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

Phase 3

Active, not recruiting

• Conditions: Pulmonary Arterial Hypertension
• Interventions: Other: Standard-of-care; Drug: Macitentan

• Registration Number: NCT02932410
• Lead Sponsor: Actelion

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-10-12
• Study First Submitted QC: 2016-10-12
• Study First Posted: 2016-10-13
• Study Start: 2017-10-24
• Primary Completion: 2024-08-28
• Status Verified: 2025-08
• Results First Submitted: 2025-08-26
• Results First Submitted QC: 2025-08-26
• Last Update Submitted: 2025-08-26
• Results First Posted: 2025-09-12
• Last Update Posted: 2025-09-12
• Study Completion: 2025-11-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 165

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard-of-care	Standard-of-care	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.
Macitentan	Macitentan	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.

Primary Outcome Measures

Name	Time	Method
Participants >=2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 12 Based on Body Weight	Pre-dose at Week 12	Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 based on body weight were reported. This outcome measure was planned to be analyzed for specified arms only.
Participants >=2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 12 Based on Age Group	Pre-dose at Week 12	Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 based on age group were reported. This outcome measure was planned to be analyzed for specified arms only.
Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4	Pre-dose at Week 4	Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 4 were reported. This outcome measure was planned to be analyzed for specified arms only.
Participants From China With >=12 to <18 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 12	Pre-dose at Week 12	Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 were reported.

Secondary Outcome Measures

Name	Time	Method
Time to the First Clinical Event Committee (CEC)-Confirmed Disease Progression Event	Baseline (Day 1) up to end of core study period (EOCP; up to 7.08 years)
Time to First CEC-confirmed Hospitalization for PAH	Baseline (Day 1) up to EOCP (up to 7.08 years)
Time to CEC-confirmed Death Due to PAH	Baseline (Day 1) up to EOCP (up to 7.08 years)
Time to Death (All Causes)	Baseline (Day 1) up to 7.26 years
Percentage of Participants With World Health Organization (WHO) Functional Class (FC) I or II Versus III or IV	At Weeks 12 and 24
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Weeks 12 and 24	Baseline (Day 1), Weeks 12 and 24
Change From Baseline in Mean Daily Time Spent in Moderate to Vigorous Physical Activity as Measured by Accelerometry at Week 48	Baseline (Day 1), Week 48
Change From Baseline in Body Surface Area (BSA) Normalized Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography at Week 24	Baseline (Day 1), Week 24
Change From Baseline in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography at Week 24	Baseline (Day 1), Week 24
Change From Baseline in Quality of Life Measured by Pediatric Quality of Life Inventory Version 4.0 (PedsQL 4.0) Generic Core Scales Short Form (SF-15)	Baseline (Day 1), Week 24
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Baseline (Day 1) up to 7.26 years
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)	Baseline (Day 1) up to 7.26 years
Number of Participants With AEs Leading to Premature Discontinuation of Macitentan or Standard of Care (SoC)	Baseline (Day 1) up to 7.26 years
Number of Participants With AEs of Special Interest	Baseline (Day 1) up to 7.26 years
Number of Participants With Marked Laboratory Abnormalities	Baseline (Day 1) up to 7.26 years
Change From Baseline in Selected Laboratory Parameters	Baseline (Day 1) up to 7.26 years
Change From Baseline in Vital Signs (Blood Pressure, Heart Rate)	Baseline (Day 1) up to 7.26 years
Change From Baseline in Growth Variable	Baseline (Day 1) up to 7.26 years
Change From Baseline in Sexual Maturation Measured by Tanner Stage	Baseline (Day 1) up to 7.26 years

Trial Locations

Locations (86)

Phoenix Childrens Hospital; 🇺🇸 Phoenix, Arizona, United States

UCLA Children's Heart Center; 🇺🇸 Los Angeles, California, United States

UCSF Medical Center; 🇺🇸 San Francisco, California, United States

Childrens Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Children's National Medical Center; 🇺🇸 Washington D.C., District of Columbia, United States

Riley Hospital For Children; 🇺🇸 Indianapolis, Indiana, United States

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Detroit Medical Center; 🇺🇸 Detroit, Michigan, United States

Mayo Clinic - PPDS; 🇺🇸 Rochester, Minnesota, United States

Children's Heart Center; 🇺🇸 Las Vegas, Nevada, United States

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