Phase 2 Study on Selexipag Pharmacokinetics in Pediatric Pulmonary Arterial Hypertension Patients Aged 2 to <18 Years

Trial ID: 2022-503042-42-00
Protocol: AC-065A203
Sponsor: Actelion Pharmaceuticals Ltd.

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Diseases & Conditions

Pulmonary arterial hypertension

Objectives

The primary objective of this study is to confirm the **selexipag** starting dose(s) for children aged ≥ 2 to < 18 years with **pulmonary arterial hypertension** (PAH). This is achieved by investigating the pharmacokinetics (PK) of selexipag and its active metabolite, ACT-333679, to ensure similar drug exposure levels as those observed in adults. This objective is clinically relevant as it aims to establish an appropriate dosing regimen for pediatric patients, ensuring efficacy and safety comparable to adult treatments.

Secondary objectives include evaluating the **tolerability** of selexipag in the pediatric population. This is crucial for understanding the safety profile and potential adverse effects in children, which can differ from adults due to developmental and physiological differences.

Participants

The clinical trial involves a total of **52 participants** diagnosed with **Pulmonary Arterial Hypertension** (PAH). The study population comprises both male and female subjects aged between **2 and 18 years**. Participants were selected based on specific inclusion criteria, including a confirmed PAH diagnosis through historical right heart catheterization and stable treatment with endothelin receptor antagonists or phosphodiesterase type 5 inhibitors, if applicable. The trial includes individuals with idiopathic, heritable, or congenital heart disease-associated PAH, as well as those with PAH linked to drug or toxin exposure, HIV, or connective tissue disease. Participants are required to be in World Health Organization functional class II to III. The study population is considered vulnerable due to the inclusion of children, and informed consent was obtained from parents or legally authorized representatives, with assent from developmentally capable children. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

Plans and Procedures

The clinical trial is a prospective, multicenter, open-label, single-arm, Phase 2 study designed to investigate the **safety**, tolerability, and pharmacokinetics of **selexipag** in children with **pulmonary arterial hypertension** (PAH). The primary objective is to confirm the selexipag starting dose(s) that lead to similar exposures as adult doses in children aged 2 to less than 18 years, by examining the pharmacokinetics of selexipag and its active metabolite ACT-333679. The trial is expected to run from May 2018 to May 2025, with a maximum treatment period of 60 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, weight, and confirmed PAH diagnosis. The inclusion criteria require signed informed consent from parents or legally authorized representatives, and assent from developmentally capable children. Participants must have a stable treatment regimen with an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor, or be unsuitable for these therapies. Females of childbearing potential must have a negative pregnancy test at screening and agree to monthly testing and reliable contraception use.

Following the screening visit, participants will proceed to the baseline/enrollment visit, where they will begin the study drug regimen. The trial involves a 12-week up-titration period to determine the primary pharmacokinetic endpoint, which is the model-based exposure of selexipag and ACT-333679. Follow-up visits will be scheduled to monitor safety, tolerability, and pharmacokinetic parameters. The end-of-study visit will conclude the participant's involvement, with assessments to ensure safety and gather final data.

Participant involvement is expected to last up to 60 days, with conditions for early termination including adverse events, withdrawal of consent, or protocol non-compliance. The study employs a single-arm design, meaning all participants receive the investigational product, and it is open-label, so both participants and investigators are aware of the treatment being administered. The trial does not include a control group, as it focuses on dose confirmation and pharmacokinetic analysis in the pediatric population.

Treatment

The clinical trial involves the administration of the experimental medication **Selexipag**, marketed under the product code JNJ-67896049. This medication is provided in the form of a **film-coated tablet** and is intended for **oral use**. The active substance, Selexipag, is a selective and long-acting nonprostanoid agonist at the prostacyclin receptor, originating from a chemical source. The maximum daily dose of Selexipag is 3200 micrograms, with a treatment period not exceeding 60 days. The trial aims to investigate the pharmacokinetics of Selexipag and its active metabolite, ACT-333679, in children aged 2 to less than 18 years with pulmonary arterial hypertension, ensuring similar exposure levels to those observed in adults.

