Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02932410




Registration number
NCT02932410
Ethics application status
Date submitted
12/10/2016
Date registered
13/10/2016
Date last updated
12/09/2025

Titles & IDs
Public title
A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension (PAH)
Scientific 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
Secondary ID [1] 0 0
AC-055-312
Universal Trial Number (UTN)
Trial acronym
TOMORROW
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Macitentan
Other interventions - Standard-of-care

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.

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.


Treatment: Drugs: Macitentan
Dispersible tablet; Oral use

Other interventions: 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.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
Pre-dose at Week 12
Primary outcome [2] 0 0
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
Timepoint [2] 0 0
Pre-dose at Week 12
Primary outcome [3] 0 0
Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4
Timepoint [3] 0 0
Pre-dose at Week 4
Primary outcome [4] 0 0
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
Timepoint [4] 0 0
Pre-dose at Week 12
Secondary outcome [1] 0 0
Time to the First Clinical Event Committee (CEC)-Confirmed Disease Progression Event
Timepoint [1] 0 0
Baseline (Day 1) up to end of core study period (EOCP; up to 7.08 years)
Secondary outcome [2] 0 0
Time to First CEC-confirmed Hospitalization for PAH
Timepoint [2] 0 0
Baseline (Day 1) up to EOCP (up to 7.08 years)
Secondary outcome [3] 0 0
Time to CEC-confirmed Death Due to PAH
Timepoint [3] 0 0
Baseline (Day 1) up to EOCP (up to 7.08 years)
Secondary outcome [4] 0 0
Time to Death (All Causes)
Timepoint [4] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [5] 0 0
Percentage of Participants With World Health Organization (WHO) Functional Class (FC) I or II Versus III or IV
Timepoint [5] 0 0
At Weeks 12 and 24
Secondary outcome [6] 0 0
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Weeks 12 and 24
Timepoint [6] 0 0
Baseline (Day 1), Weeks 12 and 24
Secondary outcome [7] 0 0
Change From Baseline in Mean Daily Time Spent in Moderate to Vigorous Physical Activity as Measured by Accelerometry at Week 48
Timepoint [7] 0 0
Baseline (Day 1), Week 48
Secondary outcome [8] 0 0
Change From Baseline in Body Surface Area (BSA) Normalized Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography at Week 24
Timepoint [8] 0 0
Baseline (Day 1), Week 24
Secondary outcome [9] 0 0
Change From Baseline in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography at Week 24
Timepoint [9] 0 0
Baseline (Day 1), Week 24
Secondary outcome [10] 0 0
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)
Timepoint [10] 0 0
Baseline (Day 1), Week 24
Secondary outcome [11] 0 0
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Timepoint [11] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [12] 0 0
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)
Timepoint [12] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [13] 0 0
Number of Participants With AEs Leading to Premature Discontinuation of Macitentan or Standard of Care (SoC)
Timepoint [13] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [14] 0 0
Number of Participants With AEs of Special Interest
Timepoint [14] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [15] 0 0
Number of Participants With Marked Laboratory Abnormalities
Timepoint [15] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [16] 0 0
Change From Baseline in Selected Laboratory Parameters
Timepoint [16] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [17] 0 0
Change From Baseline in Vital Signs (Blood Pressure, Heart Rate)
Timepoint [17] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [18] 0 0
Change From Baseline in Growth Variable
Timepoint [18] 0 0
Baseline (Day 1) up to 7.26 years
Secondary outcome [19] 0 0
Change From Baseline in Sexual Maturation Measured by Tanner Stage
Timepoint [19] 0 0
Baseline (Day 1) up to 7.26 years

