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)
UCLA Children's Heart Center
🇺🇸Los Angeles, California, United States
Riley Hospital For Children
🇺🇸Indianapolis, Indiana, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
UCSF Medical Center
🇺🇸San Francisco, California, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
Detroit Medical Center
🇺🇸Detroit, Michigan, United States
Mayo Clinic - PPDS
🇺🇸Rochester, Minnesota, United States
Columbia University Medical Center - PIN
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
University Hospitals Cleveland Medical Center, Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Lady Cilento Children's Hospital
🇦🇺South Brisbane, Australia
Royal Children's Hospital Melbourne - PIN
🇦🇺Parkville, Australia
Stollery Children's Hospital
🇨🇦Toronto, Canada
Beijing Anzhen Hospital of The Capital University of Medical Sciences
🇨🇳Beijing, China
Childrens Hospital of Shanghai
🇨🇳Shanghai, China
Shanghai Children's Medical Center
🇨🇳Shanghai, China
Hôpital de la Timone Enfants
🇫🇷Marseille, France
Groupe Hospitalier Necker Enfants Malades
🇫🇷Paris cedex 15, France
Hôpital Haut-Lévêque - Hôpital cardiologique
🇫🇷Pessac, France
Gottsegen Gyorgy Orszagos Kardiologiai Intezet
🇭🇺Budapest, Hungary
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital Yonsei University Health System - PPDS
🇰🇷Seoul, Korea, Republic of
Institut Jantung Negara
🇲🇾Kuala Lumpur, Malaysia
Instituto Nacional de Pediatría
🇲🇽Ciudad De México, Mexico
Philippine Heart Center
🇵🇭Quezon City, Philippines
Instytut Pomnik - Centrum Zdrowia Dziecka
🇵🇱Warszawa, Poland
Centro Hospitalar E Universitário de Coimbra EPE
🇵🇹Coimbra, Portugal
Centro Hospitalar de Sao Joao EPE
🇵🇹Porto, Portugal
Hospital Santa Marta
🇵🇹Lisboa, Portugal
Russian National Research Medical University n.a. N.I.Pirogov
🇷🇺Moscow, Russian Federation
Novosibirsk Research Institue of Blood Circulation Pathology n.a. E.N. Meshalkin
🇷🇺Novosibirsk, Russian Federation
Saint Petersburg State Pediatric Medical Academy
🇷🇺St. Petersburg, Russian Federation
Clinical Hospital №1
🇷🇺Tyumen, Russian Federation
University of The Free State
🇿🇦Bloemfontein, South Africa
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hanoi Heart Hospital
🇻🇳Hanoi, Vietnam
Municipal Institution of Health Care Regional Children's Clinical Hospital
🇺🇦Kharkiv, Ukraine
Children's Hospital at Westmead
🇦🇺Westmead, Australia
Childrens Hospital Colorado
🇺🇸Aurora, Colorado, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Primary Children's Medical Center
🇺🇸Salt Lake City, Utah, United States
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Qingdao Women and Children's Hospital
🇨🇳Qingdao, China
Sainte Justine Hospital
🇨🇦Montreal, Canada
Hôpital Des Enfants
🇫🇷Toulouse Cedex 9, France
Irmandade Da Santa Casa de Misericórdia de São Paulo
🇧🇷São Paulo, Brazil
Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
🇵🇱Poznań, Poland
Inkosi Albert Luthuli Central Hospital
🇿🇦Durban, South Africa
Hospital Universitario Vall d'Hebron - PPDS
🇪🇸Barcelona, Spain
C.H. Regional Reina Sofia
🇪🇸Cordoba, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸Valencia, Spain
Maharaj Nakorn Chiang Mai Chiang Mai University
🇹🇭Chiang Mai, Thailand
MI Dnipropetrovsk Specialized Clin. Med. Center of Mother and Child n.a. prof. M.F. Rudnev of DRC
🇺🇦Dnipro, Ukraine
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Centro Medico Imbanaco de Cali SA
🇨🇴Cali, Colombia
HUS Uusi lastensairaala
🇫🇮Helsinki, Finland
Chaim Sheba Medical Center
🇮🇱Ramat Gan, Israel
Instituto Nacional de Cardiologia Dr. Ignacio Chavez
🇲🇽Ciudad De México, Mexico
Childrens Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Children's Heart Center
🇺🇸Las Vegas, Nevada, United States
Medizinische Universität Graz
🇦🇹Graz, Austria
Medizinische Universitat Wien
🇦🇹Linz, Austria
Fundacion Santa Fe de Bogota
🇨🇴Bogota, Colombia
Rambam Medical Center - PPDS
🇮🇱Haifa, Israel
University Malaya Medical Centre
🇲🇾Kuala Lumpur, Malaysia
Hanoi Medical University Hospital
🇻🇳Hanoi, Vietnam
Children's Hospital 1
🇻🇳Ho Chi Minh City, Vietnam
Tam Duc Hospital
🇻🇳Ho Chi Minh, Vietnam
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Landes Frauen Und Kinderklinik Linz
🇦🇹Linz, Austria
Schneider Children's Medical Center of Israel - PIN
🇮🇱Petah-Tikva, Israel
Makati Medical Center
🇵🇭Makati City, Philippines
Wojewodzki Szpital Specjalistyczny we Wroclawiu Osrodek Badawczo-Rozwojowy
🇵🇱Wroclaw, Poland
Unidad de Investigación Clínica En Medicina SC
🇲🇽Monterrey, Mexico
Research Institute of Complex Cardiovascular Pathology
🇷🇺Kemerovo, Russian Federation
GBUZ Children's Hospital named after Bashlyaeva Z.A. Moscow
🇷🇺Moscow, Russian Federation
CICUM San Miguel
🇲🇽Guadalajara, Mexico
Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas
🇲🇽Mexico, Mexico
Centro Hospitalar de Lisboa Ocidental, EPE - Hospital de Santa Cruz
🇵🇹Carnaxide, Portugal
Bashkiria State Medical University
🇷🇺Ufa, Russian Federation
MI Scientific Practical Medical Center for Children Cardiology and Cardiosurgery of MOH of Ukraine
🇺🇦Kyiv, Ukraine
Montefiore Medical Center
🇺🇸Bronx, New York, United States