Clinical trial NCT03492177: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Keywords: Pediatric
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2018-04-10
Enrollment: 63
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: 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)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
Secondary outcomes:
measure: Area Under the Plasma Concentration-time Curve Over a Dose Interval of Selexipag at Steady State (AUCτ,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Area Under the Plasma Concentration-Time Curve Over a Dose Interval of ACT-333679 at Steady State (AUCτ,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Maximum Observed Plasma Concentration of Selexipag at Steady State (Cmax,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Cmax,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Time to Reach the Maximum Observed Plasma Concentration of Selexipag at Steady State (Tmax,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Time to Reach the Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Tmax,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Trough Concentration of Selexipag at Steady State (Ctrough,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Trough Concentration of ACT-333679 at Steady State (Ctrough,ss)
timeFrame: Week 1,Week 12: pre-dose, 1, 2, 4, 6, 8 and 12 h post-morning dose. Week 2, 4 and 6: pre-dose (Up to Week 12)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) (End of Treatment [EOT] + 3 Days)
timeFrame: EOT+3 days (Up to Week 17)
measure: Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) (EOT + 3 Days)
timeFrame: EOT+3 days (Up to Week 17)
measure: Number of Participants With Adverse Events (AEs) Leading to Permanent Discontinuation of Study Drug
timeFrame: Up to 7 years
measure: Number of Participants With Treatment-emergent Deaths (EOT + 3 Days)
timeFrame: EOT+3 days (Up to Week 17)
measure: Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (EOT + 3 Days)
timeFrame: EOT+3 days (Up to Week 17)
measure: Change From Baseline in Hematology Parameters (EOT + 3 Days)
timeFrame: EOT+3 days (Up to Week 17)
measure: Change From Baseline in Chemistry Parameters (EOT + 3 Days)
timeFrame: EOT+3 days (Up to Week 17)
measure: Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities (EOT + 3 Days)
timeFrame: EOT+3 days (Up to Week 17)
measure: Change From Baseline in Thyroid Stimulating Hormone (TSH) up to EOT + 3 Days
timeFrame: EOT+3 days (Up to Week 17)
measure: Change From Baseline in Blood Pressure
timeFrame: Up to 7 years
measure: Change From Baseline in Heart Rate
timeFrame: Up to 7 years
measure: Change From Baseline Over Time in Height up to EOT+3 Days
timeFrame: EOT+3 days (Up to Week 17)
measure: Change From Baseline Over Time in Body Mass Index (BMI) up to EOT + 3 Days
timeFrame: EOT+ 3 days (Up to Week 17)
measure: Change From Baseline in Sexual Maturation (Tanner Stage) up to End of Treatment (EOT + 3 Days)
timeFrame: EOT+ 3 days (Up to Week 17)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children'S Hospital Cardiac Care Center University Of Colorado
state: Colorado
city: Iowa City
country: United States
facility: University of Iowa Hospital
state: Iowa
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Minsk
country: Belarus
facility: State Institution Republican Scientific And Practical Center For Pediatric Surgery
city: Minsk
country: Belarus
facility: Health Institution 4Th City Children'S Clinical Hospital
city: Gent
country: Belgium
facility: UZ Gent
city: Montreal
country: Canada
facility: Centre Hospitalier Sainte Justine
state: Quebec
city: Beijing
country: China
facility: Beijing Anzhen Hospital
city: Shanghai
country: China
facility: Shanghai Childrens Medical Center
city: Montpellier Cedex 5
country: France
facility: CHU Arnaud de Villeneuve
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Toulouse Cedex 9
country: France
facility: Chu Hopital Des Enfants
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg Zentrum
city: Budapest
country: Hungary
facility: Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
city: Petach Tikvah
country: Israel
facility: Schneider Children's Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
city: Kota Samarahan
country: Malaysia
facility: Sarawak General Hospital
city: Kuala Lumpur
country: Malaysia
facility: Institut Jantung Negara (National Heart Institute)
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny We Wroclawiu
city: Kazan
country: Russian Federation
facility: Kazan State Medical University
city: Kemerovo
country: Russian Federation
facility: Federal State Budget Scientific Institution
city: Moscow
country: Russian Federation
facility: Moscow Scientific Research Institute For Pediatrics And Childrens Surgery Of Rosmedtechnologies
city: Samara
country: Russian Federation
facility: Samara Regional Clinical Cardiological Dispensary
city: St Petersburg
country: Russian Federation
facility: Federal State Budgetary Institution
city: St. Petersburg
country: Russian Federation
facility: Saint Petersburg State Pediatric Medical University
city: Belgrade
country: Serbia
facility: Univerzitetska Dečja Klinika
city: Belgrade
country: Serbia
facility: Institut Za Zdravstvenu Zastitu Majke I Deteta Srbije Dr Vukan Cupic
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Dnipro
country: Ukraine
facility: Municipal Enterprise Of The Dnipropetrovsk Regional Council
city: Kiev
country: Ukraine
facility: State Institution Of The Ministry Of Health Of Ukraine
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital
city: Zaporizhzhya
country: Ukraine
facility: Municipal Institution Of The Zaporizhzhya Regional Council
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Actelion
name: Catherine Boisson
role: STUDY_DIRECTOR
References: