Pulmonary Arterial Hypertension
Conditions
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).
Interventions
DRUGMacitentan
Dispersible tablet; Oral use
OTHERStandard-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.
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 17 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Pre-dose at Week 12 | 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. |
| 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 | Pre-dose at Week 12 | 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. |
| Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4 | Pre-dose at Week 4 | 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. |
| 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 | Pre-dose at Week 12 | Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 were reported. |
Secondary
| Measure | Time frame |
|---|---|
| Time to the First Clinical Event Committee (CEC)-Confirmed Disease Progression Event | Baseline (Day 1) up to end of core study period (EOCP; up to 7.08 years) |
| Time to First CEC-confirmed Hospitalization for PAH | Baseline (Day 1) up to EOCP (up to 7.08 years) |
| Time to CEC-confirmed Death Due to PAH | Baseline (Day 1) up to EOCP (up to 7.08 years) |
| Time to Death (All Causes) | Baseline (Day 1) up to 7.26 years |
| Percentage of Participants With World Health Organization (WHO) Functional Class (FC) I or II Versus III or IV | At Weeks 12 and 24 |
| Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Weeks 12 and 24 | Baseline (Day 1), Weeks 12 and 24 |
| Change From Baseline in Mean Daily Time Spent in Moderate to Vigorous Physical Activity as Measured by Accelerometry at Week 48 | Baseline (Day 1), Week 48 |
| Change From Baseline in Body Surface Area (BSA) Normalized Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography at Week 24 | Baseline (Day 1), Week 24 |
| Change From Baseline in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography at Week 24 | Baseline (Day 1), Week 24 |
| 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) | Baseline (Day 1), Week 24 |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline (Day 1) up to 7.26 years |
| Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | Baseline (Day 1) up to 7.26 years |
| Number of Participants With AEs Leading to Premature Discontinuation of Macitentan or Standard of Care (SoC) | Baseline (Day 1) up to 7.26 years |
| Number of Participants With AEs of Special Interest | Baseline (Day 1) up to 7.26 years |
| Number of Participants With Marked Laboratory Abnormalities | Baseline (Day 1) up to 7.26 years |
| Change From Baseline in Selected Laboratory Parameters | Baseline (Day 1) up to 7.26 years |
| Change From Baseline in Vital Signs (Blood Pressure, Heart Rate) | Baseline (Day 1) up to 7.26 years |
| Change From Baseline in Growth Variable | Baseline (Day 1) up to 7.26 years |
| Change From Baseline in Sexual Maturation Measured by Tanner Stage | Baseline (Day 1) up to 7.26 years |
Countries
Australia, Austria, Brazil, Canada, China, Colombia, Finland, France, Hungary, Israel, Malaysia, Mexico, Philippines, Poland, Portugal, Russia, South Africa, South Korea, Spain, Thailand, Ukraine, United States, Vietnam
Participant flow
Recruitment details
Eligible participants up to less than (\<) 18 years at the time of enrolment were classified into one of the treatment arms: Macitentan (greater than or equal to \[\>=\] 2 years), standard of care (SOC: \>=2 years), Macitentan (\<2 years) or China Single Arm Cohort (\>=12 years).
