Hypertension, Pulmonary
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGSelexipag
Selexipag tablet will be administered orally.
DRUGPlacebo
Matching placebo tablets will be administered orally.
DRUGStandard of Care (SOC): Endothelin receptor antagonist
ERAs will be administered as SOC therapy.
DRUGSOC: Phosphodiesterase type 5 (PDE-5) inhibitor
PDE-5 inhibitor will be administered as SOC therapy.
DRUGSOC: Soluble guanylate cyclase stimulator
Soluble guanylate cyclase stimulator will be administered as SOC therapy.
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Participants between greater than or equal to (\>=) 2 and less than (\<) 18 years of age weighing \>=9 kilogram (kg) at randomization * Pulmonary arterial hypertension (PAH) diagnosis confirmed by documented historical right heart catheterization (RHC) performed at any time before participant's screening * PAH (World Health Organization \[WHO\] Group 1), including participants with Down syndrome, of the following etiologies: Idiopathic PAH (IPAH); Heritable PAH (HPAH); PAH associated with congenital heart disease (PAH-associated with congenital heart disease \[aCHD\]) (PAH with coincidental CHD \[that is, a small atrial septal defect, ventricular septal defect, or patent ductus arteriosus that does not itself account for the development of elevated PVR\] and if approved by the BCAC) and Post-operative PAH (persisting / recurring/ developing \>=6 months after repair of CHD); Drug or toxin-induced; PAH associated with Human immunodeficiency virus (HIV) * WHO functional class (FC) II and III * Participants treated with at least 1 PAH-specific treatment, example, an Endothelin receptor antagonist (ERA) and/or a Phosphodiesterase type-5 (PDE-5) inhibitor/soluble guanylate cyclase stimulator, provided that the treatment dose(s) has been stable for at least 3 months prior to first dose of study intervention
Exclusion criteria
* PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease, and/or pulmonary capillary hemangiomatosis * PAH associated with Eisenmenger syndrome * Previous exposure to Uptravi (selexipag) * Known concomitant life-threatening disease with a life expectancy \<12 months * Pregnant, planning to become pregnant, or lactating * Known allergies, hypersensitivity, or intolerance to selexipag or its excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind Period: Time to Disease Progression | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double-blind Period: Change in log2 N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 24 | Baseline (Day 1), 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). |
| Double-blind Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious AEs (TESAEs) | 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) | 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. |
| Double-blind Period: Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment | 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) | 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. |
| Double-blind Period: Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Vital Signs: Pulse Rate | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Growth Parameter: Body Weight | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Growth Parameter: Height | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Number of Participants With Shift From Baseline in Sexual Maturation (Tanner Stage) | 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) | 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. |
| Double-blind Period: Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities | 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) | 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. |
| Double-blind Period: Number of Participants With Treatment-emergent (TE) Marked Laboratory Abnormalities | 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) | 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. |
| Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Thyroid Stimulating Hormone | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Hemoglobin | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Platelets, Leukocytes | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Electrolytes (Sodium, Potassium, Calcium, Bicarbonate and Chloride) | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Transaminases (Alanine Aminotransferase [ALT] and Aspartate Aminotransferase [AST]) | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Change From Baseline in Treatment-emergent Laboratory Parameter: Bilirubin | Baseline (Day 1), Weeks 24, 48, 72, and 96 | 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. |
| Double-blind Period: Time to First Clinical Event Committee (CEC)-Confirmed Hospitalization or Death for Pulmonary Arterial Hypertension (PAH) | 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) | 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. |
| Double-blind Period: Dose-normalized Steady-state Trough Concentrations (Ctrough,ss,dn) of Selexipag and Its Metabolite ACT-333679 by Age Cohort | 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) | 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. |
| Double-blind Period: Dose-normalized Steady-state Trough Concentrations (Ctrough,ss,dn) of Selexipag and Its Metabolite ACT-333679 by Body Weight (BW) | 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) | 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. |
Countries
Australia, Belarus, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Lithuania, Malaysia, Mexico, Poland, Portugal, Russia, Serbia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States, Vietnam
Contacts
STUDY_DIRECTORActelion Clinical Trial
Actelion
Participant flow
Pre-assignment details
The study is conducted in 2 periods: double-blind (DB) period and open label extension period (OLEP). The results presented are based on the primary completion date (11 October 2024) which includes the DB treatment period only. OLEP is still ongoing, results of OLEP will be posted within a year of study completion.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 11.8 Years STANDARD_DEVIATION 3.68 |
| Age, Customized >=12 to <18 years | 36 Participants |
| Age, Customized >=2 to <6 years | 11 Participants |
| Age, Customized >=6 to <12 years | 56 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants |
| Race (NIH/OMB) Asian | 32 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 69 Participants |
| Region of Enrollment Belarus | 4 Participants |
| Region of Enrollment Belgium | 3 Participants |
| Region of Enrollment Brazil | 14 Participants |
| Region of Enrollment Bulgaria | 2 Participants |
| Region of Enrollment Canada | 1 Participants |
| Region of Enrollment China | 24 Participants |
| Region of Enrollment Colombia | 5 Participants |
| Region of Enrollment France | 1 Participants |
| Region of Enrollment Germany | 1 Participants |
| Region of Enrollment Hungary | 0 Participants |
| Region of Enrollment Ireland | 1 Participants |
| Region of Enrollment Israel | 1 Participants |
| Region of Enrollment Italy | 4 Participants |
| Region of Enrollment Korea, South | 8 Participants |
| Region of Enrollment Malaysia | 2 Participants |
| Region of Enrollment Mexico | 1 Participants |
| Region of Enrollment Poland | 7 Participants |
| Region of Enrollment Portugal | 2 Participants |
| Region of Enrollment Russian Federation | 1 Participants |
| Region of Enrollment Spain | 0 Participants |
| Region of Enrollment Sweden | 1 Participants |
| Region of Enrollment Switzerland | 1 Participants |
| Region of Enrollment Taiwan | 4 Participants |
| Region of Enrollment Thailand | 4 Participants |
| Region of Enrollment Turkey | 9 Participants |
| Region of Enrollment Ukraine | 1 Participants |
| Region of Enrollment United States | 4 Participants |
| Region of Enrollment Vietnam | 12 Participants |
| Sex: Female, Male Female | 35 Participants |
| Sex: Female, Male Male | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 69 | 10 / 69 |
| other Total, other adverse events | 56 / 69 | 64 / 69 |
| serious Total, serious adverse events | 26 / 69 | 32 / 69 |
Outcome results
None listed