The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study

Study Overview
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Brief Summary
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The purpose of this study is to find out if spironolactone added to ambrisentan for Pulmonary Arterial Hypertension (PAH) will increase exercise capacity. We also want to find out if spironolactone and ambrisentan effect the cardiac output (amount of blood the heart pumps every minute), right ventricle function and quality of life.

Detailed Description
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A prospective, double blind, placebo-controlled clinical study involving 30 patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension being treated with ambrisentan randomized to receive placebo or spironolactone (50 mg/d) for 90 days using a cross-over trial design. Eligible participants will be randomized to receive placebo or spironolactone (50 mg/d) for 90 days (Phase I). At the completion of Phase I, participants will undergo repeat end-point assessment followed by a 21-day drug washout period. Then, the 90 day crossover phase of the trial will occur (Phase II), in which participants randomized to placebo in Phase I will be treated with spironolactone (50 mg/d) in Phase II and vice versa. At the conclusion of Phase II, end-point measures are reassessed. Spironolactone is a diuretic used in treatment of PAH patients. Spironolactone is usually added to medical treatment when doses of Lasix/Torsemide are increased and patients are at risk for hypokalemia. Study procedures being done for this research study are the standard procedures performed on all PAH patients when they are in clinic for follow-up except for the Cardiopulmonary Exercise Test (CPET) with Innocor.

Official Title
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The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study (The CAPS-PAH Study)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Ambrisentan plus Spironolactone
* Drug: Ambrisentan plus Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily gives informed consent to participate in the study. Right heart catheterization demonstrating conventional mean pulmonary artery pressure (mPAP) >25, pulmonary vascular resistance (PVR) >3.0 Wood Units, pulmonary capillary wedge pressure (PCWP) <16 mmHg within two years of enrollment Subject is 18 years of age or older at Screening. Diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with Connective Tissue Disease (CTD), PAH associated with repaired/unrepaired congenital systemic-to-pulmonary shunt, Portopulmonary hypertension or PAH associated with HIV infection. New York Heart Association Functional Class II or III Stable therapy with ambrisentan 5 or 10 mg every day for > 90 days. Baseline 6-Minute Walk Distance 50-450m Exclusion Criteria: Substantial Primary Lung disease forced expiratory volume at one second (FEV-1)/forced vital capacity (FVC) <0.6 and FEV-1 <70% predicted diffusing capacity of lung for carbon monoxide (DLCO) <30% predicted Pulmonary fibrosis Left ventricular ejection fraction < 50% Pulmonary capillary wedge pressure > 16 mm Hg Aortic valve disease Ischemic heart disease Systemic hypotension (SBP <90 mm Hg) Co-existing treatment with other endothelin receptor antagonists or prostacyclin analogues New York Heart Association Functional Class IV Chronic thromboembolic pulmonary hypertension Known or suspected pulmonary veno-occlusive disease Serum creatinine >2.0 mg/dL in women, Serum creatinine >2.5 mg/dL in men Baseline serum potassium >5.0 milliequivalent (mEq)/L Participation in ongoing drug/intervention-based clinical trial Pregnancy Unable to provide consent

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AMB + Spiro, Cardiopulmonary fitness<br>Ambrisentan 5 or 10 mg every day (QD) Spironolactone 50 mg QD | Drug: Ambrisentan plus Spironolactone<br>* Cardiopulmonary fitness<br>* Other names: Letairis plus Aldactone;|
| Placebo Comparator: Placebo Cardiopulmonary fitness<br>Placebo mimics spironolactone 50 mg and will be taken QD | Drug: Ambrisentan plus Placebo<br>* Placebo is a sugar pill manufactured to resemble spironolactone 50 mg Cardiopulmonary fitness<br>* Other names: Letairis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Combination Ambrisentan + Spironolactone on Peak Volume of Oxygen Consumption (pVO2) and Cardiac Output | Study the effect of combination ambrisentan (5-10 mg/d) + spironolactone (50 mg/d) on pVO2 and cardiac output. The pVO2 refers to a measure of general physical fitness measured during exercise. | Up to average of 20 min | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ambrisentan, Pulmonary Arterial Hypertension (PAH), Spironolactone, Selective Endothelin A (ETA) inhibition, Aldosterone antagonism, Cardiac output (CO), Right ventricular (RV) function, Heart failure, Quality of life, Pro-inflammatory cytokine, Interleukin-6 (IL-6), Troponin-I, N-terminal pro-brain natriuretic peptide (NT-BNP), Collagen metabolism, N-terminal procollagen type I, Collagen III, Echocardiography, WHO Functional Class, Cardiopulmonary Exercise Test with Innocor, Peak oxygen consumption (pVO2), Liver function markers (AST/ALT), Renal function markers (creatinine and potassium)