Pre-assignment details
Participants from 2 to \<18 years were randomized (1:1) to either macitentan or to SoC. Randomization was stratified by ongoing/planned Endothelin Receptor Antagonist treatment at randomization (yes vs no) and by WHO Functional Class (FC) at randomization (FC I/II vs FC III). Participants \<2 years or participants in China single arm cohort were assigned to macitentan arm without randomization. Adverse events are reported until end of core period analysis which is beyond primary completion date.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan (JNJ-67896062) (>=2 Years) Randomized participants aged \>=2 years received macitentan orally (dispersible tablet reconstituted in water) once daily based on their body weight (BW): 3.5 milligrams (mg) for BW \>=10 kilograms (kg) and \<15 kg, 5.0 mg for \>=15 kg and \<25 kg, 7.5 mg for \>=25 kg and \<50 kg, and 10.0 mg for \>=50 kg. Every 12 weeks body weight was checked for potential dose adjustment. Phosphodiesterase Type 5 inhibitor (PDE-5i) was the only allowed PAH-specific background medication until disease progression. Participants received treatment from Day 1 up to 312.4 weeks. | 73 |
| Standard of Care (SoC; >=2 Years) Randomized participants aged \>=2 years continued their SoC as per site's clinical practice which comprised treatment with the pulmonary arterial hypertension (PAH) non-specific treatment and/or up to 2 PAH-specific medications excluding macitentan and intravenous (IV)/subcutaneous (SC) prostanoids. Participants continued to receive the PDE-5i (sildenafil and tadalafil), or other PAH-specific treatment such as an ERA (bosentan and ambrisentan) or oral prostanoids (soluble guanylate cyclase stimulators \[riociguat\]), which was ongoing at the time of randomization. Additional PAH-specific therapy other than macitentan and IV or SC prostanoids initiated prior to randomization was continued. Participants received treatment from Day 1 up to 316.4 weeks. For participants with disease progression, crossover to macitentan was offered after confirmation of a disease progression event by the blinded Clinical Event Committee. | 75 |
| Macitentan (JNJ-67896062) (<2 Years) Enrolled participants aged \<2 years received macitentan 2.5 mg once daily orally (dispersible tablet reconstituted in water). Oral or inhaled prostanoid treatment were allowed as PAH-specific background therapy. Participants received treatment from Day 1 up to 72.9 weeks. | 9 |
| China Single-arm Cohort (>=12 to <18 Years) Enrolled participants aged \>=12 to \<18 years received macitentan orally (dispersible tablet reconstituted in water) once daily based on their body weight (BW): 3.5 milligrams (mg) for BW \>=10 kilograms (kg) and \<15 kg, 5.0 mg for \>=15 kg and \<25 kg, 7.5 mg for \>=25 kg and \<50 kg and 10.0 mg for \>=50 kg. Every 12 weeks body weight was checked for potential dose adjustment. Phosphodiesterase Type 5 (PDE-5) inhibitor was the only allowed PAH-specific background medication until disease progression. Participants received treatment from Day 1 up to 48.29 weeks. | 8 |
| Total | 165 |
Baseline characteristics
| Characteristic | Macitentan (JNJ-67896062) (>=2 Years) | Standard of Care (SoC; >=2 Years) | Total | Macitentan (JNJ-67896062) (<2 Years) | China Single-arm Cohort (>=12 to <18 Years) |
|---|---|---|---|---|---|
| Age, Continuous | 10.5 years STANDARD_DEVIATION 4.43 | 9 years STANDARD_DEVIATION 4.32 | 9.4 years STANDARD_DEVIATION 4.65 | 1.7 years STANDARD_DEVIATION 0.27 | 12.9 years STANDARD_DEVIATION 1.13 |
| Age, Customized >= 0.5 to < 2 years | 0 Participants | 0 Participants | 9 Participants | 9 Participants | 0 Participants |
| Age, Customized >= 0 to < 0.5 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >= 12 to < 18 years | 31 Participants | 21 Participants | 60 Participants | 0 Participants | 8 Participants |
| Age, Customized >= 2 to < 6 years | 13 Participants | 22 Participants | 35 Participants | 0 Participants | 0 Participants |
| Age, Customized >= 6 to < 12 years | 29 Participants | 32 Participants | 61 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 22 Participants | 48 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 51 Participants | 112 Participants | 6 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 5 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 15 Participants | 22 Participants | 48 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 18 Participants | 32 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 44 Participants | 32 Participants | 78 Participants | 2 Participants | 0 Participants |
| Region of Enrollment AUSTRALIA | 2 Participants | 2 Participants | 4 Participants | 0 Participants | 0 Participants |
| Region of Enrollment BRAZIL | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Region of Enrollment CHINA | 1 Participants | 0 Participants | 9 Participants | 0 Participants | 8 Participants |
| Region of Enrollment COLOMBIA | 7 Participants | 7 Participants | 14 Participants | 0 Participants | 0 Participants |
| Region of Enrollment FRANCE | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| Region of Enrollment HUNGARY | 3 Participants | 1 Participants | 5 Participants | 1 Participants | 0 Participants |
| Region of Enrollment ISRAEL | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Korea, Republic of | 4 Participants | 3 Participants | 7 Participants | 0 Participants | 0 Participants |
| Region of Enrollment MALAYSIA | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment MEXICO | 15 Participants | 14 Participants | 31 Participants | 2 Participants | 0 Participants |
| Region of Enrollment PHILIPPINES | 3 Participants | 4 Participants | 9 Participants | 2 Participants | 0 Participants |
| Region of Enrollment POLAND | 2 Participants | 2 Participants | 4 Participants | 0 Participants | 0 Participants |
| Region of Enrollment PORTUGAL | 3 Participants | 1 Participants | 5 Participants | 1 Participants | 0 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 7 Participants | 6 Participants | 13 Participants | 0 Participants | 0 Participants |
| Region of Enrollment SPAIN | 3 Participants | 2 Participants | 5 Participants | 0 Participants | 0 Participants |
| Region of Enrollment THAILAND | 2 Participants | 2 Participants | 4 Participants | 0 Participants | 0 Participants |
| Region of Enrollment UKRAINE | 8 Participants | 7 Participants | 15 Participants | 0 Participants | 0 Participants |
| Region of Enrollment UNITED STATES | 6 Participants | 6 Participants | 14 Participants | 2 Participants | 0 Participants |
| Region of Enrollment VIETNAM | 4 Participants | 13 Participants | 17 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 50 Participants | 38 Participants | 93 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 23 Participants | 37 Participants | 72 Participants | 8 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 73 | 0 / 9 | 6 / 75 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 60 / 72 | 6 / 9 | 44 / 75 | 5 / 8 | 6 / 8 |
| serious Total, serious adverse events | 26 / 72 | 4 / 9 | 21 / 75 | 0 / 8 | 1 / 8 |
Outcome results
Primary
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
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.
Time frame: Pre-dose at Week 12
Population: The Pharmacokinetics (PK) 1 set included all participants aged \>=2 years randomized to and treated with macitentan, for whom a PK blood sample at trough had been taken and who did not deviate from the protocol in a way that affected the evaluation of the PK trough endpoints. Here N (Number of participants analyzed) signifies the number of participants that were evaluable for this outcome measure and n(number analyzed) signifies number of participants analyzed for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan: >=2 to <6 years | 159.767 nanograms per milliliter (ng/mL) | Standard Deviation 84.5424 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan: >=6 to <12 years | 184.792 nanograms per milliliter (ng/mL) | Standard Deviation 148.253 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan: >=12 to <18 years | 196.484 nanograms per milliliter (ng/mL) | Standard Deviation 88.1549 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan: >=2 to <6 years | 1063.333 nanograms per milliliter (ng/mL) | Standard Deviation 376.4173 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan: >=6 to <12 years | 957.211 nanograms per milliliter (ng/mL) | Standard Deviation 335.0858 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan: >=12 to <18 years | 970.842 nanograms per milliliter (ng/mL) | Standard Deviation 298.5151 |
Primary
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
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.
Time frame: Pre-dose at Week 12
Population: The Pharmacokinetics (PK) 1 set included all participants aged \>=2 years randomized to and treated with macitentan, for whom a PK blood sample at trough had been taken and who did not deviate from the protocol in a way that affected the evaluation of the PK trough endpoints. Here N (Number of participants analyzed) signifies the number of participants that were evaluable for this outcome measure and n(number analyzed) signifies number of participants analyzed for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan: >=10 kg and <15 kg | 150.133 nanograms per milliliter (ng/mL) | Standard Deviation 67.5742 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan: >=15 kg and <25 kg | 153.892 nanograms per milliliter (ng/mL) | Standard Deviation 108.3185 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan: >=25 kg and <50 kg | 200.975 nanograms per milliliter (ng/mL) | Standard Deviation 151.6511 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan: >=50 kg | 208.067 nanograms per milliliter (ng/mL) | Standard Deviation 92.4246 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan: >=10 kg to <15 kg | 1165.000 nanograms per milliliter (ng/mL) | Standard Deviation 390.7628 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan: >=15 kg and <25 kg | 859.333 nanograms per milliliter (ng/mL) | Standard Deviation 217.2926 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan: >=25 kg and <50 kg | 980.857 nanograms per milliliter (ng/mL) | Standard Deviation 391.3308 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan: >=50 kg | 1011.267 nanograms per milliliter (ng/mL) | Standard Deviation 288.3632 |
Primary
Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4
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.
Time frame: Pre-dose at Week 4
Population: PK Set 3 included all participants aged \<2 years and treated with macitentan for whom a PK blood sample had been taken and who did not deviate from the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan (JNJ-67896062) (>=2 Years) | Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4 | Macitentan | 101.822 ng/mL | Standard Deviation 91.9652 |
| Macitentan (JNJ-67896062) (>=2 Years) | Participants <2 Years of Age: Observed Steady-State Trough (Pre-dose) Plasma Concentration of Macitentan and Aprocitentan (Active Metabolite) at Week 4 | Aprocitentan | 707.089 ng/mL | Standard Deviation 465.576 |
Primary
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
Observed steady-state trough (pre-dose) plasma concentration of macitentan and aprocitentan (active metabolite) at Week 12 were reported.
Time frame: Pre-dose at Week 12
Population: PK Analysis Set China (PK CHN) included all participants \>=12 years to \<18 years who were treated with macitentan, for whom a PK blood sample has been taken and who did not deviate from the protocol in a way that might affect the evaluation of the PK endpoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Macitentan | 201.61 ng/mL | Standard Deviation 116.685 |
| Macitentan (JNJ-67896062) (>=2 Years) | 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 | Aprocitentan | 1313.75 ng/mL | Standard Deviation 293.644 |
Secondary
Change From Baseline in Body Surface Area (BSA) Normalized Tricuspid Annular Plane Systolic Excursion (TAPSE) Measured by Echocardiography at Week 24
Time frame: Baseline (Day 1), Week 24
Secondary
Change From Baseline in Growth Variable
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Change From Baseline in Left Ventricular Eccentricity Index (LVEI) Measured by Echocardiography at Week 24
Time frame: Baseline (Day 1), Week 24
Secondary
Change From Baseline in Mean Daily Time Spent in Moderate to Vigorous Physical Activity as Measured by Accelerometry at Week 48
Time frame: Baseline (Day 1), Week 48
Secondary
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Weeks 12 and 24
Time frame: Baseline (Day 1), Weeks 12 and 24
Secondary
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)
Time frame: Baseline (Day 1), Week 24
Secondary
Change From Baseline in Selected Laboratory Parameters
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Change From Baseline in Sexual Maturation Measured by Tanner Stage
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Change From Baseline in Vital Signs (Blood Pressure, Heart Rate)
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Number of Participants With AEs Leading to Premature Discontinuation of Macitentan or Standard of Care (SoC)
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Number of Participants With AEs of Special Interest
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Number of Participants With Marked Laboratory Abnormalities
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Percentage of Participants With World Health Organization (WHO) Functional Class (FC) I or II Versus III or IV
Time frame: At Weeks 12 and 24
Secondary
Time to CEC-confirmed Death Due to PAH
Time frame: Baseline (Day 1) up to EOCP (up to 7.08 years)
Secondary
Time to Death (All Causes)
Time frame: Baseline (Day 1) up to 7.26 years
Secondary
Time to First CEC-confirmed Hospitalization for PAH
Time frame: Baseline (Day 1) up to EOCP (up to 7.08 years)
Secondary
Time to the First Clinical Event Committee (CEC)-Confirmed Disease Progression Event
Time frame: Baseline (Day 1) up to end of core study period (EOCP; up to 7.08 years)