Study to Compare Triple Therapy (Oral Treprostinil, Ambrisentan, and Tadalafil) With Dual Therapy (Ambrisentan, Tadalafil, and Placebo) in Subjects With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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This is a multicenter, randomized (2:1 oral treprostinil: placebo), double-blind, placebo-controlled study in subjects with Pulmonary Arterial Hypertension (PAH) who are currently receiving background dual therapy (ambrisentan, tadalafil) for at least 30 days at randomization for their PAH. Once randomized, subjects will return for 5 study visits up to Week 28 during the blinded period. After the Week 28 Visit, eligible subjects will transition to the open-label period of the study for up to 20 weeks.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Study to Compare the Efficacy and Safety of Triple Therapy (Oral Treprostinil, Ambrisentan, and Tadalafil) With Dual Therapy (Ambrisentan, Tadalafil, and Placebo) in Subjects With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Oral Treprostinil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 18 and 79 years of age, inclusive PAH that is idiopathic / heritable, PAH associated with connective tissue disease, HIV infection, repaired congenital systemic-to-pulmonary shunts (repaired > 1 year), or appetite suppressant / toxin use Receiving dual therapy (ambrisentan and tadalafil) Previous testing (e.g. right heart catheterization, echocardiography) consistent with diagnosis of PAH Exclusion Criteria: Nursing or pregnant PAH due to conditions other than noted in the above inclusion criteria Received PAH-specific drug therapy for >2 years History of uncontrolled sleep apnea, severe liver disease, severe renal impairment, left sided heart disease, uncontrolled systemic hypertension Participated in an investigational drug or device study within 90 days prior to signing consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching placebo (sugar pill) | Drug: Placebo<br>* Placebo (sugar pill) for three times daily oral administration<br>* Other names: matching placebo (sugar pill);|
| Active Comparator: Active<br>Oral treprostinil sustained release tablet | Drug: Oral Treprostinil<br>* Sustained release oral tablets for three times daily administration<br>* Other names: treprostinil diethanolamine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-Minute Walk Distance (6MWD) |  | Baseline to Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the effects of triple therapy versus dual therapy on the time to clinical worsening | clinical worsening is defined by 1 of the following: Death (all causes) Hospitalization due to worsening PAH Initiation of long-term parenteral therapy Disease progression Unsatisfactory long-term clinical response | Baseline to Week 28 | 
| Change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations From Baseline to Week 28 | The level of this biomarker of the (NT-proBNP) serum concentration will be assessed to compare the severity of heart failure at Baseline and Week 28. | Baseline to week 28 | 
| Number of Participants with a Change From Baseline World Health Organization (WHO) Functional Classification at Week 28. | The WHO Functional Class of pulmonary hypertension is a physical activity rating scale as follows: Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms. | Baseline to week 28 | 
| Change in Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) From Baseline to Week 28. | The CAMPHOR is a health related quality of life instrument validated for pulmonary hypertension that assesses impairment (symptoms), disability (activities) and quality of life. The questionnaire is divided into three sections; Symptoms (Scores 025; high scores indicate more symptoms), Activity (Score 030; low score indicates good functioning) and Quality of Life (025; high scores indicate poor QoL). The sum of these scores equates to the Total score (080). In the CAMPHOR scores, lower scores indicate improvements. | Baseline to week 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH, Oral Treprostinil, dual therapy, 6 Minute Walk Test