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

April 23, 2024 updated by: Actelion

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

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Australia
      • Parkville, Australia, 3052
        • Recruiting
        • Royal Children's Hospital Melbourne - PIN
        • Contact:
      • South Brisbane, Australia, 4101
        • Recruiting
        • Lady Cilento Children's Hospital
        • Contact:
      • Westmead, Australia, 2145
        • Completed
        • Children's Hospital at Westmead
  • Austria
      • Graz, Austria, 8036
        • Completed
        • Medizinische Universität Graz
      • Linz, Austria, 4020
        • Completed
        • Landes Frauen Und Kinderklinik Linz
      • Linz, Austria, 4020
        • Completed
        • Medizinische Universitat Wien
  • Brazil
      • São Paulo, Brazil, 01221-020
        • Recruiting
        • Irmandade Da Santa Casa de Misericordia de Sao Paulo
  • Canada
      • Montreal, Canada, H3T 1C5
        • Recruiting
        • Sainte Justine Hospital
        • Contact:
          • Principal Investigator
      • Toronto, Canada, T6G 2B7
        • Completed
        • Stollery Children's Hospital
  • China
      • Beijing, China, 100037
        • Withdrawn
        • Beijing Children's Hospital，Capital Medical University
      • Beijing, China, 100037
        • Withdrawn
        • Fuwai Hospital
      • Beijing, China, 100029
        • Recruiting
        • Beijing Anzhen Hospital of The Capital University of Medical Sciences
        • Contact:
      • Hangzhou, China, 310003
        • Withdrawn
        • The Children's Hospital, Zhejiang University school of medicine
      • Qingdao, China, 26600
        • Recruiting
        • Qingdao Women and Children's Hospital
      • Shanghai, China, 200127
        • Recruiting
        • Shanghai Children's Medical Center
        • Contact:
      • Shanghai, China, 200062
        • Recruiting
        • Childrens Hospital of Shanghai
      • Shenyang, China, 110015
        • Withdrawn
        • General Hospital of Shenyang Military Region
      • Wuhan, China, 430015
        • Withdrawn
        • Wuhan Asia Heart Hospital
  • Colombia
      • Bogota, Colombia, 220246
        • Recruiting
        • Fundacion Santa Fe de Bogota
      • Cali, Colombia, 760042
        • Recruiting
        • Centro Medico Imbanaco de Cali SA
  • Finland
      • Helsinki, Finland, 00290
        • Completed
        • HUS Uusi lastensairaala
  • France
      • Marseille, France, 13385
        • Recruiting
        • Hôpital de la Timone Enfants
        • Contact:
      • Paris cedex 15, France, 75743
        • Recruiting
        • Groupe Hospitalier Necker Enfants Malades
        • Contact:
      • Pessac, France, 33604
        • Recruiting
        • Hôpital Haut-Lévêque - Hôpital cardiologique
        • Contact:
      • Toulouse Cedex 9, France, 31059
        • Recruiting
        • Hôpital Des Enfants
        • Contact:
  • Hungary
      • Budapest, Hungary, 1096
        • Recruiting
        • Gottsegen György Országos Kardiológiai Intézet
        • Contact:
  • Israel
      • Haifa, Israel, 31096
      • Petah-Tikva, Israel, 49100
        • Recruiting
        • Schneider Children's Medical Center of Israel - PIN
        • Contact:
      • Ramat Gan, Israel, 52621
        • Completed
        • Chaim Sheba Medical Center
  • Korea, Republic of
      • Seoul, Korea, Republic of, 03080
        • Recruiting
        • Seoul National University Hospital
        • Contact:
      • Seoul, Korea, Republic of, 03722
        • Recruiting
        • Severance Hospital Yonsei University Health System - PPDS
        • Contact:
          • Principal Investigator
          • Phone Number: +82222288470
          • Email: jwjung@yuhs.ac
  • Malaysia
      • Kuala Lumpur, Malaysia, 59100
        • Recruiting
        • University Malaya Medical Centre
      • Kuala Lumpur, Malaysia, 50400
        • Completed
        • Institut Jantung Negara
  • Mexico
      • Ciudad De México, Mexico, 04530
        • Recruiting
        • Instituto Nacional de Pediatría
        • Contact:
      • Ciudad De México, Mexico, 14080
        • Recruiting
        • Instituto Nacional de Cardiologia Dr. Ignacio Chavez
      • Guadalajara, Mexico, 44160
      • Mexico, Mexico, 52763
        • Recruiting
        • Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas
        • Contact:
      • Monterrey, Mexico, 64718
        • Recruiting
        • Unidad de Investigación Clínica En Medicina SC
        • Contact:
  • Philippines
      • Makati City, Philippines, 1229
        • Completed
        • Makati Medical Center
      • Quezon City, Philippines, 0850
        • Recruiting
        • Philippine Heart Center
        • Contact:
  • Poland
      • Poznań, Poland, 60-572
        • Recruiting
        • Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
        • Contact:
      • Warszawa, Poland, 04-730
        • Recruiting
        • Instytut Pomnik - Centrum Zdrowia Dziecka
        • Contact:
          • Principal Investigator
          • Phone Number: 48228157329
          • Email: m.zuk@ipczd.pl
      • Wroclaw, Poland, 51-124
        • Recruiting
        • Wojewodzki Szpital Specjalistyczny we Wroclawiu Osrodek Badawczo-Rozwojowy
        • Contact:
  • Portugal
      • Carnaxide, Portugal, 2790-134
        • Recruiting
        • Centro Hospitalar de Lisboa Ocidental, EPE - Hospital de Santa Cruz
        • Contact:
      • Coimbra, Portugal, 3000-075
        • Recruiting
        • Centro Hospitalar E Universitário de Coimbra EPE
        • Contact:
      • Lisboa, Portugal, 1169-024
      • Porto, Portugal, 4200-319
  • Russian Federation
      • Kemerovo, Russian Federation, 650002
        • Recruiting
        • Research Institute of Complex Cardiovascular Pathology
        • Contact:
      • Moscow, Russian Federation, 125412
        • Recruiting
