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

Pulmonary Arterial Hypertension Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03492177
• Other study ID #: AC-065A203
• Secondary ID: 2018-000145-39AC
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 23, 2018
• Est. completion date: December 31, 2026

Study information

• Verified date: April 2024
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 63
• Est. completion date: December 31, 2026
• Est. primary completion date: March 28, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• selexipag (Uptravi)
Film-coated tablets for oral administration

Locations

Country	Name	City	State
Belarus	Health Institution 4Th City Children'S Clinical Hospital	Minsk
Belarus	State Institution Republican Scientific And Practical Center For Pediatric Surgery	Minsk
Belgium	UZ Gent	Gent
Canada	Centre Hospitalier Sainte Justine	Montreal	Quebec
China	Beijing Anzhen Hospital	Beijing
China	Shanghai Childrens Medical Center	Shanghai
France	CHU Arnaud de Villeneuve	Montpellier Cedex 5
France	Hôpital Necker - Enfants Malades	Paris
France	Chu Hopital Des Enfants	Toulouse Cedex 9
Germany	Universitätsklinikum Freiburg Zentrum	Freiburg
Hungary	Gottsegen György Országos Kardiológiai Intézet, Felnott kardiológiai osztály	Budapest
Israel	Schneider Children's Medical Center	Petach Tikvah
Israel	Sheba Medical Center	Ramat Gan
Malaysia	Institut Jantung Negara (National Heart Institute)	Kuala Lumpur
Malaysia	Sarawak General Hospital	Kuching
Poland	Wojewodzki Szpital Specjalistyczny We Wroclawiu	Wroclaw
Russian Federation	Kazan State Medical University	Kazan
Russian Federation	Federal State Budget Scientific Institution	Kemerovo
Russian Federation	Moscow Scientific Research Institute For Pediatrics And Childrens Surgery Of Rosmedtechnologies	Moscow
Russian Federation	Samara Regional Clinical Cardiological Dispensary	Samara
Russian Federation	Federal State Budgetary Institution	St Petersburg
Russian Federation	Saint Petersburg State Pediatric Medical University	St. Petersburg
Serbia	Institut Za Zdravstvenu Zaštitu Majke I Deteta Srbije ''Dr Vukan Cupic''	Belgrade
Serbia	Univerzitetska Decja Klinika	Belgrade
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Ukraine	Municipal Enterprise Of The Dnipropetrovsk Regional Council	Dnipro
Ukraine	State Institution Of The Ministry Of Health Of Ukraine	Kiev
Ukraine	Lviv Regional Clinical Hospital	Lviv
Ukraine	Municipal Institution Of The Zaporizhzhya Regional Council	Zaporizhzhya
United Kingdom	Great Ormond Street Hospital	London
United States	Children'S Hospital Cardiac Care Center University Of Colorado	Aurora	Colorado
United States	University of Iowa Hospital	Iowa City	Iowa
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Belarus,  Belgium,  Canada,  China,  France,  Germany,  Hungary,  Israel,  Malaysia,  Poland,  Russian Federation,  Serbia,  Taiwan,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-time Curve Over a Dose Interval at Steady State of Selexipag and Its Metabolite ACT-333679 Combined (AUCt, ss, Combined)	AUCt, ss, combined was defined as the area under the plasma concentration-time curve over one dosing interval at steady state. AUCt,ss,combined was calculated as 1/38 AUCt,ss,selexipag plus 37/38 AUCt,ss,ACT-333679.	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	Area Under the Plasma Concentration-time Curve Over a Dose Interval of Selexipag at Steady State (AUCt,ss)		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	Area Under the Plasma Concentration-Time Curve Over a Dose Interval of ACT-333679 at Steady State (AUCt,ss)		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	Maximum Observed Plasma Concentration of Selexipag at Steady State (Cmax,ss)		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	Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Cmax,ss)		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	Time to Reach the Maximum Observed Plasma Concentration of Selexipag at Steady State (Tmax,ss)		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	Time to Reach the Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Tmax,ss)		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	Trough Concentration of Selexipag at Steady State (Ctrough,ss)		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	Trough Concentration of ACT-333679 at Steady State (Ctrough,ss)		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	Number of Participants With Treatment-emergent Adverse Events (TEAEs) (End of Treatment [EOT] + 3 Days)		EOT+3 days (Up to Week 17)
Secondary	Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) (EOT + 3 Days)		EOT+3 days (Up to Week 17)
Secondary	Number of Participants With Adverse Events (AEs) Leading to Permanent Discontinuation of Study Drug		Up to 7 years
Secondary	Number of Participants With Treatment-emergent Deaths (EOT + 3 Days)		EOT+3 days (Up to Week 17)
Secondary	Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (EOT + 3 Days)		EOT+3 days (Up to Week 17)
Secondary	Change From Baseline in Hematology Parameters (EOT + 3 Days)		EOT+3 days (Up to Week 17)
Secondary	Change From Baseline in Chemistry Parameters (EOT + 3 Days)		EOT+3 days (Up to Week 17)
Secondary	Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities (EOT + 3 Days)		EOT+3 days (Up to Week 17)
Secondary	Change From Baseline in Thyroid Stimulating Hormone (TSH) up to EOT + 3 Days		EOT+3 days (Up to Week 17)
Secondary	Change From Baseline in Blood Pressure		Up to 7 years
Secondary	Change From Baseline in Heart Rate		Up to 7 years
Secondary	Change From Baseline Over Time in Height up to EOT+3 Days		EOT+3 days (Up to Week 17)
Secondary	Change From Baseline Over Time in Body Mass Index (BMI) up to EOT + 3 Days		EOT+ 3 days (Up to Week 17)
Secondary	Change From Baseline in Sexual Maturation (Tanner Stage) up to End of Treatment (EOT + 3 Days)		EOT+ 3 days (Up to Week 17)