Pulmonary Arterial Hypertension (PAH)Phase 4ASCEND-PAHNCT07713914
Randomized Study of Triple Therapy vs Sildenafil Dose Optimization in Pulmonary Arterial Hypertension
A Phase 4 study testing Prostacyclin Pathway Agent and Sildenafil Dose Optimization in people with Pulmonary Arterial Hypertension (PAH), run by University of Sao Paulo General Hospital at 1 site in Brazil.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pulmonary Arterial Hypertension (PAH)
- What is being tested?
- Prostacyclin Pathway Agent and Sildenafil Dose Optimization
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 196 participants
- Where
- 1 siteBrazil
- Study dates
- 22 Jul 2026to 31 Dec 2028
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Brazil1 site, 1 recruiting
- Recruiting
Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo
São Paulo, São Paulo, 04551-060
Caio Fernandes, Principal Investigator, 1126615034, cjcfernandes@yahoo.com.br
About this study
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
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.
Read more
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
Read the 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
- Conditions
- Pulmonary Arterial Hypertension (PAH)
- Being tested
- Prostacyclin Pathway Agent, Sildenafil Dose Optimization
- Keywords
- Pulmonary Arterial Hypertension, Therapeutic Escalation, Triple Therapy, Sildenafil Dose Optimization, Randomized Clinical Trial
- Medical subject headings
- Pulmonary Arterial Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Prostacyclin Pathway AgentDrug
Also called Iloprost, Selexipag
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.
Sildenafil Dose OptimizationDrug
Also called Sildenafil
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Sildenafil Dose Optimization |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: From randomization through 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jul 2026
- Study start22 Jul 2026 (estimated)
- Primary completion1 Jul 2028 (estimated)
- Study completion31 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pulmonary Arterial Hypertension (PAH)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 196 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Caio Júlio César dos Santos Fernandes, University of Sao Paulo General Hospital
- Investigators
- Caio Fernandes, Principal investigator, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07713914
- Sponsor's protocol ID
- CAAE: 97708926.6.0000.0068
- Acronym
- ASCEND-PAH
- Status last verified
- Jul 2026
- First submitted
- 14 Jul 2026
- Last updated
- 30 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 30 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT07713914
- Acronym / sponsor ID
- ASCEND-PAH / CAAE: 97708926.6.0000.0068
- Conditions
- Pulmonary Arterial Hypertension (PAH)
- Keywords
- Pulmonary Arterial Hypertension, Therapeutic Escalation, Triple Therapy, Sildenafil Dose Optimization, Randomized Clinical Trial
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 196 participants (estimated)
- Lead sponsor
- University of Sao Paulo General HospitalUniversity, hospital or other
- Study start
- 22 Jul 2026 (estimated)
- Primary completion
- 1 Jul 2028 (estimated)
- Study completion
- 31 Dec 2028 (estimated)
- First posted
- 20 Jul 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Triple Therapy Escalation (Inhaled Iloprost or Selexipag) | Experimental | Drug: Prostacyclin Pathway AgentParticipants 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. |
| Sildenafil Dose Optimization | Active comparator | Drug: Sildenafil Dose OptimizationParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Prostacyclin Pathway AgentAlso: Iloprost, SelexipagAddition 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 | Triple Therapy Escalation (Inhaled Iloprost or Selexipag) |
| Sildenafil Dose OptimizationAlso: SildenafilOptimization 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. | Drug | Sildenafil Dose Optimization |
Primary outcome
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)
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.
8 secondary outcomes
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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jul 2026.
- Individual participant dataSharing planned: Undecided
Related trials for Pulmonary Arterial Hypertension (PAH)
RecruitingPhase 2
Study of REGN13335 in Adult Participants With Pulmonary Arterial Hypertension (PAH)
Pulmonary Arterial Hypertension (PAH)
RecruitingPhase 2
A Study of ROC-101 in Patients With Pulmonary Arterial Hypertension (PAH) and Pulmonary Hypertension Associated With Interstitial Lung Disease (ILD-PH) (ROCSTAR STUDY)
Pulmonary Arterial Hypertension (PAH), Pulmonary Hypertension, Interstitial Lung Disease
Enrolling by invitationPhase 3
A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
PAH, Pulmonary Hypertension
RecruitingPhase 1
Study of Intravenous ZMA001 in Healthy Subjects
Pulmonary Arterial Hypertension PAH
RecruitingPhase 4
A Study of Inhaled Treprostinil (LIQ861) in Adults With Pulmonary Arterial Hypertension Transitioning From Oral Selexipag
Pulmonary Arterial Hypertension (PAH)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Caio Fernandes principal investigator
Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Prostacyclin Pathway Agent and Sildenafil Dose Optimization in people with Pulmonary Arterial Hypertension (PAH), run by University of Sao Paulo General Hospital at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 30 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Caio Fernandes, MD, PhD (+551126615034, cjcfernandes@yahoo.com.br), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jul 2026; AzTrials last refreshed its copy on 26 Oct 2026.