Pulmonary Arterial Hypertension

The selection of the starting dose for pediatric participants is based on the PK extrapolation from adults, taking into account the children body weight category, in order to lead to an exposure similar to that in adult PAH participants at a starting dose of 200 micrograms (mcg). As in adults, selexipag will be up-titrated to the individual maximum tolerated dose (iMTD) during the first 12 weeks. Approximately 60 participants will be enrolled in 3 different age cohorts to obtain at least 45 participants with evaluable PK profiles: Cohort 1: >= 12 to < 18 years of age, Cohort 2: >= 6 to < 12 years of age, Cohort 3: >= 2 to < 6 years of age. In each age cohort the starting dose will depend on the body weight. Enrollment will start with both Cohort 1 and Cohort 2. After completion of PK assessments in at least 15 participants from Cohort 1 at Week 12, a first interim analysis will be conducted to establish the dose-exposure relationship using a population PK model. The PK data from any participants in Cohort 2 who have completed their PK assessments at this time will be included in this first interim analysis. Results of this model-based analysis will be used to confirm or adjust the selexipag doses initially selected. Enrollment of Cohort 3 (children >= 2 to < 6 years of age) will start once the appropriate doses have been confirmed in a second interim analysis of PK data from Cohorts 1 and 2, and if there is no safety concern based on review by an Independent Data Monitoring Committee (IDMC).

Selexipag

ACT-293987

FILM-COATED TABLETS

200 mcg, 50 mcg, 25 mcg

Primary Outcome Measures :
Area Under the Plasma Concentration-Time Curve Over a Dose Interval at Steady State of Selexipag and its Metabolite ACT-333679 Combined (AUCτ, ss, Combined) [ Time Frame: PK sampling at Week 1 (or Week 12) at pre-dose, 1, 2, 4, 6, 8, and 12 post-morning dose as well as Weeks 2, 4 and 6 (prior to morning dose) ]
The AUCτ,ss,combined is the sum of the selexipag and ACT-333679 exposures weighted by their potency ratio, and determined during the 12 weeks up-titration period. The model will describe the body weight dependence of dose-exposure relationship for pediatric PAH participants. Blood samples for pharmacokinetic analyses will be collected in the 3 age cohorts.


Secondary Outcome Measures :
Area Under the Plasma Concentration-Time Curve Over a Dose Interval at Steady State (AUCτ,ss) of Selexipag [ Time Frame: PK sampling at Week 1 (or Week 12) at pre-dose, 1, 2, 4, 6, 8, and 12 post-morning dose as well as Weeks 2, 4 and 6 (prior to morning dose) ]
The AUCτ,ss for selexipag is calculated by non compartmental analysis to determine the total exposure to selexipag over a dosing interval.

Area Under the Plasma Concentration-Time Curve Over a Dose Interval at Steady State (AUCτ,ss) of ACT-333679 [ Time Frame: PK sampling at Week 1 (or Week 12) at pre-dose, 1, 2, 4, 6, 8, and 12 post-morning dose as well as Weeks 2, 4 and 6 (prior to morning dose) ]
The AUCτ,ss for ACT-333679 is calculated by non compartmental analysis to determine the total exposure to ACT-333679 over a dosing interval.

Maximum Observed Plasma Concentration (Cmax,ss) of Selexipag at Steady State [ Time Frame: PK sampling at Week 1 (or Week 12) at pre-dose, 1, 2, 4, 6, 8, and 12 post-morning dose as well as Weeks 2, 4 and 6 (prior to morning dose) ]
Cmax,ss of selexipag is directly obtained from the selexipag concentrations measured in the blood samples collected after at least 3 days on the same dose in order to reach steady state.

Maximum Observed Plasma Concentration (Cmax,ss) of ACT-333679 at Steady State [ Time Frame: PK sampling at Week 1 (or Week 12) at pre-dose, 1, 2, 4, 6, 8, and 12 post-morning dose as well as Weeks 2, 4 and 6 (prior to morning dose) ]
Cmax,ss of ACT-333679 is directly obtained from the ACT-333679 concentrations measured in the blood samples collected after at least 3 days on the same dose in order to reach steady state.

