The purpose of this study is to evaluate whether the addition of selexipag to standard of care treatment delays disease progression in children with Pulmonary Arterial Hypertension (PAH) in comparison to placebo.
Pediatric PAH is a rare and progressive disorder associated with considerable morbidity and mortality. Given the significant medical need to develop treatments in children with PAH, further clinical studies in the pediatric population are therefore needed to provide more data for the management of PAH in children. Selexipag (JNJ-67896049) is an orally available, selective, and long-acting non-prostanoid agonist of the prostacyclin receptor approved and commercially available for the treatment of adult participants with PAH. Selexipag and its metabolite possess anti-fibrotic, anti-proliferative, and anti-thrombotic properties. Currently, no medicines targeting prostacyclin pathway are approved for pediatric use in PAH. An effective and orally available therapy acting on the prostacyclin receptor such as selexipag introduced at medically appropriate stage of PAH disease, and primarily in combination with current first-line oral PAH-specific medicines in participants in need of additional therapy because of insufficient disease control would represents a major advance to the therapeutic management of PAH pediatric participants. This study consists of a screening period of up to 6 weeks and a double-blind treatment period, including up-titration and maintenance periods, followed by a 3-year open-label extension period (OLEP) and a 30-day safety follow-up period that occurs after the last dose of study intervention (either double-blind or open-label). Safety, pharmacokinetic and efficacy assessments will be performed during the study. An Independent Data Monitoring Committee (IDMC) will be established to monitor data on an ongoing basis, to review interim data, and to ensure the continuing safety of the participants enrolled in this study. The approximate duration of the study is 8 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
138
Double-blind Period: Time to Disease Progression
Time to disease progression: time from randomization to first Clinical Event Committee (CEC)-confirmed disease progression event occurring between date of randomization until double-blind end date (DBED) + 7 days. Disease progression event as adjudicated by CEC, defined as any of the following: death (all causes); atrial septostomy or Potts' anastomosis, or registration on lung transplant list; hospitalization due to worsening pulmonary arterial hypertension (PAH); clinical worsening of PAH. Clinical worsening of PAH was defined as initiation of new PAH-specific therapy or intravenous diuretics or continuous oxygen use and at least 1 of the following: worsening in World Health Organization (WHO) functional class (FC); new occurrence or worsening: of syncope, of at least 2 PAH symptoms (shortness of breath/dyspnea, chest pain, cyanosis, dizziness/near syncope, or fatigue), of signs of right heart failure not responding to oral diuretics. Kaplan-Meier method was used for estimation.
Time frame: Placebo arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 199 weeks); Selexipag arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 213 weeks)
Double-blind Period: Change in log2 N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24
Change in log2 NT-proBNP from baseline to Week 24 was reported. Change from baseline to Week 24 in the central laboratory NT-proBNP (nanograms per liter \[ng/L\]) value, expressed as the log2-transformed ratio of the Week 24 NT-proBNP value over the baseline value: log2 (Week 24 NT-proBNP divided by Baseline NT-proBNP). Clinically, a reduction from baseline in NT-proBNP (ratio \< 1) was considered an improvement. The baseline value was the last non-missing assessment obtained before or on the DB start date (DBSD).
Time frame: Baseline (Day 1), Week 24
Double-blind Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious AEs (TESAEs)
Number of participants with TEAEs (included serious and non-serious events) and TESAEs during DB period was reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A serious AE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a suspected transmission of any infectious agent via a medicinal product, or was medically important. TEAEs were defined as any AE occurring on or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 3 days and/or prior to start of OL study administration.
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PDE-5 inhibitor will be administered as SOC therapy.
Soluble guanylate cyclase stimulator will be administered as SOC therapy.
