameter: creatinine clearance was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Chemistry Parameters: Glomerular Filtration Rate (GFR) From Cystatin C Adjusted for Body Surface Area (BSA)	Change from baseline in chemistry parameter: GFR from Cystatin C Adjusted for BSA was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and Alkaline Phosphatase (ALP)	Change from baseline in chemistry parameters: AST, ALT, and ALP was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Vital Signs: Blood Pressure	Change from baseline in vital signs: blood pressure was reported. It included systolic blood pressure (SBP) and diastolic blood pressure (DBP).	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Vital Signs: Pulse Rate	Change from baseline in vital signs: pulse rate was reported.	Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 40, 52
Change From Baseline in Electrocardiogram (ECG) Parameter: Heart Rate	Change from baseline in ECG: heart rate was reported.	Baseline (Day 1), Weeks 12, 24, and 52
Change From Baseline in Electrocardiogram (ECG) Parameter: PR, QRS, QT, Corrected QT Interval-Bazett's Formula (QTcB), and Corrected QT Interval-Fridericia's Formula (QTcF)	Change from baseline in ECG: PR, QRS, QT, QTcB, and QTcF intervals was reported.	Baseline (Day 1), Weeks 12, 24, and 52
Plasma Concentration of Macitentan: Participants >=2 Years Old	Plasma concentration of macitentan was reported.	Day 11 (0, 1, 2, 4, 8, 12, 24 hours post-dose), Week 12
Plasma Concentration of Aprocitentan (Active Metabolite): Participants >=2 Years Old	Plasma concentration of aprocitentan was reported.	Day 11 (0, 1, 2, 4, 8, 12, 24 hours post-dose), Week 12
Plasma Concentration of Macitentan: Participants <2 Years Old	Plasma concentration of macitentan was reported.	Day 1 (2, 5, 24 hours post-dose), Weeks 4 and 8
Plasma Concentration of Aprocitentan (Active Metabolite): Participants <2 Years Old	Plasma concentration of aprocitentan was reported.	Day 1 (2, 5, 24 hours post-dose), Weeks 4 and 8

Collaborators and Investigators

• Sponsor: Janssen Pharmaceutical K.K.
• Investigators: Study Director: Janssen Pharmaceutical K.K. Clinical Trial, Janssen Pharmaceutical K.K.

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2022
• Primary Completion (Actual): August 23, 2024
• Study Completion (Actual): March 5, 2025

Study Registration Dates

• First Submitted: November 24, 2021
• First Submitted That Met QC Criteria: December 21, 2021
• First Posted (Actual): December 22, 2021

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Molecular Mechanisms of Pharmacological Action; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin B Receptor Antagonists; macitentan
• Other Study ID Numbers: CR109128; 67896062PAH3001 (Other Identifier: Janssen Research & Development, LLC); 2023-000984-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes