Randomized Study of Triple Therapy vs Sildenafil Dose Optimization in Pulmonary Arterial Hypertension (ASCEND-PAH)

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

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

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Arterial Hypertension (PAH)
• Intervention / Treatment: Drug: Prostacyclin Pathway Agent; Drug: Sildenafil Dose Optimization

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

• Study Type: Interventional
• Enrollment (Estimated): 196
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Caio Fernandes, MD, PhD; Phone Number: +551126615034; Email: cjcfernandes@yahoo.com.br

Study Locations

• Brazil
  • São Paulo
    • São Paulo, São Paulo, Brazil, 04551-060
      • Recruiting
      • Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo
      • Contact: Caio Fernandes, PhD; Phone Number: 1126615034; Email: cjcfernandes@yahoo.com.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Triple Therapy Escalation; Participants will receive escalation to triple therapy through addition of a prostacyclin pathway agent (inhaled iloprost or selexipag) to ongoing dual therapy with an endothelin receptor antagonist and sildenafil. The specific prostacyclin pathway agent will be selected according to clinical judgment and availability. Participants will remain on triple therapy during follow-up unless modification is clinically indicated.	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.; Other Names: Selexipag; Iloprost
Active Comparator: Sildenafil Dose Optimization; Participants will continue dual therapy with an endothelin receptor antagonist and sildenafil, with optimization of sildenafil dose according to clinical practice. No additional pulmonary arterial hypertension pathway agent will be added at randomization. Treatment adjustments after randomization will be recorded if clinically required.	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.; Other Names: Sildenafil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Between 3 and 6 months after randomization (assessment closest to 6 months within the predefined window)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Between 3 and 6 months after randomization
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.	From randomization through 6 months of follow-up
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.	Between 3 and 6 months after randomization
Change in 6-Minute Walk Distance (6MWD)	Absolute change in 6-minute walk distance (meters) between baseline and follow-up assessment.	Between 3 and 6 months after randomization
Change in BNP or NT-proBNP Levels	Percent change in BNP or NT-proBNP levels between baseline and follow-up. Higher values indicate greater cardiac strain and worse prognosis.	Between 3 and 6 months after randomization
Time to Clinical Worsening	Time from randomization to first occurrence of clinical worsening event as defined in the composite clinical worsening outcome.	From randomization through 6 months of follow-up
Treatment Persistence	Proportion of participants who remain on their initially assigned therapeutic strategy without permanent discontinuation by the follow-up visit.	From randomization through 6 months of follow-up
Safety and Adverse Events	Incidence, type, and severity of adverse events and serious adverse events occurring during the study period.	From randomization through 6 months

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Investigators: Principal Investigator: Caio Fernandes, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo

Study record dates

Study Major Dates

• Study Start (Estimated): July 22, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: July 14, 2026
• First Submitted That Met QC Criteria: July 14, 2026
• First Posted (Actual): July 20, 2026

Study Record Updates

• Last Update Posted (Actual): July 20, 2026
• Last Update Submitted That Met QC Criteria: July 14, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension; Randomized Clinical Trial; Triple Therapy; Therapeutic Escalation; Sildenafil Dose Optimization
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Fatty Acids; Lipids; Biological Factors; Amides; Purines; Sulfonamides; Sulfones; Prostaglandins, Synthetic; Prostaglandins; Eicosanoids; Fatty Acids, Unsaturated; Autacoids; Inflammation Mediators; Piperazines; Sildenafil Citrate; Iloprost; selexipag
• Other Study ID Numbers: CAAE: 97708926.6.0000.0068

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No