Phoenix Children's Hospital
Phoenix, Arizona, United States
UCLA Medical Center
Los Angeles, California, United States
UCSF
San Francisco, California, United States
Childrens Hospital Colorado
Aurora, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Congenital Heart Center of the University of Florida
Gainesville, Florida, United States
Riley Hospital for Children
Indianapolis, Indiana, United States
Detroit Medical Center
Detroit, Michigan, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Childrens Hospital Of Philadelphia
Philadelphia, Pennsylvania, United States
...and 106 more locations
Time frame: Placebo arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks)
Double-blind Period: Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment
Number of participants with AEs leading to premature discontinuation of study treatment during DB period was reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention.
Time frame: Placebo arm: Start of treatment (Day 1) up to last dose in the DB treatment (maximum up to 198 weeks); Selexipag arm: Start of treatment (Day 1) up to last dose in the DB treatment (maximum up to 212 weeks)
Double-blind Period: Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Change from baseline in vital signs parameters: systolic and diastolic blood pressure during DB period was reported. Vital signs were measured after the participant has rested at least 5 minutes in sitting position. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Vital Signs: Pulse Rate
Change from baseline in vital signs parameter: pulse rate during DB period was reported. Vital signs were measured after the participant has rested for at least 5 minutes in sitting position. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Growth Parameter: Body Weight
Change from baseline in growth parameter: body weight during DB period was reported. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Growth Parameter: Height
Change from baseline in growth parameter: height during DB period was reported. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Number of Participants With Shift From Baseline in Sexual Maturation (Tanner Stage)
Tanner staging were assessed for pubic hair growth and genitalia development (GD) in males (M) and for pubic hair growth and breast development (BD) in females (F) in stages(S) 1 to 5 and missing data. If a participant had reached Tanner stage 5, no further tanner pubertal stage assessment were to be completed. Tanner stage was assessed in F \>=8 years; M \>=9 years. Pubic hair growth (M and F) stages: S1: No hair, S2: Downy hair, S3: More coarse and curly hair, S4: Adult-like hair quality; S5: Hair extends to medial surface of thighs. BD in females: S1: Nipple raised a little, rest of breast still flat, S2: Breast bud forms, S3: More elevated, outside areola, S4: Increased breast size, S5: Final adult-size breasts. GD in males: S1: Testes, scrotum, and penis about same size, S2: Enlargement of scrotum, testes, and penis, S3: Enlargement of penis, S4: Penis and glands became larger, S5: Genitalia size and shape same an adult male. Categories with at least 1 non-zero data are reported.
Time frame: Placebo arm: Baseline (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Baseline (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks)
Double-blind Period: Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities
Number of participants with treatment-emergent ECG abnormalities were reported. Any abnormality occurring on or after the initial administration of study intervention through the day of last dose in the DB treatment period plus 3 days was considered to be treatment-emergent. Abnormalities that were not present at baseline were reported. Abnormalities were assessed as per investigator's discretion. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Placebo arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks)
Double-blind Period: Number of Participants With Treatment-emergent (TE) Marked Laboratory Abnormalities
Number of participants with TE marked laboratory abnormalities during DB period was reported. TE marked laboratory abnormalities included hemoglobin, platelet count, leukocyte count, potassium, calcium, thyrotropin, thyroxine free and triiodothyronine free. Any abnormality occurring or worsening at or after the DB study treatment start date through the DB study treatment end date plus 3 days was considered to be treatment-emergent. If the abnormality was present at baseline, then any post-baseline abnormality was considered treatment-emergent only if the post-baseline abnormality was in a category worse than at baseline. HH, HHH, HHHH = marked abnormally high values; LL, LLL = marked abnormally low values. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Placebo arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 198.42 weeks); Selexipag arm: Start of treatment (Day 1) up to 3 days after last dose in the DB treatment (maximum up to 212.42 weeks)
Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Thyroid Stimulating Hormone
Change from baseline in treatment-emergent laboratory parameter: thyroid stimulating hormone during DB period was reported. Any abnormality occurring or worsening at or after the DB study treatment start date through the DB study treatment end date plus 3 days was considered to be treatment-emergent. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Hemoglobin
Change from baseline in treatment-emergent laboratory parameter: hemoglobin during DB period was reported. Any abnormality occurring or worsening at or after the DB study treatment start date through the DB study treatment end date plus 3 days was considered to be treatment-emergent. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Platelets, Leukocytes
Change from baseline in treatment-emergent laboratory parameter: platelets, leukocytes during DB period was reported. Any abnormality occurring or worsening at or after the DB study treatment start date through the DB study treatment end date plus 3 days was considered to be treatment-emergent. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Electrolytes (Sodium, Potassium, Calcium, Bicarbonate and Chloride)
Change from baseline in treatment-emergent laboratory parameter: electrolytes (sodium, potassium, calcium, bicarbonate and chloride) during DB period was reported. Any abnormality occurring or worsening at or after the DB study treatment start date through the DB study treatment end date plus 3 days was considered to be treatment-emergent. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Transaminases (Alanine Aminotransferase [ALT] and Aspartate Aminotransferase [AST])
Change from baseline in treatment-emergent laboratory parameter: transaminases (ALT and AST) during DB period was reported. Any abnormality occurring or worsening at or after the DB study treatment start date through the DB study treatment end date plus 3 days was considered to be treatment-emergent. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Bilirubin
Change from baseline in treatment-emergent laboratory parameter: bilirubin during DB period was reported. Any abnormality occurring or worsening at or after the DB study treatment start date through the DB study treatment end date plus 3 days was considered to be treatment-emergent. The baseline value was the last non-missing assessment obtained before or on the DBSD.
Time frame: Baseline (Day 1), Weeks 24, 48, 72, and 96
Double-blind Period: Time to First Clinical Event Committee (CEC)-Confirmed Hospitalization or Death for Pulmonary Arterial Hypertension (PAH)
Time to first CEC-confirmed hospitalization or death for PAH was calculated as the onset date of the first CEC-confirmed death or hospitalization due to PAH minus date of randomization+1 day. Kaplan-Meier method was used for estimation.
Time frame: Placebo arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 199 weeks); Selexipag arm: Randomization (Day 1) up to 7 days after last dose in the DB treatment (maximum up to 213 weeks)
Double-blind Period: Dose-normalized Steady-state Trough Concentrations (Ctrough,ss,dn) of Selexipag and Its Metabolite ACT-333679 by Age Cohort
Dose-normalized trough plasma concentration at steady-state (Ctrough,ss,dn) was defined as the plasma concentration just prior to the morning dose, with the last study intervention administration one day prior to the PK sampling. Steady-state was considered achieved if the participant has received a stable dose for at least 3 days prior to collection of the plasma sample. PK samples were collected at two protocol-specified visits per participant occurring between Week 16 and end of DB treatment period. Exact visit timing varied by participant.
Time frame: Cohort (C) 1: Predose between Week (W) 16 to end of DB treatment period (maximum up to W212); C 2: Predose between Week 16 to end of DB treatment period (maximum up to W198); C 3: Predose between Week 16 to end of DB treatment period (maximum up to W96)
Double-blind Period: Dose-normalized Steady-state Trough Concentrations (Ctrough,ss,dn) of Selexipag and Its Metabolite ACT-333679 by Body Weight (BW)
Dose-normalized steady-state trough concentration (Ctrough,ss,dn) was defined as the plasma concentration just prior to the morning dose, with the last study intervention administration one day prior to the PK sampling. Steady-state was considered achieved if the participant has received a stable dose for at least 3 days prior to collection of the plasma sample. PK samples were collected at two protocol-specified visits per participant occurring between Week 16 and end of DB treatment period. Exact visit timing varied by participant.
Time frame: BW >=50kg: Predose between W16 to end of DB treatment period (maximum up to W212); BW >=25-<50kg: Predose between W16 to end of DB treatment period (maximum up to W198); BW >=9- <25kg: Predose between W16 to end of DB treatment period (maximum up to W175)