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

Pulmonary Arterial Hypertension Clinical Trial

— TOMORROW  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02932410
• Other study ID #: AC-055-312
• Status: Recruiting
• Phase: Phase 3
• Start date: October 24, 2017
• Est. completion date: December 31, 2024

Study information

• Verified date: June 2024
• Source: Actelion
• Contact: Study Contact
• Phone: 844-434-4210
• Email: JNJ.CT[@]sylogent.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 31, 2024
• Est. primary completion date: November 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Macitentan
Dispersible tablet; Oral use

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.

Locations

Country	Name	City	State
Australia	Royal Children's Hospital Melbourne - PIN	Parkville
Australia	Lady Cilento Children's Hospital	South Brisbane
Australia	Children's Hospital at Westmead	Westmead
Austria	Medizinische Universität Graz	Graz
Austria	Landes Frauen Und Kinderklinik Linz	Linz
Austria	Medizinische Universitat Wien	Linz
Brazil	Irmandade Da Santa Casa de Misericórdia de São Paulo	São Paulo
Canada	Sainte Justine Hospital	Montreal
Canada	Stollery Children's Hospital	Toronto
China	Beijing Anzhen Hospital of The Capital University of Medical Sciences	Beijing
China	Beijing Children's Hospital,Capital Medical University	Beijing
China	Fuwai Hospital	Beijing
China	The Children's Hospital, Zhejiang University school of Medicine	Hangzhou
China	Qingdao Women and Children's Hospital	Qingdao
China	Childrens Hospital of Shanghai	Shanghai
China	Shanghai Children's Medical Center	Shanghai
China	General Hospital of Shenyang Military Region	Shenyang
China	Wuhan Asia Heart Hospital	Wuhan
Colombia	Fundacion Santa Fe de Bogota	Bogota
Colombia	Centro Medico Imbanaco de Cali SA	Cali
Finland	HUS Uusi lastensairaala	Helsinki
France	Hôpital de la Timone Enfants	Marseille
France	Groupe Hospitalier Necker Enfants Malades	Paris cedex 15
France	Hôpital Haut-Lévêque - Hôpital cardiologique	Pessac
France	Hôpital Des Enfants	Toulouse Cedex 9
Hungary	Gottsegen Gyorgy Orszagos Kardiologiai Intezet	Budapest
Israel	Rambam Medical Center - PPDS	Haifa
Israel	Schneider Children's Medical Center of Israel - PIN	Petah-Tikva
Israel	Chaim Sheba Medical Center	Ramat Gan
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System - PPDS	Seoul
Malaysia	Institut Jantung Negara	Kuala Lumpur
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Mexico	Instituto Nacional de Cardiologia Dr. Ignacio Chavez	Ciudad De México
Mexico	Instituto Nacional de Pediatría	Ciudad De México
Mexico	CICUM San Miguel	Guadalajara
Mexico	Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas	Mexico
Mexico	Unidad de Investigación Clínica En Medicina SC	Monterrey
Philippines	Makati Medical Center	Makati City
Philippines	Philippine Heart Center	Quezon City
Poland	Szpital Kliniczny im. Karola Jonschera Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Poznan
Poland	Instytut Pomnik - Centrum Zdrowia Dziecka	Warszawa
Poland	Wojewodzki Szpital Specjalistyczny we Wroclawiu Osrodek Badawczo-Rozwojowy	Wroclaw
Portugal	Centro Hospitalar de Lisboa Ocidental, EPE - Hospital de Santa Cruz	Carnaxide
Portugal	Centro Hospitalar E Universitário de Coimbra EPE	Coimbra
Portugal	Hospital Santa Marta	Lisboa
Portugal	Centro Hospitalar de Sao Joao EPE	Porto
Russian Federation	Research Institute of Complex Cardiovascular Pathology	Kemerovo
Russian Federation	GBUZ Children's Hospital named after Bashlyaeva Z.A. Moscow	Moscow
Russian Federation	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	Bashkiria State Medical University	Ufa
South Africa	University of The Free State	Bloemfontein
South Africa	Inkosi Albert Luthuli Central Hospital	Durban
Spain	Hospital Universitario Vall d'Hebron - PPDS	Barcelona
Spain	C.H. Regional Reina Sofia	Cordoba
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Thailand	Ramathibodi Hospital Mahidol University	Bangkok
Thailand	Siriraj Hospital Mahidol University	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Chiang Mai University	Chiang Mai
Ukraine	MI Dnipropetrovsk Specialized Clin. Med. Center of Mother and Child n.a. prof. M.F. Rudnev of DRC	Dnipro
Ukraine	Municipal Institution of Health Care Regional Children's Clinical Hospital	Kharkiv
Ukraine	MI Scientific Practical Medical Center for Children Cardiology and Cardiosurgery of MOH of Ukraine	Kyiv
United States	Childrens Hospital Colorado	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	University of Virginia Health System	Charlottesville	Virginia
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	Nationwide Children's Hospital	Columbus	Ohio
United States	Detroit Medical Center	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Texas Children's Hospital	Houston	Texas
United States	Riley Hospital For Children	Indianapolis	Indiana
United States	Children's Heart Center	Las Vegas	Nevada
United States	UCLA Children's Heart Center	Los Angeles	California
United States	Childrens Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Columbia University Medical Center - PIN	New York	New York
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Mayo Clinic - PPDS	Rochester	Minnesota
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	UCSF Medical Center	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia
Vietnam	Hanoi Heart Hospital	Hanoi
Vietnam	Hanoi Medical University Hospital	Hanoi
Vietnam	Tam Duc Hospital	Ho Chi Minh
Vietnam	Children's Hospital 1	Ho Chi Minh City

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Vietnam,  Australia,  Austria,  Brazil,  Canada,  China,  Colombia,  Finland,  France,  Hungary,  Israel,  Korea, Republic of,  Malaysia,  Mexico,  Philippines,  Poland,  Portugal,  Russian Federation,  South Africa,  Spain,  Thailand,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.	Week 12
Primary	Participants Less than (<) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 4	Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.	Week 4
Secondary	Time to the first CEC-confirmed Disease Progression Event	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
Secondary	Time to First CEC-confirmed Hospitalization for PAH	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
Secondary	Time to CEC-confirmed death due to PAH	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
Secondary	Time to death (all causes)	Time to death (all causes) occurring between randomization/visit 2 and EOCP.	Between randomization/visit 2 and EOCP; up to 7 years
Secondary	The Percentage of Participants with World Health Organization (WHO) Functional Class (FC) I or II versus III or IV	Percentage of participants with WHO FC I or II versus III or IV will be reported.	Week 24
Secondary	Change from Baseline to Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)	The quantitation of NT-proBNP plasma levels will be performed and reported.	Baseline to Week 24
Secondary	Change from Baseline to Week 48 in Moderate to Vigorous Physical Activity as Measured by Accelerometry	Change from baseline to Week 48 in moderate to vigorous physical activity as measured by accelerometry will be reported.	Baseline to Week 48
Secondary	Change from Baseline to Week 24 in Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography	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
Secondary	Change from Baseline to Week 24 in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography	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
Secondary	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)	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