Time to the Maximum Observed Plasma Concentration (tmax,ss) of Selexipag at Steady State [ Time Frame: PK sampling at Week 1 (or Week 12) at pre-dose, 1, 2, 4, 6, 8, and 12 post-morning dose as well as Weeks 2, 4 and 6 (prior to morning dose) ]
tmax,ss of selexipag is directly obtained from the selexipag concentrations measured in the blood samples collected after at least 3 days on the same dose in order to reach steady state.

Time to the Maximum Observed Plasma Concentration (tmax,ss) of ACT-333679 at Steady State [ Time Frame: PK sampling at Week 1 (or Week 12) at pre-dose, 1, 2, 4, 6, 8, and 12 post-morning dose as well as Weeks 2, 4 and 6 (prior to morning dose) ]
tmax,ss of ACT-333679 is directly obtained from the ACT-333679 concentrations measured in the blood samples collected after at least 3 days on the same dose in order to reach steady state.

Trough Concentration of Selexipag at Steady State (Ctrough,ss) [ Time Frame: PK sampling at Weeks 2, 4, and 6 (pre-morning dose) ]
Ctrough, ss of selexipag is directly obtained from the selexipag concentrations measured in the blood samples collected prior to the morning administration of selexipag on Day 15 and at Weeks 4 and 6, after at least 3 days on the same dose in order to reach steady state.

Trough Concentration of ACT-333679 at Steady state (Ctrough,ss) [ Time Frame: PK sampling at Weeks 2, 4 and 6 (pre-morning dose) ]
Ctrough, ss of ACT-333679 is directly obtained from the ACT-333679 concentrations measured in the blood samples collected prior to the morning administration of selexipag on Day 15 and at Weeks 4 and 6, after at least 3 days on the same dose.

Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to 7 years ]
A TEAE is any adverse event (including marked laboratory abnormalities and ECG abnormalities) temporally associated with the use of study treatment (from study treatment initiation until 3 days after study treatment discontinuation) whether or not considered by the investigator as related to study treatment.

Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: Up to 7 years ]
A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TESAEs are defined as SAEs with onset or worsening on or after date of first dose of study treatment.

Number of Participants with Adverse Events (AEs) Leading to Permanent Discontinuation of study drug [ Time Frame: Up to 7 years ]
Number of participants with AEs leading to permanent discontinuation of study drug will be reported.

Number of Participants with Treatment-emergent Deaths (EOT + 3 days) [ Time Frame: Up to 7 years ]
Number of participants with treatment-emergent deaths (all causes) will be reported.

Number of Participants with Treatment-emergent Marked Laboratory Abnormalities (EOT + 3 days) [ Time Frame: Up to 7 years ]
Number of participants with treatment-emergent marked laboratory abnormalities (hematology and blood chemistry tests) over time will be reported.

Number of Participants with Change from Baseline in Laboratory Parameters (EOT + 3 days) [ Time Frame: Up to 7 years ]
Number of participants with change from baseline in laboratory parameters (hematology and blood chemistry) over time will be reported.

Number of Participants with Treatment-emergent Electrocardiogram (ECG) Abnormalities (EOT + 3 days) [ Time Frame: Up to 7 years ]
Number of participants with treatment-emergent ECG abnormalities over time will be reported.

Change from Baseline in Thyroid Stimulating Hormone (TSH) up to End of Treatment (EOT + 3 days) [ Time Frame: Baseline, up to 7 years ]
Change from baseline in TSH over time will be reported.

Number of Participants with Change from Baseline in Vital Signs [ Time Frame: Up to 7 years ]
Number of participants with Change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP] and heart rate) will be reported.

Change from Baseline Over Time in Height and Body Mass Index (BMI) up to End of Treatment (EOT + 3 days) [ Time Frame: Baseline, up to 7 years ]
Individual weight and height are used to determine BMI expressed in Kg/m2.

Change from Baseline in Tanner Stage up to End of Treatment (EOT + 3 days) [ Time Frame: Baseline, up to 7 years ]
Tanner Stages will be assessed to determine pubertal development up to end of treatment. Tanner stage (TS) is a 5-stage based scale ranging from TS 1 (prepubertal / preadolescent characteristics) to TS 5 (mature or adult characteristics).

