Comparison of Initial Dual Oral Therapy with Tadalafil and Ambrisentan Versus Tadalafil Monotherapy in Pulmonary Arterial Hypertension with Cardiovascular Comorbidities

The primary objective of the study is to analyze the effect of the initial treatment strategy, comparing **tadalafil** and **ambrisentan** versus tadalafil and placebo, on disease control assessed at 6 months in treatment-naïve patients with newly diagnosed **pulmonary arterial hypertension** (PAH) and cardiovascular comorbidities. This objective is clinically relevant as it aims to determine the efficacy of combination therapy in managing PAH, a condition characterized by high blood pressure in the lungs' arteries, which can lead to heart failure if not effectively controlled.

Secondary objectives include:

• Documenting the effect of the initial treatment strategy at 24 weeks on mortality, morbidity, quality of life, cardiopulmonary hemodynamic parameters, echocardiographic parameters, exercise capacity, and biomarkers in the same patient population.
• Analyzing the effect of the initial treatment strategy on disease control assessed at 12 weeks.
• Documenting the safety and tolerability of the initial treatment strategy.

The clinical trial focuses on **pulmonary arterial hypertension** and involves a study population comprising both male and female participants aged 18 years and older. The participants are treatment-naïve patients with a newly diagnosed condition of pulmonary arterial hypertension, with the diagnosis made less than six months prior to the start of the trial. The trial population includes individuals with cardiovascular comorbidities, such as essential hypertension, diabetes mellitus, obesity, and coronary heart disease. The selection criteria ensure that participants have a mean pulmonary arterial pressure (mPAP) of at least 25 mmHg, a pulmonary arterial wedge pressure (PAWP) of 15 mmHg or less, and a pulmonary vascular resistance (PVR) of at least 3 Wood units. The sponsor has not provided the total number of participants involved in the study. The trial does not include a vulnerable population, and the participants are expected to have a general health status that aligns with the inclusion criteria, which are based on the European pulmonary hypertension guidelines.

The clinical trial is designed to evaluate the efficacy of initial dual oral combination therapy compared to monotherapy in patients with **pulmonary arterial hypertension** (PAH) and cardiovascular comorbidities. This is a randomized, double-blind, controlled trial involving the administration of **ambrisentan** and **tadalafil** versus **tadalafil** and placebo. The trial is structured to assess the primary endpoint of achieving a low- or intermediate-low risk profile after six months, as per the 2022 European pulmonary hypertension guidelines. Secondary endpoints include changes in pulmonary vascular resistance, BNP or NT-proBNP levels, 6-minute walk distance, and other clinical parameters.

The trial will span approximately three years, with an estimated recruitment start date of September 15, 2025, and an estimated end date of October 15, 2028. Participants will be involved for a maximum treatment period of 175 days. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, recent PAH diagnosis, and hemodynamic parameters; regular follow-up visits to monitor treatment effects and safety; and an end-of-study visit to evaluate the primary and secondary endpoints.

Participants are expected to adhere to the study protocol for the entire duration unless specific conditions necessitate early termination. These conditions include the occurrence of treatment-emergent adverse events leading to premature discontinuation of the study drug, or any other medical reasons deemed significant by the investigators. The trial will ensure that all participants receive the study medication in a blinded manner, with the active drug and placebo indistinguishable in appearance, to maintain the integrity of the double-blind design.

The clinical trial involves the administration of **Ambrisentan Viatris 5 mg film-coated tablets** as an experimental medication. Ambrisentan is a chemical compound administered orally in the form of film-coated tablets. The maximum daily dose is 10 mg, with a total maximum dose of 1750 mg over a treatment period of 175 days. The tablets are provided in a blinded form, packaged in neutral blisters with specific labeling to maintain the integrity of the study. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Tadalafil** is used as a comparator treatment in the study. It is also a chemical compound administered orally in the form of film-coated tablets. The maximum daily dose for tadalafil is 40 mg, with a total maximum dose of 7000 mg over the same treatment period of 175 days. The administration of tadalafil follows a similar compliance monitoring protocol to ensure accurate dosing and adherence throughout the trial.

A **placebo** is utilized in the study to compare the effects of the active treatments. The placebo is designed to mimic the appearance of the Ambrisentan Viatris 5 mg film-coated tablets and is composed of cellulose microcrystalline, lactose monohydrate, colloidal anhydrous silica, magnesium stearate (vegetable origin), Opadry II 85G94065 pink, and purified water. The placebo is administered orally, with no active substance, and is used to maintain blinding in the trial. The placebo is given over the same treatment period of 175 days, with compliance monitored similarly to the active treatments.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint is the proportion of patients with **pulmonary arterial hypertension (PAH)** and cardiovascular comorbidities who achieve a low- or intermediate-low risk profile after 6 months, as determined by the non-invasive 4-risk strata method outlined in the 2022 European pulmonary hypertension guidelines.

Secondary endpoints include a variety of measures to provide a comprehensive evaluation of treatment efficacy. These include changes in pulmonary vascular resistance, percent change in BNP or NT-proBNP levels, and changes in the 6-minute walk distance. Additionally, the trial will assess the proportion of participants who show improvement in WHO/NYHA functional class at the end of the double-blind, placebo-controlled treatment period. Other secondary endpoints involve changes in the TAPSE/systolic pulmonary artery pressure (SPAP) ratio, the rate of death or nonfatal clinical worsening, and changes in the emPHasis10 score and EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L). Further assessments will include changes in other hemodynamic and echocardiographic parameters, changes in WHO/NYHA functional class, and rates of death due to PAH.

Data collection will occur at specified intervals, with the primary endpoint evaluated at the 6-month mark. Secondary endpoints will be measured throughout the trial duration, with specific timepoints for each parameter as per the trial protocol. The analysis will utilize validated scales and laboratory tests to ensure accuracy and reliability of the results. The trial will also monitor treatment-emergent adverse events, serious adverse events, and any adverse events leading to premature discontinuation of the study drug, alongside changes in laboratory variables, weight, and vital signs such as arterial blood pressure and heart rate.