A Clinical Study of to Confirm the Doses of Selexipag in Children With Pulmonary Arterial Hypertension

• ClinicalTrials.gov Identifier: NCT03492177
• Recruitment Status: Active, not recruiting
• First Posted: April 10, 2018
• Last Update Posted: March 1, 2023
• Sponsor: Actelion
• Information provided by (Responsible Party): Actelion

Tracking Information

• First Submitted Date: April 3, 2018
• First Posted Date: April 10, 2018
• Last Update Posted Date: March 1, 2023
• Actual Study Start Date: July 23, 2018
• Actual Primary Completion Date: March 28, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 17, 2021)

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.

Original Primary Outcome Measures (submitted: April 3, 2018)

Area under the plasma concentration-time curve over a dose interval at steady state of selexipag and 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 patients. Blood samples for pharmacokinetic analyses will be collected in the 3 age cohorts.

Current Secondary Outcome Measures (submitted: June 17, 2021)

• 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).

Original Secondary Outcome Measures (submitted: April 3, 2018)

• 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. A
• Change from baseline in Tanner stage up to end of treatment (EOT + 3 days) [ Time Frame: 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).
• Change from baseline over time in body mass index (BMI) up to end of treatment (EOT + 3 days) [ Time Frame: Up to 7 years ]
  Individual weight and height are used to determine BMI expressed in Kg/m2
• Change from baseline in thyroid stimulating hormone (TSH) up to end of treatment (EOT + 3 days) [ Time Frame: Up to 7 years ]
  Safety monitoring of thyroid function

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Clinical Study of to Confirm the Doses of Selexipag in Children With Pulmonary Arterial Hypertension
• Official Title: A Prospective, Multicenter, Open Label, Single Arm, Phase 2 Study to Investigate the Safety, Tolerability and Pharmacokinetics of Selexipag in Children With Pulmonary Arterial Hypertension
• Brief Summary: The purpose of this study to confirm the selexipag starting dose(s), selected based on pharmacokinetic (PK) extrapolation from adults, that leads to similar exposure as adults doses in children from greater than or equal to (>=) 2 to less than (˂) 18 years of age with Pulmonary Arterial Hypertension (PAH), by investigating the PK of selexipag and its active metabolite ACT-333679 in this population.
• Detailed Description: 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).
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pulmonary Arterial Hypertension

Intervention

Drug: selexipag (Uptravi)

Film-coated tablets for oral administration

Other Names:

• ACT-293987
• JNJ-67896049

Study Arms

Experimental: open label selexipag

The first dose of selexipag (Uptravi) will be administered in the evening of Day 1 and will be based on the body weight. Thereafter selexipag will be administered twice daily (morning and evening). Selexipag will be up-titrated during the first 12 weeks, with weekly increments equal to the starting dose until the participants reach their individual maximum tolerated dose (iMTD) or until a maximum dose corresponding to their baseline weight category is achieved (which will be 8-fold of the corresponding starting dose). Up-titration is followed by a stable maintenance treatment period from Week 12 to Week 16, at the maximum tolerated dose. Thereafter, participants will be treated with selexipag as long as the treatment is beneficial to the participants, as per investigator's decision.

Intervention: Drug: selexipag (Uptravi)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 1, 2022): 63
• Original Estimated Enrollment (submitted: April 3, 2018): 55
• Estimated Study Completion Date: December 31, 2026
• Actual Primary Completion Date: March 28, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Signed and dated informed consent by the parent(s) or Legally authorized representative(s) AND assent from developmentally capable children
• Males or females between greater than or equal to (>=) 2 and less than (<) 18 years of age with weight >= 9 kilograms (kg)
• Pulmonary arterial hypertension (PAH) diagnosis confirmed by documented historical right heart catheterization (RHC) performed at any time before participant's enrollment

• PAH with one of the following etiologies:

  • idiopathic (iPAH),
  • heritable (hPAH),
  • associated with congenital heart disease (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 associated with connective tissue disease
• Word Health Organization functional class (WHO FC) II to III
• Participants treated with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor provided that the treatment dose(s) has been stable for at least 3 months prior to enrollment, or participants who are not candidates for these therapies
• 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)

Key Exclusion Criteria:

• Participants with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis
• Participants with PAH associated with Eisenmenger syndrome
• Participants with moderate to large left-to-right shunts
• Participants 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 Participants with Fontan-palliation
• Participants with pulmonary hypertension due to lung disease
• Previous treatment with Uptravi (selexipag) within 2 weeks prior to enrollment
• Participants having received prostacyclin (epoprostenol) or prostacyclin analogs (that is, treprostinil, iloprost, beraprost) within 2 months prior to enrollment or are scheduled to receive any of these compounds during the trial
• Treatment with another investigational drug within 4 weeks prior to enrollment
• History, or current suspicion of intussusception or ileus or gastrointestinal obstruction as per investigator's judgment
• Uncontrolled thyroid disease as per investigator judgment
• Hemoglobin or hematocrit < 75 percentage (%) of the lower limit of normal range
• Known severe or moderate hepatic impairment
• Clinical signs of hypotension that in the investigator's judgment would preclude initiation of a PAH-specific therapy
• Participants with severe renal insufficiency
• Known hypersensitivity to the investigational treatment or to any of the excipients of the drug formulations

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belarus, Belgium, Canada, China, France, Germany, Hungary, Israel, Malaysia, Poland, Russian Federation, Serbia, Taiwan, Ukraine, United Kingdom, United States
• Removed Location Countries: Romania

Administrative Information

• NCT Number: NCT03492177
• Other Study ID Numbers: AC-065A203; 2018-000145-39 ( EudraCT Number ); AC-065A203 ( Other Identifier: Actelion )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Actelion
• Original Responsible Party: Same as current
• Current Study Sponsor: Actelion
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Catherine Boisson; Actelion

• PRS Account: Actelion
• Verification Date: February 2023