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

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ClinicalTrials.gov Identifier: NCT03492177
Recruitment Status : Recruiting
First Posted : April 10, 2018
Last Update Posted : April 14, 2021
Sponsor:
Information provided by (Responsible Party):
Actelion

Tracking Information
First Submitted Date  ICMJE April 3, 2018
First Posted Date  ICMJE April 10, 2018
Last Update Posted Date April 14, 2021
Actual Study Start Date  ICMJE July 23, 2018
Estimated Primary Completion Date February 11, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2018)
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 patients. Blood samples for pharmacokinetic analyses will be collected in the 3 age cohorts.
Original Primary Outcome Measures  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Clinical Study of to Confirm the Doses of Selexipag in Children With Pulmonary Arterial Hypertension
Official Title  ICMJE 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 Selexipag is available for the treatment of pulmonary arterial hypertension (PAH) in adults in various countries. The efficacy of selexipag to delay disease progression was shown in a previous pivotal study conducted in 1156 adult patients with PAH. Given the similarities in the functional changes of PAH in children and adults, it is expected that children suffering from PAH could benefit from treatment with selexipag. The aim of the present study is to confirm the doses of selexipag to be used in pediatric patients with PAH older than 2 years. To fulfill this aim, blood levels of selexipag (pharmacokinetic assessments) as well as the safety, and tolerability of selexipag in children with PAH will be assessed.
Detailed Description

The selection of the starting dose for pediatric patients is based on the pharmacokinetic (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 patients at a starting dose of 200 microgram (μg). As in adults, selexipag will be up-titrated to the individual maximum tolerated dose (iMTD) during the first 12 weeks.

Approximately 55 subjects will be enrolled in 3 different age cohorts to obtain at least 40 subjects 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 subjects from Cohort 1 at Week 12, a first interim analysis will be conducted to establish the dose-exposure relationship using a population PK model.

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Arterial Hypertension
Intervention  ICMJE Drug: selexipag (Uptravi)
Film-coated tablets for oral administration
Other Name: ACT-293987
Study Arms  ICMJE 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 subjects 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, subjects will be treated with selexipag as long as the treatment is beneficial to the subject, as per investigator's decision
Intervention: Drug: selexipag (Uptravi)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 24, 2020)
66
Original Estimated Enrollment  ICMJE
 (submitted: April 3, 2018)
55
Estimated Study Completion Date  ICMJE July 30, 2026
Estimated Primary Completion Date February 11, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 ≥ 2 and < 18 years of age with weight ≥ 9 kg.
  • PAH diagnosis confirmed by documented historical right heart catheterization (RHC) performed at any time before subject'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.
  • Subjects 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 patients 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:

  • Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis.
  • Subjects with PAH associated with Eisenmenger syndrome.
  • Subjects with moderate to large left-to-right shunts.
  • 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.
  • Subjects with pulmonary hypertension due to lung disease.
  • Previous treatment with Uptravi (selexipag) within 2 weeks prior to enrollment.
  • Subjects having received prostacyclin (epoprostenol) or prostacyclin analogs (i.e., 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% 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.
  • Subjects with severe renal insufficiency.
  • Known hypersensitivity to the investigational treatment or to any of the excipients of the drug formulations.
  • 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).
  • Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Study Contact 844-434-4210 JNJ.CT@sylogent.com
Listed Location Countries  ICMJE 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  ICMJE NCT03492177
Other Study ID Numbers  ICMJE AC-065A203
2018-000145-39 ( EudraCT Number )
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  ICMJE Not Provided
Responsible Party Actelion
Study Sponsor  ICMJE Actelion
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Sofija Cerovic Actelion
PRS Account Actelion
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP