Randomized Study of Triple Therapy vs Sildenafil Dose Optimization in Pulmonary Arterial Hypertension
Trial statusRecruiting
Trial phasePhase 4
Trial typeInterventional
Biological sexAll
Age18+
SponsorUniversity of Sao Paulo General Hospital
About this trial
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
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
Disqualifiers
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
Trial design
Design model
Parallel
Treatments tested in this trial
Prostacyclin Pathway Agent
DrugAddition 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.
Sildenafil Dose Optimization
DrugOptimization 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.
Treatment groups
196 Participants
are divided into 2 treatment groupsGroup A: Triple Therapy Escalation (Inhaled Iloprost or Selexipag)Experimental treatment 1 intervention
Group B: Sildenafil Dose OptimizationActive comparator 1 intervention
Trial outcomes
Primary outcomes
1
Improvement in Risk Stratification According to the COMPERA 2.0 Four-Stratum Model
Proportion of participants who achieve improvement in clinical risk category between baseline and follow-up, defined as a decrease of at least one risk category according to the COMPERA 2.0 four-stratum model (low, intermediate-low, intermediate-high, high risk). Risk status is determined using World Health Organization functional class, 6-minute walk distance, and BNP or NT-proBNP levels, when available.
Time frame
Between 3 and 6 months after randomization (assessment closest to 6 months within the predefined window)Secondary outcomes
1
Composite Clinical Improvement at 3-6 Months
Proportion of participants who achieve composite clinical improvement between baseline and follow-up (3-6 months), defined as improvement in at least two of the following without worsening in any: (1) improvement of ≥1 WHO functional class; (2) increase of ≥30 meters in 6-minute walk distance; (3) reduction of ≥30% in BNP or NT-proBNP levels.
Time frame
Between 3 and 6 months after randomization2
Composite Clinical Worsening
Occurrence of clinical worsening defined as any of the following during follow-up: worsening of ≥1 WHO functional class; decrease of ≥30 meters in 6-minute walk distance; increase of ≥30% in BNP or NT-proBNP; need for additional therapeutic escalation; hospitalization related to pulmonary arterial hypertension; or death from any cause.
Time frame
From randomization through 6 months of follow-up3
Change in WHO Functional Class
Change in World Health Organization (WHO) functional class between baseline and follow-up. WHO functional class ranges from I (least severe) to IV (most severe), with higher classes indicating worse functional limitation.
Time frame
Between 3 and 6 months after randomization4
Change in 6-Minute Walk Distance (6MWD)
Absolute change in 6-minute walk distance (meters) between baseline and follow-up assessment.
Time frame
Between 3 and 6 months after randomizationSponsors and contacts
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Source ClinicalTrials.gov