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).
Brief Title
A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension (PAH)
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Pulmonary Arterial Hypertension
Eligibility Criteria
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
* 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
Inclusion Criteria
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)
* 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)
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
17 Years
Minimum Age
1 Month
NCT Id
NCT02932410
Org Class
Industry
Org Full Name
Actelion
Org Study Id
AC-055-312
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.
Outcome Measure
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
Outcome Time Frame
Week 12
Outcome Description
Observed steady-state trough plasma concentration of macitentan and its active metabolite ACT-132577 will be reported.
Outcome Measure
Participants Less than (<) 2 Years: Observed Steady-state Trough Plasma Concentration of Macitentan and its Active Metabolite ACT-132577 at Week 4
Outcome Time Frame
Week 4
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Between randomization/visit 2 and end of core study period (EOCP); up to 7 years
Outcome Measure
Time to the first CEC-confirmed Disease Progression Event
Outcome Description
Time to first CEC-confirmed hospitalization for PAH occurring between randomization/visit 2 and EOCP.
Outcome Time Frame
Between randomization/visit 2 and EOCP/; up to 7 years
Outcome Measure
Time to First CEC-confirmed Hospitalization for PAH
Outcome Description
Time to CEC-confirmed death due to PAH occurring between randomization/visit 2 and EOCP.
Outcome Time Frame
Between randomization/visit 2 and EOCP; up to 7 years
Outcome Measure
Time to CEC-confirmed death due to PAH
Outcome Description
Time to death (all causes) occurring between randomization/visit 2 and EOCP.
Outcome Time Frame
Between randomization/visit 2 and EOCP; up to 7 years
Outcome Measure
Time to death (all causes)
Outcome Description
Percentage of participants with WHO FC I or II versus III or IV will be reported.
Outcome Time Frame
Week 24
Outcome Measure
The Percentage of Participants with World Health Organization (WHO) Functional Class (FC) I or II versus III or IV
Outcome Description
The quantitation of NT-proBNP plasma levels will be performed and reported.
Outcome Time Frame
Baseline to Week 24
Outcome Measure
Change from Baseline to Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
Outcome Description
Change from baseline to Week 48 in moderate to vigorous physical activity as measured by accelerometry will be reported.
Outcome Time Frame
Baseline to Week 48
Outcome Measure
Change from Baseline to Week 48 in Moderate to Vigorous Physical Activity as Measured by Accelerometry
Outcome Description
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.
Outcome Time Frame
Baseline to Week 24
Outcome Measure
Change from Baseline to Week 24 in Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography
Outcome Description
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.
Outcome Time Frame
Baseline to Week 24
Outcome Measure
Change from Baseline to Week 24 in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography
Outcome Description
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.
Outcome Time Frame
Baseline to Week 24
Outcome Measure
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)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Locked Fields
Render the field
Maximum Age Number (converted to Years and rounded down)
17
Minimum Age Number (converted to Years and rounded down)
0
Investigators
Investigator Type
Principal Investigator
Investigator Name
Nicole Sutton
Investigator Email
nsutton@montefiore.org
Investigator Phone
718-741-2343