A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension (PAH)
- Conditions
- Pulmonary Arterial Hypertension
- Interventions
- Other: Standard-of-care
- 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
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 165
- 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
- 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 Greater than or Equal to (>=) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 12 Week 12 Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.
Participants Less than (<) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 4 Week 4 Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.
- Secondary Outcome Measures
Name Time Method Time to First CEC-confirmed Hospitalization for PAH Between randomization/visit 2 and EOCP/; up to 7 years Time to first CEC-confirmed hospitalization for PAH occurring between randomization/visit 2 and EOCP.
Time to CEC-confirmed death due to PAH Between randomization/visit 2 and EOCP; up to 7 years Time to CEC-confirmed death due to PAH occurring between randomization/visit 2 and EOCP.
Time to death (all causes) Between randomization/visit 2 and EOCP; up to 7 years Time to death (all causes) occurring between randomization/visit 2 and EOCP.
Change from Baseline to Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Baseline to Week 24 The quantitation of NT-proBNP plasma levels will be performed and reported.
Change from Baseline to Week 48 in Moderate to Vigorous Physical Activity as Measured by Accelerometry Baseline to Week 48 Change from baseline to Week 48 in moderate to vigorous physical activity as measured by accelerometry will be reported.
The Percentage of Participants with World Health Organization (WHO) Functional Class (FC) I or II versus III or IV Week 24 Percentage of participants with WHO FC I or II versus III or IV will be reported.
Change from Baseline to Week 24 in Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography Baseline to Week 24 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.
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) Baseline to Week 24 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.
Time to the first CEC-confirmed Disease Progression Event Between randomization/visit 2 and end of core study period (EOCP); up to 7 years 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.
Change from Baseline to Week 24 in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography Baseline to Week 24 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.
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, 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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