Phase 3 Randomized Study Comparing Efficacy and Safety of Macitentan 75 mg vs. 10 mg in Pulmonary Arterial Hypertension Patients

The primary objective of this Phase 3 study is to demonstrate the superiority of **macitentan** 75 mg in prolonging the time to the first CEC-adjudicated morbidity or mortality event in participants with symptomatic **pulmonary arterial hypertension** (PAH) compared to macitentan 10 mg. This is clinically relevant as it aims to improve long-term outcomes and survival rates in patients suffering from PAH, a progressive and life-threatening condition. The study also evaluates the efficacy, safety, and tolerability of the higher dose of macitentan, which could potentially offer enhanced therapeutic benefits over the standard 10 mg dose.

The clinical trial involves a total of **790 participants** diagnosed with **pulmonary arterial hypertension** (PAH). The study population includes both male and female subjects, aged 18 years and older, encompassing individuals who are legally considered adults in their respective jurisdictions. Participants are required to have symptomatic PAH classified under WHO Functional Class II, III, or IV, with subtypes including idiopathic, heritable, drug- or toxin-induced, or related to conditions such as connective tissue disease, HIV infection, portal hypertension, or congenital heart disease. The selection process ensures that participants have a confirmed PAH diagnosis through hemodynamic evaluation, with specific criteria for mean pulmonary artery pressure, pulmonary artery wedge pressure, and pulmonary vascular resistance. Participants must be capable of performing a six-minute walk test within a specified distance range and adhere to lifestyle restrictions outlined in the study protocol. The trial includes individuals already on stable PAH therapies, with specific guidelines for those on endothelin receptor antagonist therapy. Both vulnerable populations and those willing to provide optional biomarker research samples are included, provided they meet the informed consent requirements.

The clinical trial is a **Phase 3**, prospective, multicenter, double-blind, double-dummy, randomized, active-controlled, parallel-group, group-sequential, adaptive, event-driven study. It aims to compare the efficacy, safety, and tolerability of **macitentan** 75 mg versus macitentan 10 mg in patients with **pulmonary arterial hypertension** (PAH). The trial includes a follow-up open-label treatment period with macitentan 75 mg. The primary objective is to demonstrate the superiority of macitentan 75 mg in prolonging the time to the first CEC-adjudicated morbidity or mortality event in participants with symptomatic PAH compared to macitentan 10 mg. The trial is expected to conclude by January 15, 2026, with recruitment having started on January 15, 2020.

Participants will be involved in the study for a maximum treatment period of 72 weeks. The trial design includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as age, PAH diagnosis, and ability to perform a 6-minute walk test. Following the screening, eligible participants will be randomized to receive either macitentan 75 mg, macitentan 10 mg, or a matching placebo. The study is double-blind, ensuring that neither the participants nor the investigators know which treatment is being administered, thus minimizing bias.

Study visits are scheduled at regular intervals to monitor the participants' health status, adherence to the study protocol, and any adverse events. These visits include assessments such as physical examinations, laboratory tests, and efficacy evaluations. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant.

The trial's primary endpoint is the time to the first CEC-adjudicated morbidity or mortality event on-treatment, up to 7 days after the last dose of the double-blind study intervention. The study is designed to ensure rigorous evaluation of the treatment's impact on PAH, with the aim of providing valuable data on the long-term efficacy and safety of macitentan at different dosages.

The clinical trial involves the administration of **macitentan** in various dosages to evaluate its efficacy, safety, and tolerability in patients with pulmonary arterial hypertension. The experimental medication, JNJ 67896062, is a **film-coated tablet** containing macitentan as the active substance. It is manufactured by Janssen-Cilag International N.V. and is administered orally. The trial includes two dosages of JNJ 67896062: 37.5 mg and 75 mg. The maximum daily dose for the 37.5 mg formulation is 37 mg, while the 75 mg formulation has a maximum daily dose of 75 mg. Both dosages are administered once daily for a maximum treatment period of 72 weeks.

Opsumit 10 mg film-coated tablets, also containing macitentan, serve as the comparator treatment in the study. These tablets are also produced by Janssen-Cilag International NV and are administered orally. The maximum daily dose for Opsumit is 10 mg, with a treatment period extending up to 72 weeks. The tablets are specifically packaged for the study to ensure blinding, with no debossing of "10" as seen in commercial versions.

In addition to the active treatments, the study employs matching placebos for each dosage of macitentan to maintain the double-blind design. These placebos are used to mimic the appearance and administration route of the active treatments, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebos are administered orally, corresponding to the respective dosages of 10 mg, 37.5 mg, and 75 mg of macitentan.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The trial is designed to assess the superiority of macitentan 75 mg in prolonging the time to the first CEC-adjudicated morbidity or mortality event compared to macitentan 10 mg, with a subsequent open-label treatment period using macitentan 75 mg.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the time to the first CEC-adjudicated morbidity or mortality (M/M) event on-treatment. This assessment will be conducted up to 7 days after the last dose of the double-blind study intervention. The trial aims to demonstrate the superiority of **macitentan** 75 mg in prolonging the time to the first M/M event in participants with symptomatic pulmonary arterial hypertension (PAH) compared to **macitentan** 10 mg. The study is designed as a Phase 3, prospective, multicenter, double-blind, double-dummy, randomized, active-controlled, parallel-group, group-sequential, adaptive, event-driven study. The trial will follow a structured schedule to ensure accurate and consistent data collection and analysis. The efficacy parameters will be collected and analyzed using validated methods to ensure the reliability of the results. The study will include an open-label treatment period with **macitentan** 75 mg following the double-blind phase.