In addition to the experimental medication, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the available data. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to confirm the starting dose of Selexipag based on pharmacokinetic extrapolation from adult data, aiming to achieve similar exposure levels in the pediatric population.

Efficacy

Efficacy in this clinical trial will be assessed primarily through pharmacokinetic (PK) endpoints. The primary endpoint involves the model-based exposure (AUCτ,ss, combined) of **selexipag** and its active metabolite ACT-333679, corrected for their potency. This will be determined during the 12-week up-titration period. The study aims to confirm the starting dose(s) of selexipag that lead to similar exposures in children with pulmonary arterial hypertension (PAH) as those observed in adults. The PK of selexipag and its active metabolite will be investigated in the pediatric population aged ≥ 2 to < 18 years. The trial is designed as a prospective, multicenter, open-label, single-arm, Phase 2 study, focusing on safety, tolerability, and pharmacokinetics.

Inclusion and Exclusion Criteria

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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 at Baseline / Enrollment / Visit 2 weighing ≥ 9 kg
PAH diagnosis confirmed by documented historical right heart catheterization (RHC) performed at any time before the participants'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 • PAH associated with HIV • PAH associated with connective tissue disease
Word Health Organizaition 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 + 30 days (EOS)

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Exclusion Criteria

Participants with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis
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 subjects with Fontan palliation
Participants with PH due to lung disease and/or hypoxia. For subjects with Down syndrome, exclusion of lung disease and hypoxia causing PH should be documented (e.g., computed tomography scan, polysomnography, lung function tests)
Previous treatment with Uptravi® (selexipag) within 2 weeks prior to enrollment
Previous having received prostacyclin (epoprostenol) or prostacyclin analogs2 (i.e., treprostinil, iloprost, beraprost) within 2 months prior to enrollment or who are scheduled to receive any of these compounds during the trial
Treatment with another investigational drug within 4 weeks prior to enrollment
Treatment with strong and moderate inhibitors of CYP2C8 (eg, gemfibrozil, clopidogrel, deferasirox, teriflunomide) within 2 weeks prior to enrollment until the last dose of selexipag + 3 days
1 Moderate or severe hepatic impairment, eg, Child-Pugh Class B or C [see Appendix 4]
Clinical signs of hypotension that, in the investigator's judgment, would preclude the initiation of a PAH-specific therapy
Participants with severe renal insufficiency (estimated creatinine clearance < 30 mL/min or serum creatinine > 221 μmol/L)
Severe coronary heart disease or unstable angina as assessed by the investigator
Treatment with inhibitors of UGT1A3 and UGT2B7 (valproic acid, probenecid, and fluconazole) are prohibited from 2 weeks prior to enrollment and until the last dose of selexipag + 3 days
Myocardial infarction within the last 6 months prior to enrollment
Decompensated cardiac failure if not under close supervision
Severe arrhythmias as assessed by the investigator
Cerebrovascular events (eg, transient ischemic attack, stroke) within the last 3 months prior to enrollment.
Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to PH
Pregnancy (including family planning) or breastfeeding
Known hypersensitivity to the investigational treatment or to any of the excipients of the drug formulations
Drug or substance abuse, or any condition that, in the opinion of the investigator, may prevent compliance with the protocol or adherence to study treatment
Loss of 250 mL or more of blood within 3 months prior to screening
History or clinical evidence of any disease and/or existence of any surgical or medical condition that might interfere with the absorption, distribution, metabolism, or excretion of the study treatment(s) (e.g., cholecystectomy)
Any PAH-related surgical intervention planned, or participants listed for organ transplantation related to PAH
History or current suspicion of intussusception or ileus or gastrointestinal obstruction, per investigator's judgment
Known concomitant life-threatening disease with a life expectancy < 12 months
Uncontrolled thyroid disease, per investigator's judgment
Hemoglobin or hematocrit < 75% of the lower limit of normal range
Participants with PAH associated with Eisenmenger syndrome
Participants with moderate to large left-to-right shunts
"Criterion deleted per Amendment 6".