        • Russian National Research Medical University n.a. N.I.Pirogov
        • Contact:
      • Moscow, Russian Federation, 125408
        • Completed
        • GBUZ Children's Hospital named after Bashlyaeva Z.A. Moscow
      • Novosibirsk, Russian Federation, 630055
        • Recruiting
        • Novosibirsk Research Institue of Blood Circulation Pathology n.a. E.N. Meshalkin
        • Contact:
          • Principal Investigator
          • Phone Number: +73833322353
      • St. Petersburg, Russian Federation, 194100
        • Completed
        • Saint Petersburg State Pediatric Medical Academy
      • Tyumen, Russian Federation, 625023
        • Recruiting
        • Clinical Hospital №1
        • Contact:
      • Ufa, Russian Federation, 450000
        • Completed
        • Bashkiria State Medical University
  • South Africa
      • Bloemfontein, South Africa, 9300
        • Completed
        • University of The Free State
      • Durban, South Africa, 4001
        • Completed
        • Inkosi Albert Luthuli Central Hospital
  • Spain
      • Barcelona, Spain, 08035
        • Completed
        • Hospital Universitario Vall d'Hebron - PPDS
      • Cordoba, Spain, 14001
        • Completed
        • C.H. Regional Reina Sofia
      • Madrid, Spain, 28034
        • Recruiting
        • Hospital Universitario Ramon Y Cajal
        • Contact:
          • Principal Investigator
      • Madrid, Spain, 28041
        • Completed
        • Hospital Universitario 12 de Octubre
      • Madrid, Spain, 28046
        • Completed
        • Hospital Universitario La Paz
      • Madrid, Spain, 28009
        • Completed
        • Hospital General Universitario Gregorio Maranon
      • Valencia, Spain, 46026
        • Recruiting
        • Hospital Universitari i Politecnic La Fe de Valencia
        • Contact:
  • Thailand
      • Bangkok, Thailand, 10400
        • Withdrawn
        • Ramathibodi Hospital Mahidol University
      • Bangkok, Thailand, 10700
        • Withdrawn
        • Siriraj Hospital Mahidol University
      • Chiang Mai, Thailand, 50200
        • Recruiting
        • Maharaj Nakorn Chiang Mai Chiang Mai University
        • Contact:
          • Principal Investigator
  • Ukraine
      • Dnipro, Ukraine, 49000
        • Recruiting
        • MI Dnipropetrovsk Specialized Clin. Med. Center of Mother and Child n.a. prof. M.F. Rudnev of DRC
        • Contact:
      • Kharkiv, Ukraine, 61093
        • Recruiting
        • Municipal Institution of Health Care Regional Children's Clinical Hospital
        • Contact:
      • Kyiv, Ukraine, 04050
        • Recruiting
        • MI Scientific Practical Medical Center for Children Cardiology and Cardiosurgery of MOH of Ukraine
        • Contact:
          • Principal Investigator
          • Phone Number: +380677996331
          • Email: lillit@ukr.net
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85016
        • Completed
        • Phoenix Childrens Hospital
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • UCLA Children's Heart Center
        • Contact:
      • San Francisco, California, United States, 94143-2202
        • Completed
        • UCSF Medical Center
    • Colorado
      • Aurora, Colorado, United States, 80045
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
        • Recruiting
        • Children's National Medical Center
        • Contact:
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Recruiting
        • Riley Hospital for Children
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Completed
        • Detroit Medical Center
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Completed
        • Mayo Clinic - PPDS
    • Nevada
      • Las Vegas, Nevada, United States, 89109
    • New York
      • Bronx, New York, United States, 10467
        • Recruiting
        • Montefiore Medical Center
        • Contact:
      • New York, New York, United States, 10032
        • Recruiting
        • Columbia University Medical Center - PIN
        • Contact:
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Recruiting
        • Duke University Medical Center
        • Contact:
      • Greenville, North Carolina, United States, 27834
        • Completed
        • East Carolina University
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Recruiting
        • Cincinnati Children's Hospital Medical Center
        • Contact:
      • Cleveland, Ohio, United States, 44106
        • Completed
        • University Hospitals Cleveland Medical Center, Rainbow Babies and Childrens Hospital
      • Columbus, Ohio, United States, 43205
        • Completed
        • Nationwide Children's Hospital
    • Texas
      • Houston, Texas, United States, 77030
        • Withdrawn
        • Texas Children's Hospital
    • Utah
      • Salt Lake City, Utah, United States, 84113
        • Completed
        • Primary Children's Medical Center
    • Virginia
      • Charlottesville, Virginia, United States, 19803
        • Recruiting
        • University of Virginia Health System
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Completed
        • Childrens Hospital of Wisconsin
  • Vietnam
      • Hanoi, Vietnam, 100000
        • Recruiting
        • Hanoi Heart Hospital
        • Contact:
      • Hanoi, Vietnam, 100000
        • Recruiting
        • Hanoi Medical University Hospital
        • Contact:
      • Ho Chi Minh, Vietnam, 700000
        • Recruiting
        • Tam Duc Hospital
        • Contact:
      • Ho Chi Minh City, Vietnam, 700000
        • Recruiting
        • Children's Hospital 1
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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 Greater than or Equal to (>=) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 12
Time Frame: Week 12
Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.
Week 12
Participants Less than (<) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 4
Time Frame: Week 4
Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.
Week 4

