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

NCT07713914 | Recruiting Phase 4

• 1 other identifier: CAAE: 97708926.6.0000.0068
• Study Type: interventional
• Target: 196
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Pulmonary Arterial Hypertension (PAH)

Keywords

Pulmonary Arterial Hypertension; Therapeutic Escalation; Triple Therapy; Sildenafil Dose Optimization; Randomized Clinical Trial

Outcome Measures

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.

  Between 3 and 6 months after randomization (assessment closest to 6 months within the predefined window)

Secondary Outcomes (8)

• Composite Clinical Improvement at 3-6 Months

  Between 3 and 6 months after randomization

• Composite Clinical Worsening

  From randomization through 6 months of follow-up

• Change in WHO Functional Class

  Between 3 and 6 months after randomization

• Change in 6-Minute Walk Distance (6MWD)

  Between 3 and 6 months after randomization

• Change in BNP or NT-proBNP Levels

  Between 3 and 6 months after randomization

Study Arms (2)

Triple Therapy Escalation (Inhaled Iloprost or Selexipag)

EXPERIMENTAL

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

Sildenafil Dose Optimization

ACTIVE COMPARATOR

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

Interventions

Prostacyclin Pathway Agent DRUG

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.

Also known as: Iloprost, Selexipag

Triple Therapy Escalation (Inhaled Iloprost or Selexipag)

Sildenafil Dose Optimization DRUG

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.

Also known as: Sildenafil

Sildenafil Dose Optimization

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead

Study Sites (1)

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

São Paulo, São Paulo, 04551-060, Brazil

RECRUITING

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

Iloprost; selexipag; Sildenafil Citrate

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Prostaglandins, Synthetic; Prostaglandins; Eicosanoids; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Autacoids; Inflammation Mediators; Biological Factors; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Caio Fernandes

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

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Caio Fernandes, MD, PhD

CONTACT

+551126615034; cjcfernandes@yahoo.com.br

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: This is an open-label study. Neither participants nor investigators are blinded to treatment allocation. No outcome assessors or data analysts are formally masked.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Participants will be randomized in a 1:1 ratio to one of two parallel treatment strategies: (1) escalation to triple therapy through addition of a prostacyclin pathway agent (inhaled iloprost or selexipag) to ongoing dual therapy, or (2) optimization of dual therapy by increasing the dose of sildenafil. Participants will remain in their assigned strategy throughout the follow-up period, and outcomes will be assessed between 3 and 6 months after randomization.

Study Record Dates

• First Submitted: July 14, 2026
• First Posted: July 20, 2026
• Study Start: July 22, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: July 30, 2026

Record last verified: 2026-07

Locations

BR (1)