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
Estimated
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 (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.
Outcome Measure
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
Outcome Time Frame
Pre-dose at Week 12
Outcome Description
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.
Outcome Measure
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
Outcome Time Frame
Pre-dose at Week 12
Outcome Description
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.
Outcome Measure
Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4
Outcome Time Frame
Pre-dose at Week 4
Outcome Description
Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 were reported.
Outcome Measure
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
Outcome Time Frame
Pre-dose at Week 12
Secondary Outcomes
Outcome Time Frame
Baseline (Day 1) up to end of core study period (EOCP; up to 7.08 years)
Outcome Measure
Time to the First Clinical Event Committee (CEC)-Confirmed Disease Progression Event
Outcome Time Frame
Baseline (Day 1) up to EOCP (up to 7.08 years)
Outcome Measure
Time to First CEC-confirmed Hospitalization for PAH
Outcome Time Frame
Baseline (Day 1) up to EOCP (up to 7.08 years)
Outcome Measure
Time to CEC-confirmed Death Due to PAH
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Time to Death (All Causes)
Outcome Time Frame
At Weeks 12 and 24
Outcome Measure
Percentage of Participants With World Health Organization (WHO) Functional Class (FC) I or II Versus III or IV
Outcome Time Frame
Baseline (Day 1), Weeks 12 and 24
Outcome Measure
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Weeks 12 and 24
Outcome Time Frame
Baseline (Day 1), Week 48
Outcome Measure
Change From Baseline in Mean Daily Time Spent in Moderate to Vigorous Physical Activity as Measured by Accelerometry at Week 48
Outcome Time Frame
Baseline (Day 1), Week 24
Outcome Measure
Change From Baseline in Body Surface Area (BSA) Normalized Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography at Week 24
Outcome Time Frame
Baseline (Day 1), Week 24
Outcome Measure
Change From Baseline in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography at Week 24
Outcome Time Frame
Baseline (Day 1), Week 24
Outcome Measure
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)
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Number of Participants With AEs Leading to Premature Discontinuation of Macitentan or Standard of Care (SoC)
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Number of Participants With AEs of Special Interest
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Number of Participants With Marked Laboratory Abnormalities
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Change From Baseline in Selected Laboratory Parameters
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Change From Baseline in Vital Signs (Blood Pressure, Heart Rate)
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Change From Baseline in Growth Variable
Outcome Time Frame
Baseline (Day 1) up to 7.26 years
Outcome Measure
Change From Baseline in Sexual Maturation Measured by Tanner Stage
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
Categories Mesh Debug
Heart/Cardiovascular --- PULMONARY ARTERIAL HYPERTENSION
Lung & Chest Cancers --- LUNG DISEASES
COVID-19 --- LUNG DISEASES
Lung --- LUNG DISEASES
Asthma and Other Respiratory Diseases --- RESPIRATORY TRACT DISEASES
Lung & Chest Cancers --- RESPIRATORY TRACT DISEASES
COVID-19 --- RESPIRATORY TRACT DISEASES
Lung --- RESPIRATORY TRACT DISEASES
MeSH Terms
PULMONARY ARTERIAL HYPERTENSION
HYPERTENSION, PULMONARY
LUNG DISEASES
RESPIRATORY TRACT DISEASES
MACITENTAN
STANDARD OF CARE
QUALITY INDICATORS, HEALTH CARE
QUALITY OF HEALTH CARE
HEALTH SERVICES ADMINISTRATION
HEALTH CARE QUALITY, ACCESS, AND EVALUATION