Inclusion criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not
permitted to waive any of the criteria for any subject:
1. Signed and dated informed consent by the parent(s) or LAR(s) AND assent from
developmentally capable children.
2. Males or females between ≥ 2 and < 18 years of age with weight ≥ 9 kg.
3. PAH diagnosis confirmed by documented historical RHC performed at any time
before subject’s enrollment, and characterized by:
• mPAP ≥ 25 mmHg,
and
• PAWP ≤ 15 mmHg
(in the absence of pulmonary vein obstruction and/or significant lung
disease PAWP, can be replaced by LAP or, in absence of mitral stenosis,
by LVEDP)
and
• PVRi > 3 WU × m2
4. PAH belonging to Nice 2013 Updated Classification Group 1 (including Down
syndrome) and of one of the following etiologies:
• iPAH
• hPAH
• aPAH-CHD:
– PAH with co-incidental CHD
– Post-operative PAH (persisting/ recurring/ developing ≥ 6 months after
repair of CHD)
• Drug or toxin-induced
• PAH associated with HIV
• PAH-aCTD
5. WHO FC II to III.
6. Subjects treated with an ERA and/or a PDE-5 inhibitor provided that the
treatment dose(s) has been stable for at least 3 months prior to enrollment, or
patients who are not candidates for these therapies.
7. Females of childbearing potential must have a negative pregnancy test at
Screening and at Enrollment, and must agree to undertake monthly pregnancy
tests, and to use a reliable method of contraception (if sexually active) from
screening up to study drug discontinuation plus 30 days (EOS).

Exclusion criteria
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to
waive any of the criteria for any subject:
Etiology
1. Subjects with PAH due to portal hypertension, schistosomiasis, PVOD, and/or
pulmonary capillary hemangiomatosis.
2. Subjects with PAH associated with Eisenmenger syndrome.
3. Subjects with moderate to large left-to-right shunts.
4. Subjects with cyanotic congenital cardiac lesions such as transposition of the great
arteries, truncus arteriosus, univentricular heart or pulmonary atresia with ventricular
septal defect, as well as subjects with Fontan-palliation.
5. Subjects with pulmonary hypertension due to lung disease (e.g., bronchopulmonary
dysplasia).
Treatment and intervention
6. Previous treatment with Uptravi (selexipag) within 2 weeks prior to enrollment.
7. Subjects having received prostacyclin (epoprostenol) or prostacyclin analogs2 (i.e.,
treprostinil, iloprost, beraprost) within 2 months prior to enrollment or are scheduled
to receive any of these compounds during the trial.
8. Treatment with another investigational drug within 4 weeks prior to enrollment.
9. Treatment with strong and moderate inhibitors of CYP2C8 (e.g., gemfibrozil,
clopidogrel, deferasirox, teriflunomide) within 2 weeks prior to enrollment until the
last dose of selexipag + 3 days.
10. Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and
fluconazole), are prohibited from 2 weeks prior to enrollment and until the last dose
of selexipag + 3 days.
11. Any PAH-related surgical intervention planned, or subjects listed for organ
transplantation related to PAH.
12. History, or current suspicion of intussusception or ileus or gastrointestinal obstruction
as per investigator’s judgment.
Baseline abnormalities
13. Known concomitant life-threatening disease with a life expectancy < 12 months.
14. Uncontrolled thyroid disease as per investigator judgment.
15. Hemoglobin or hematocrit < 75% of the lower limit of normal range.
16. Known severe or moderate hepatic impairment, i.e., Child-Pugh Class B or C
[see Appendix 4]
17. Clinical signs of hypotension that in the investigator’s judgment would preclude
initiation of a PAH-specific therapy.
18. Subjects with severe renal insufficiency (estimated creatinine clearance < 30 mL/min
or serum creatinine > 221 µmol/L).
Pregnancy and breastfeeding
19. Pregnancy (including family planning) or breastfeeding.
Other categories
20. Known hypersensitivity to the investigational treatment or to any of the excipients of
the drug formulations.
21. Drug or substance abuse, or any condition that, in the opinion of the investigator, may
prevent compliance with the protocol or adherence to study treatment.
22. Loss of 250 mL or more of blood within 3 months prior to screening.
23. History or clinical evidence of any disease and/or existence of any surgical or medical
condition which might interfere with the absorption, distribution, metabolism or
excretion of the study treatment(s) (e.g., cholecystectomy).