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

Primary Purpose

Pulmonary Arterial Hypertension

Status

Active

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

selexipag (Uptravi)

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring Pediatric

Eligibility Criteria

2 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Children'S Hospital Cardiac Care Center University Of Colorado
University of Iowa Hospital
Seattle Children's Hospital
State Institution Republican Scientific And Practical Center For Pediatric Surgery
Health Institution 4Th City Children'S Clinical Hospital
UZ Gent
Centre Hospitalier Sainte Justine
Beijing Anzhen Hospital
Shanghai Children's Medical Center
CHU Arnaud de Villeneuve
Hôpital Necker - Enfants Malades
Chu Hopital Des Enfants
Universitätsklinikum Freiburg Zentrum
Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
Schneider Children's Medical Center
Sheba Medical Center
Institut Jantung Negara (National Heart Institute)
Sarawak General Hospital
Wojewodzki Szpital Specjalistyczny We Wroclawiu
Kazan State Medical University
Federal State Budget Scientific Institution
Moscow Scientific Research Institute For Pediatrics And Childrens Surgery Of Rosmedtechnologies
Samara Regional Clinical Cardiological Dispensary
Federal State Budgetary Institution
Saint Petersburg State Pediatric Medical University
Univerzitetska Dečja Klinika
Institut Za Zdravstvenu Zaštitu Majke I Deteta Srbije ''Dr Vukan Čupić''
National Cheng Kung University Hospital
National Taiwan University Hospital
Municipal Enterprise Of The Dnipropetrovsk Regional Council
State Institution Of The Ministry Of Health Of Ukraine
Lviv Regional Clinical Hospital
Municipal Institution Of The Zaporizhzhya Regional Council
Great Ormond Street Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

open label selexipag

Arm Description

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.

Outcomes

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)

AUCτ, ss, combined was defined as the area under the plasma concentration-time curve over one dosing interval at steady state. AUCτ,ss,combined was calculated as 1/38 AUCτ,ss,selexipag plus 37/38 AUCτ,ss,ACT-333679.

Secondary Outcome Measures

Area Under the Plasma Concentration-time Curve Over a Dose Interval of Selexipag at Steady State (AUCτ,ss)

Area Under the Plasma Concentration-Time Curve Over a Dose Interval of ACT-333679 at Steady State (AUCτ,ss)

Maximum Observed Plasma Concentration of Selexipag at Steady State (Cmax,ss)

Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Cmax,ss)

Time to Reach the Maximum Observed Plasma Concentration of Selexipag at Steady State (Tmax,ss)

Time to Reach the Maximum Observed Plasma Concentration of ACT-333679 at Steady State (Tmax,ss)

Trough Concentration of Selexipag at Steady State (Ctrough,ss)

Trough Concentration of ACT-333679 at Steady State (Ctrough,ss)

Number of Participants With Treatment-emergent Adverse Events (TEAEs) (End of Treatment [EOT] + 3 Days)

Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) (EOT + 3 Days)

Number of Participants With Adverse Events (AEs) Leading to Permanent Discontinuation of Study Drug

Number of Participants With Treatment-emergent Deaths (EOT + 3 Days)

Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (EOT + 3 Days)

Change From Baseline in Hematology Parameters (EOT + 3 Days)

Change From Baseline in Chemistry Parameters (EOT + 3 Days)

Number of Participants With Treatment-emergent Electrocardiogram (ECG) Abnormalities (EOT + 3 Days)

Change From Baseline in Thyroid Stimulating Hormone (TSH) up to EOT + 3 Days

Change From Baseline in Blood Pressure

Change From Baseline in Heart Rate

Change From Baseline Over Time in Height up to EOT+3 Days

Change From Baseline Over Time in Body Mass Index (BMI) up to EOT + 3 Days

Change From Baseline in Sexual Maturation (Tanner Stage) up to End of Treatment (EOT + 3 Days)

Full Information

NCT ID

NCT03492177

First Posted

April 3, 2018

Last Updated

October 10, 2023

Sponsor

Actelion

1. Study Identification

Unique Protocol Identification Number

NCT03492177

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

July 23, 2018 (Actual)

Primary Completion Date

March 28, 2022 (Actual)

Study Completion Date

December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Actelion

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Arterial Hypertension

Keywords

Pediatric

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

63 (Actual)

8. Arms, Groups, and Interventions

Arm Title

open label selexipag

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

selexipag (Uptravi)

Other Intervention Name(s)

ACT-293987, JNJ-67896049

Intervention Description

Film-coated tablets for oral administration

Primary Outcome Measure Information:

Title

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)

Description

Time Frame