Randomized Study of Triple Therapy vs Sildenafil Dose Optimization in Pulmonary Arterial Hypertension

Official title

A Prospective, Randomized, Open-Label Study Comparing Triple Therapy Versus Sildenafil Dose Optimization in Patients With Pulmonary Arterial Hypertension Using COMPERA 2.0 Risk Stratification as the Primary Outcome

Overview

Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterized by increased pressure in the pulmonary arteries, leading to right heart failure and premature death. Although combination therapy has improved outcomes, many patients remain at intermediate or high clinical risk despite treatment. When patients do not reach low-risk status, treatment escalation is recommended. However, different escalation strategies are used in clinical practice, including increasing the dose of existing medications or adding a third drug that targets a different biological pathway. There is limited prospective randomized evidence directly comparing these approaches. The ASCEND-PAH study is a prospective, randomized, open-label clinical trial designed to compare two therapeutic escalation strategies in adults with PAH who remain at intermediate or high risk despite dual therapy with an endothelin receptor antagonist and sildenafil. Participants will be randomized to either: (1) escalation to triple therapy with the addition of a prostacyclin pathway agent, or (2) optimization of dual therapy by increasing the dose of sildenafil. The primary objective is to compare the proportion of patients who improve their risk category according to the COMPERA 2.0 four-stratum risk model within 3 to 6 months after randomization. Secondary outcomes include changes in functional status, exercise capacity, biomarkers, clinical worsening, safety, and treatment persistence

Detailed description

This is a prospective, randomized, open-label, parallel-group clinical trial designed to evaluate therapeutic escalation strategies in adults with pulmonary arterial hypertension (PAH, Group 1) who remain at intermediate-low, intermediate-high, or high risk according to the COMPERA 2.0 four-stratum model despite stable dual therapy.

Eligible participants must be receiving an endothelin receptor antagonist in combination with sildenafil and have a clinical indication for treatment escalation. After confirmation of eligibility and baseline assessments, participants will be randomized in a 1:1 ratio to one of two strategies:

Escalation to triple therapy through addition of a prostacyclin pathway agent (inhaled iloprost or selexipag), according to clinical judgment and availability.

Optimization of dual therapy by increasing the dose of sildenafil according to clinical practice.

Baseline assessments may include WHO functional class, 6-minute walk distance, and BNP or NT-proBNP levels obtained within 90 days prior to randomization. Follow-up evaluation will occur between 3 and 6 months after randomization, with the primary analysis based on the assessment closest to 6 months within that window.

The primary endpoint is the proportion of patients who achieve improvement in risk stratification, defined as a decrease of at least one risk category according to the COMPERA 2.0 four-stratum model. Secondary endpoints include composite clinical improvement and worsening, change in individual clinical parameters, time to clinical worsening, safety outcomes, need for additional therapeutic escalation, and treatment persistence.

The study is powered to detect a clinically meaningful absolute difference of 20 percentage points in risk improvement between groups, with planned enrollment of approximately 196 participants to account for potential losses to follow-up

Interventions

• Drug Prostacyclin Pathway Agent
  Addition of a prostacyclin pathway agent (inhaled iloprost or oral selexipag) to ongoing dual therapy with an endothelin receptor antagonist and sildenafil as part of therapeutic escalation to triple therapy. The specific agent will be selected according to clinical judgment and availability. Dosing will follow approved labeling and routine clinical practice.
• Drug Sildenafil Dose Optimization
  Optimization of sildenafil dose within approved dosing ranges as part of dual therapy with an endothelin receptor antagonist. Dose adjustments will be performed according to clinical practice to achieve maximal tolerated and guideline-recommended dosing without addition of a new PAH pathway agent at randomization.

Primary outcome measures

• Improvement in Risk Stratification According to the COMPERA 2.0 Four-Stratum Model [Time frame: Between 3 and 6 months after randomization (assessment closest to 6 months within the predefined window)]

Secondary outcome measures (8)

• Composite Clinical Improvement at 3-6 Months [Time frame: Between 3 and 6 months after randomization]
• Composite Clinical Worsening [Time frame: From randomization through 6 months of follow-up]
• Change in WHO Functional Class [Time frame: Between 3 and 6 months after randomization]
• Change in 6-Minute Walk Distance (6MWD) [Time frame: Between 3 and 6 months after randomization]
• Change in BNP or NT-proBNP Levels [Time frame: Between 3 and 6 months after randomization]
• Time to Clinical Worsening [Time frame: From randomization through 6 months of follow-up]
• Treatment Persistence [Time frame: From randomization through 6 months of follow-up]
• Safety and Adverse Events [Time frame: From randomization through 6 months]

Eligibility criteria

Inclusion criteria

• Age ≥18 years
• Diagnosis of pulmonary arterial hypertension (PAH, Group 1) confirmed according to accepted clinical and hemodynamic criteria
• Stable treatment with an endothelin receptor antagonist in combination with sildenafil prior to randomization
• Classified as intermediate-low, intermediate-high, or high risk according to the COMPERA 2.0 four-stratum model
• Clinical indication for therapeutic escalation
• Availability for follow-up assessment between 3 and 6 months after randomization
• Ability to provide written informed consent

Exclusion criteria

• Participation in another interventional clinical trial that mandates treatment modification
• Known contraindication to prostacyclin pathway agents (including iloprost or selexipag)
• Known contraindication to sildenafil dose escalation
• Pregnancy or breastfeeding
• Women of childbearing potential not using effective contraception
• Any clinical condition that, in the investigator's judgment, would interfere with study participation or outcome assessment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Univer — São Paulo

Identifiers

NCT: NCT07713914 · CAAE: 97708926.6.0000.0068

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