Pharmacokinetics, Safety, and Efficacy of Macitentan Versus Standard Care in Pediatric Pulmonary Arterial Hypertension: A Multicenter, Open-Label, Randomized Study

Trial ID: 2023-509845-10-00
Protocol: AC-055-312
Sponsor: Actelion Pharmaceuticals Ltd.

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Diseases & Conditions

Pulmonary arterial hypertension

Objectives

The primary objective of this study is to assess the **pharmacokinetics**, safety, and efficacy of **macitentan** compared to the standard of care in children with **pulmonary arterial hypertension** (PAH). This is clinically relevant as understanding the pharmacokinetic profile and safety of macitentan in a pediatric population can inform dosing strategies and therapeutic efficacy, potentially improving treatment outcomes for children with PAH.

Secondary objectives include:

To assess the safety and tolerability of macitentan in children with PAH.
To evaluate the efficacy of macitentan in this population.

Participants

The clinical trial involves a total of **143 participants** diagnosed with **pediatric pulmonary arterial hypertension**. The study population includes both male and female subjects, ranging in age from 1 month to less than 18 years. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of pulmonary arterial hypertension (PAH) and a body weight of at least 3.5 kg at randomization. The trial includes subjects with various etiologies of PAH, such as idiopathic, heritable, and those associated with congenital heart disease, drug or toxin exposure, HIV, or connective tissue disease. The participants may be treatment-naïve or on PAH-specific therapy, either as monotherapy or in combination. The study population is considered vulnerable, given the pediatric nature of the participants. Lifestyle factors such as diet and physical activity are not specified in the available data. The trial aims to evaluate the pharmacokinetics, safety, and efficacy of macitentan compared to the standard of care in this demographic.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label study with a single-arm extension period to evaluate the pharmacokinetics, safety, and efficacy of **macitentan** compared to the standard of care in children with **pediatric pulmonary arterial hypertension**. The trial is expected to run until November 28, 2025, with recruitment starting on October 27, 2023. Participants will be involved in the study for a maximum treatment period of 84 days, receiving a daily dose of 10 mg of macitentan in the form of a dispersible tablet administered orally. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes.

Inclusion criteria require participants to be between 1 month and 18 years of age, with a confirmed diagnosis of pulmonary arterial hypertension (PAH) as per historical right heart catheterization. Participants must also meet specific hemodynamic criteria and belong to the Nice 2013 Updated Classification Group 1 for PAH. Exclusion criteria are not explicitly detailed in the provided data. The primary endpoints focus on measuring trough plasma concentrations of macitentan and its active metabolite at steady-state, with secondary endpoints including time to hospitalization or death due to PAH, changes in WHO functional class, and quality of life assessments.

Study visits are structured to ensure comprehensive data collection and participant safety. The initial screening visit will confirm eligibility based on the inclusion criteria. Follow-up visits will occur at regular intervals to monitor drug levels, safety, and efficacy, with specific assessments at weeks 4, 12, 24, and 48. The end-of-study visit will conclude the participant's involvement, with final evaluations of the primary and secondary endpoints. Participants may be withdrawn from the study if they experience adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial aims to provide valuable insights into the treatment of pediatric pulmonary arterial hypertension, contributing to the optimization of therapeutic strategies for this rare condition.

Treatment

The clinical trial involves the administration of the experimental medication **macitentan**, marketed under the product code JNJ-67896062. This medication is provided in the form of a **dispersible tablet** and is intended for oral administration. The maximum daily dose is 10 mg, with a total maximum dose of 10 mg per day. The treatment period extends up to 84 days. The formulation is available in both paediatric and non-paediatric versions, with the paediatric formulation specifically designed for children. The active substance, macitentan, is of chemical origin and is produced by Actelion Pharmaceuticals Ltd. The medication is designated as an orphan drug under the designation number EU/3/11/909.

In addition to the experimental treatment, the study includes a comparator treatment, which is the standard of care for children with **pulmonary arterial hypertension**. The trial is designed to assess the pharmacokinetics, safety, and efficacy of macitentan in comparison to this standard treatment. The study is open-label and randomized, with a single-arm extension period to further evaluate the outcomes. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy

The efficacy of **macitentan** in the clinical trial will be assessed through a series of primary and secondary endpoints. For subjects aged 2 years and older in the macitentan arm, the primary endpoint involves measuring the trough (pre-dose) plasma concentrations of macitentan and its active metabolite, ACT-132 577, at Week 12 to determine steady-state levels. For subjects under 2 years of age, the trough concentrations will be measured at Week 4.

Secondary endpoints include several time-to-event analyses: time to first CEC-confirmed hospitalization for pulmonary arterial hypertension (PAH) and time to CEC-confirmed death due to PAH, both occurring between randomization and the end of the core period. Additionally, the time to death from all causes will be assessed from randomization to study closure. Other secondary endpoints involve changes from baseline to specific time points, such as WHO Functional Class status at Week 24, percent change in plasma NT-proBNP levels at Week 24, and changes in mean daily time spent in moderate to vigorous physical activity by Week 48, as measured by accelerometry.

Further assessments include changes from baseline to Week 24 in tricuspid annular plane systolic excursion (TAPSE) and left ventricular eccentricity index, both measured by echocardiography. Quality of life will also be evaluated using the PedsQLTM 4.0 Generic Core Scales Short Form (SF15) at Week 24. These efficacy parameters will be collected and analyzed at specified time points to provide a comprehensive evaluation of macitentan's impact on children with pulmonary arterial hypertension.

Inclusion and Exclusion Criteria

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Inclusion Criteria

" 1. Signed informed consent by the parent(s) or legally designated representative AND assent from developmentally capable children prior to initiation of any study-mandated procedure. 2. Criterion modified per Amendment 8 Version 9: Males or females between ≥ 1 month and < 18years of age. 3. Criterion modified per Amendment 8 Version 9: Subjects with body weight ≥ 3.5 kg at randomization. 4. Criterion modified per Amendment 6: PAH diagnosis confirmed by historical RHC (mPAP ≥ 25 mm Hg, and PAWP ≤ 15 mm Hg, and PVRi > 3 WU x m2), where in the absence of pulmonary vein obstruction and/or significant lung disease PAWP can be replaced by LAP or LVEDP (in absence of mitral stenosis) assessed by heart catheterization. 5. PAH belonging to the Nice 2013 Updated Classification Group 1 (including subjects with Down Syndrome) and of following etiologies: iPAH hPAH PAH associated with CHD: − PAH with co-incidental CHD (confirmed by BCAC) − Post-operative PAH (persisting/recurring/developing ≥ 6 months after repair of CHD) Drug or toxin-induced PAH PAH associated with HIV PAH-aCTD 6. WHO FC I to III. 7. PAH-specific treatment-naïve subjects or subjects on PAH-specific treatment (mono-therapy or combination of two therapies)*. 8. Females of childbearing potential must have a negative pregnancy test at Screening and at Baseline, and must agree to undertake monthly pregnancy tests, and to use a reliable method of contraception (if sexually active) up to EOS . "

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Exclusion Criteria

"Etiology 1. Subjects with PAH due to portal hypertension, schistosomiasis, pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of the newborn. 2. Subjects with PAH associated with open shunts, as specified below: a. Eisenmenger syndrome b. Moderate to large left-to-right shunts. 3. Subjects with the following congenital cardiac abnormalities: a. Cyanotic congenital cardiac lesions such as transposition of the great arteries, truncus arteriosus, pulmonary atresia with ventricular septal defect, unless operatively repaired and with no residual shunt b. Univentricular heart and/or subjects with Fontan-palliation. 4. Subjects with pulmonary hypertension due to lung disease (e.g., bronchopulmonary dysplasia). 5. Criterion added per Amendment 8 Version 9: Subjects with known diagnosis of bronchopulmonary dysplasia. Treatment and intervention 6. Subjects receiving a combination of > 2 PAH-specific treatments at randomization. 7. Treatment with IV or SC prostanoids within 4 weeks before randomization, unless given for vasoreactivity testing. 8. Criterion added per Amendment 8 Version 9: In children ≥ 2 y.o.: Previous treatment with macitentan at any time. 9. Treatment with another investigational drug within 4 weeks prior to randomization. 10. Any PAH-related surgical intervention planned, or subjects listed for organ transplantation related to PAH. 11. Treatment with strong inducers of CYP3A4 such as rifabutin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s wort (hypericum perforatum), within 4 weeks prior to randomization. 12. Systemic treatment with strong inhibitors of CYP3A4 such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole within 4 weeks prior to randomization. 13. Criterion modified per Amendment 3.1 Version 4.1: Systemic treatment with moderate dual CYP3A4/ CYP2C9 inhibitor (e.g., fluconazole and amiodarone), or administration of a combination of a moderate CYP3A4 (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) together with a moderate CYP2C9 inhibitor (e.g., miconazole, piperine) within 4 weeks prior to randomization Baseline abnormalities 14. Subjects with pulmonary vein stenosis. 15. Known concomitant life-threatening disease with a life expectancy < 12 months. 16. Hemoglobin or hematocrit < 75% of the lower limit of normal range (LLN). 17. Serum AST and/or ALT > 3 ×ULN. 18. Criterion modified per Amendment 6 Version 7: Severe hepatic impairment, e.g., Child-Pugh Class C [see Appendix 1]. 19. Clinical signs of hypotension which in the investigator’s judgment would preclude initiation of a PAH-specific therapy. 20. Criterion added per Amendment 6 Version 7: Severe renal insufficiency (estimated creatinine clearance <30 mL/min or serum creatinine >221 µmol/L) Pregnancy and breastfeeding 21. Pregnancy (including family planning) or breastfeeding. Other categories 22. Known hypersensitivity to ERAs, or any of the excipients. 23. 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. "