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to the first CEC-confirmed Disease Progression Event
Time Frame: 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.
Between randomization/visit 2 and end of core study period (EOCP); up to 7 years
Time to First CEC-confirmed Hospitalization for PAH
Time Frame: 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.
Between randomization/visit 2 and EOCP/; up to 7 years
Time to CEC-confirmed death due to PAH
Time Frame: 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.
Between randomization/visit 2 and EOCP; up to 7 years
Time to death (all causes)
Time Frame: Between randomization/visit 2 and EOCP; up to 7 years
Time to death (all causes) occurring between randomization/visit 2 and EOCP.
Between randomization/visit 2 and EOCP; up to 7 years
The Percentage of Participants with World Health Organization (WHO) Functional Class (FC) I or II versus III or IV
Time Frame: Week 24
Percentage of participants with WHO FC I or II versus III or IV will be reported.
Week 24
Change from Baseline to Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
Time Frame: Baseline to Week 24
The quantitation of NT-proBNP plasma levels will be performed and reported.
Baseline to Week 24
Change from Baseline to Week 48 in Moderate to Vigorous Physical Activity as Measured by Accelerometry
Time Frame: Baseline to Week 48
Change from baseline to Week 48 in moderate to vigorous physical activity as measured by accelerometry will be reported.
Baseline to Week 48
Change from Baseline to Week 24 in Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography
Time Frame: 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.
Baseline to Week 24
Change from Baseline to Week 24 in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography
Time Frame: 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.
Baseline to Week 24
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)
Time Frame: 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.
Baseline to Week 24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Actelion

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 24, 2017

Primary Completion (Actual)

November 21, 2023

Study Completion (Estimated)

December 31, 2024

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)

April 24, 2024

Last Update Submitted That Met QC Criteria

April 23, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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