Eligibility
Key inclusion criteria
Key

* 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
Minimum age
1 Month
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
24/10/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/11/2025
Actual
Sample size
Target
Accrual to date
Final
165
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Royal Children's Hospital Melbourne - PIN - Parkville
Recruitment hospital [2] 0 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 0 0
3052 - Parkville
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
District of Columbia
Country [5] 0 0
United States of America
State/province [5] 0 0
Indiana
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
Minnesota
Country [9] 0 0
United States of America
State/province [9] 0 0
Nevada
Country [10] 0 0
United States of America
State/province [10] 0 0
New York
Country [11] 0 0
United States of America
State/province [11] 0 0
North Carolina
Country [12] 0 0
United States of America
State/province [12] 0 0
Ohio
Country [13] 0 0
United States of America
State/province [13] 0 0
Utah
Country [14] 0 0
United States of America
State/province [14] 0 0
Virginia
Country [15] 0 0
United States of America
State/province [15] 0 0
Wisconsin
Country [16] 0 0
Austria
State/province [16] 0 0
Graz
Country [17] 0 0
Austria
State/province [17] 0 0
Linz
Country [18] 0 0
Brazil
State/province [18] 0 0
São Paulo
Country [19] 0 0
Canada
State/province [19] 0 0
Montreal
Country [20] 0 0
Canada
State/province [20] 0 0
Toronto
Country [21] 0 0
China
State/province [21] 0 0
Beijing
Country [22] 0 0
China
State/province [22] 0 0
Qingdao
Country [23] 0 0
China
State/province [23] 0 0
Shanghai
Country [24] 0 0
Colombia
State/province [24] 0 0
Bogotá
Country [25] 0 0
Colombia
State/province [25] 0 0
Santiago de Cali
Country [26] 0 0
Finland
State/province [26] 0 0
Helsinki
Country [27] 0 0
France
State/province [27] 0 0
Marseille
Country [28] 0 0
France
State/province [28] 0 0
Paris
Country [29] 0 0
France
State/province [29] 0 0
Pessac
Country [30] 0 0
France
State/province [30] 0 0
Toulouse
Country [31] 0 0
Hungary
State/province [31] 0 0
Budapest
Country [32] 0 0
Israel
State/province [32] 0 0
Haifa
Country [33] 0 0
Israel
State/province [33] 0 0
Petah Tikva
Country [34] 0 0
Israel
State/province [34] 0 0
Ramat Gan
Country [35] 0 0
Malaysia
State/province [35] 0 0
Kuala Lumpur
Country [36] 0 0
Mexico
State/province [36] 0 0
Guadalajara
Country [37] 0 0
Mexico
State/province [37] 0 0
Mexico City
Country [38] 0 0
Mexico
State/province [38] 0 0
México
Country [39] 0 0
Mexico
State/province [39] 0 0
Monterrey
Country [40] 0 0
Philippines
State/province [40] 0 0
Makati City
Country [41] 0 0
Philippines
State/province [41] 0 0
Quezon City
Country [42] 0 0
Poland
State/province [42] 0 0
Poznan
Country [43] 0 0
Poland
State/province [43] 0 0
Warsaw
Country [44] 0 0
Poland
State/province [44] 0 0
Wroclaw
Country [45] 0 0
Portugal
State/province [45] 0 0
Carnaxide
Country [46] 0 0
Portugal
State/province [46] 0 0
Coimbra
Country [47] 0 0
Portugal
State/province [47] 0 0
Lisbon
Country [48] 0 0
Portugal
State/province [48] 0 0
Porto
Country [49] 0 0
Russia
State/province [49] 0 0
Kemerovo
Country [50] 0 0
Russia
State/province [50] 0 0
Moscow
Country [51] 0 0
Russia
State/province [51] 0 0
Novosibirsk
Country [52] 0 0
Russia
State/province [52] 0 0
Saint Petersburg
Country [53] 0 0
Russia
State/province [53] 0 0
Tyumen
Country [54] 0 0
Russia
State/province [54] 0 0
Ufa
Country [55] 0 0
South Africa
State/province [55] 0 0
Bloemfontein
Country [56] 0 0
South Africa
State/province [56] 0 0
Durban
Country [57] 0 0
South Korea
State/province [57] 0 0
Seoul
Country [58] 0 0
Spain
State/province [58] 0 0
Barcelona
Country [59] 0 0
Spain
State/province [59] 0 0
Córdoba
Country [60] 0 0
Spain
State/province [60] 0 0
Madrid
Country [61] 0 0
Spain
State/province [61] 0 0
Valencia
Country [62] 0 0
Thailand
State/province [62] 0 0
Chiang Mai
Country [63] 0 0
Ukraine
State/province [63] 0 0
Dnipro
Country [64] 0 0
Ukraine
State/province [64] 0 0
Kharkiv
Country [65] 0 0
Ukraine
State/province [65] 0 0
Kyiv
Country [66] 0 0
Vietnam
State/province [66] 0 0
Hanoi
Country [67] 0 0
Vietnam
State/province [67] 0 0
Ho Chi Minh City

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Actelion
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Study Contact
Address 0 0
Country 0 0
Phone 0 0
844-434-4210
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT02932410