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

A Multicenter, Open-label, Randomized, Study With Single-arm Extension Period to Assess the Pharmacokinetics, Safety and Efficacy of Macitentan Versus Standard of Care in Children With Pulmonary Arterial Hypertension

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).

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Macitentan; Other: Standard-of-care

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Parkville, Australia, 3052
    • Royal Children's Hospital Melbourne - PIN
  • South Brisbane, Australia, 4101
    • Lady Cilento Children's Hospital
  • Westmead, Australia, 2145
    • Children's Hospital at Westmead
• Austria
  • Graz, Austria, 8036
    • Medizinische Universitat Graz
  • Linz, Austria, 4020
    • Landes Frauen Und Kinderklinik Linz
  • Linz, Austria, 4020
    • Medizinische Universitat Wien
• Brazil
  • São Paulo, Brazil, 01221-020
    • Irmandade Da Santa Casa De Misericordia De Sao Paulo
• Canada
  • Montreal, Canada, H3T 1C5
    • Sainte Justine Hospital
• China
  • Beijing, China, 100029
    • Beijing Anzhen Hospital of the Capital University of Medical Sciences
  • Qingdao, China, 26600
    • Qingdao Women and Children's Hospital
  • Shanghai, China, 200127
    • Shanghai Children's Medical Center
  • Shanghai, China, 200062
    • Childrens Hospital of Shanghai
• Colombia
  • Bogotá, Colombia, 220246
    • Fundacion Santa Fe de Bogota
  • Cali, Colombia, 760042
    • Centro Medico Imbanaco de Cali SA
• Finland
  • Helsinki, Finland, 00290
    • HUS Uusi lastensairaala
• France
  • Marseille, France, 13385
    • Hôpital de la Timone Enfants
  • Paris, France, 75743
    • Groupe Hospitalier Necker Enfants Malades
  • Pessac, France, 33604
    • Hôpital Haut-Lévêque - Hôpital cardiologique
  • Toulouse, France, 31059
    • Hopital des Enfants
• Hungary
  • Budapest, Hungary, 1096
    • Gottsegen György Országos Kardiológiai Intézet
• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Center - PPDS
  • Petah Tikva, Israel, 49100
    • Schneider Children's Medical Center of Israel - PIN
  • Ramat Gan, Israel, 52621
    • Chaim Sheba Medical Center
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Kuala Lumpur, Malaysia, 50400
    • Institut Jantung Negara
• Mexico
  • Guadalajara, Mexico, 44160
    • CICUM San Miguel
  • Mexico City, Mexico, 04530
    • Instituto Nacional de Pediatría
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Cardiologia Dr. Ignacio Chavez
  • Monterrey, Mexico, 64716
    • Unidad de Investigación Clínica En Medicina SC
  • México, Mexico, 52763
    • Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas
• Philippines
  • Makati City, Philippines, 1229
    • Makati Medical Center
  • Quezon City, Philippines, 0850
    • Philippine Heart Center
• Poland
  • Poznan, Poland, 60-572
    • Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
  • Warsaw, Poland, 04-730
    • Instytut Pomnik - Centrum Zdrowia Dziecka
  • Wroclaw, Poland, 51-124
    • Wojewodzki Szpital Specjalistyczny we Wroclawiu Osrodek Badawczo-Rozwojowy
• Portugal
  • Carnaxide, Portugal, 2790-134
    • Centro Hospitalar de Lisboa Ocidental, EPE - Hospital de Santa Cruz
  • Coimbra, Portugal, 3000-075
    • Centro Hospitalar E Universitario de Coimbra EPE
  • Lisbon, Portugal, 1169-024
    • Hospital Santa Marta
  • Porto, Portugal, 4200-319
    • Centro Hospitalar de Sao Joao Epe
• Russia
  • Kemerovo, Russia, 650002
    • Research Institute of Complex Cardiovascular Pathology
  • Moscow, Russia, 125408
    • GBUZ Children's Hospital named after Bashlyaeva Z.A. Moscow
  • Moscow, Russia, 125412
    • Russian National Research Medical University n.a. N.I.Pirogov
  • Novosibirsk, Russia, 630055
    • Novosibirsk Research Institue of Blood Circulation Pathology n.a. E.N. Meshalkin
  • Saint Petersburg, Russia, 194100
    • Saint Petersburg State Pediatric Medical Academy
  • Tyumen, Russia, 625023
    • Clinical Hospital №1
  • Ufa, Russia, 450000
    • Bashkiria State Medical University
• South Africa
  • Bloemfontein, South Africa, 9300
    • University of the Free State
  • Durban, South Africa, 4001
    • Inkosi Albert Luthuli Central Hospital
• South Korea
  • Seoul, South Korea, 03080
    • Seoul National University Hospital
  • Seoul, South Korea, 03722
    • Severance Hospital Yonsei University Health System - PPDS
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron - PPDS
  • Córdoba, Spain, 14004
    • C.H. Regional Reina Sofia
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28009
    • Hospital General Universitario Gregorio Marañon
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
• Thailand
  • Chiang Mai, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Chiang Mai University
• Ukraine
  • Dnipro, Ukraine, 49000
    • MI Dnipropetrovsk Specialized Clin. Med. Center of Mother and Child n.a. prof. M.F. Rudnev of DRC
  • Kharkiv, Ukraine, 61093
    • Municipal Institution of Health Care Regional Children's Clinical Hospital
  • Kyiv, Ukraine, 04050
    • MI Scientific Practical Medical Center for Children Cardiology and Cardiosurgery of MOH of Ukraine
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Children's Heart Center
    • San Francisco, California, United States, 94143-2202
      • UCSF Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Childrens Hospital Colorado
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Detroit Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - PPDS
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Children's Heart Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center - PIN
    • The Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center, Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 19803
      • University of Virginia Health System
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Childrens Hospital of Wisconsin
• Vietnam
  • Hanoi, Vietnam, 100000
    • Hanoi Heart Hospital
  • Hanoi, Vietnam, 100000
    • Hanoi Medical University Hospital
  • Ho Chi Minh City, Vietnam, 700000
    • Children's Hospital 1
  • Ho Chi Minh City, Vietnam, 700000
    • Tam Duc Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Key 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Macitentan; Dispersible tablet; Oral use; Other Names: ACT-064992
Other: 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.	Other: Standard-of-care; Standard-of-care as per site's clinical practice which may comprise treatment with PAH non-specific treatment and/or up to two PAH-specific medications excluding macitentan and IV/SC prostanoids.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Pre-dose at Week 12
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	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.	Pre-dose at Week 12
Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) 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.	Pre-dose at Week 4
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	Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 were reported.	Pre-dose at Week 12

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Actelion

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2017
• Primary Completion (Actual): August 28, 2024
• Study Completion (Actual): November 27, 2025

Study Registration Dates

• First Submitted: October 12, 2016
• First Submitted That Met QC Criteria: October 12, 2016
• First Posted (Estimated): October 13, 2016

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care; macitentan
• Other Study ID Numbers: AC-055-312

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No