A Study of Selexipag as Add-On Treatment to Standard of Care in Children With Pulmonary Arterial Hypertension

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.