Effects of Spironolactone on Collagen Metabolism in Patients With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to determine the effects of spironolactone on collagen markers in a large number of patients with pulmonary hypertension. In addition, safety and tolerability of spironolactone, an aldosterone receptor antagonist, in patients with pulmonary arterial hypertension, will be determined.

Detailed Description
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Pulmonary arterial hypertension (PAH) is an orphan disease characterized by pulmonary artery hypertrophy, and resulting vascular remodeling of involved vessels, often leading to right heart failure. Accumulating evidence from vascular biology, animal models, and therapeutic drug trials suggests significant contributions of the neurohormonal milieu to the disease process, morbidity, and mortality. The renin-angiotensin-aldosterone system (RAAS) is an important neurohormonal pathway that induces collagen synthesis in the myocardium and systemic vasculature. There is paucity of data regarding the contribution of RAAS in the pathogenesis of PAH and the effects of aldosterone blockade in the amelioration of PAH. Thus, the overall goal of this proposal is to investigate the contribution of RAAS to the pathogenesis of PAH, and to explore the effects of an aldosterone blocker, spironolactone, in PAH.

Official Title
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Effects of Spironolactone on Collagen Metabolism in Pulmonary Arterial Hypertension

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: Spironolactone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Body weight > 40 kg PAH Diagnostic Group I Stable subjects with no change in PAH specific therapy within the last 4 weeks No change in dose of background therapy (digoxin, diuretic) within the last 2 weeks excluding anticoagulation Exclusion Criteria: Unable to give informed consent Hemodynamically unstable subjects Pregnant or breast feeding Have significant renal insufficiency (serum creatinine >2.5 mg per deciliter or required hemodialysis) Have significant liver dysfunction (AST or ALT more than three times upper limit of normal) Currently on aldosterone receptor blocker (spironolactone or eplerenone) or ACE inhibitor PH due to left heart disease Unable or unwilling to comply with study procedures

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Spironolactone<br>Drug: Spironolactone Drug: Placebo | Drug: Spironolactone<br>* 50 mg po daily of spironolactone for 8 weeks. A cross-over study where each subject will receive spironolactone or placebo in a random order for 8 weeks each.<br>* Other names: Aldactone;|
| Experimental: Placebo<br>Drug: Placebo Drug: Spironolactone | Drug: Placebo<br>* Each subject will receive placebo or spironolactone for 8 weeks. At the end of week 8, treatment arm for each subject will be blindly switched. So if a study patient received placebo for the first 8 weeks then he/she will be switched to receive active drug (spironolactone) for the next 8 weeks.<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in biomarker levels in the spironolactone treated as compared to placebo treated group. | 50 participants will be enrolled in a 16-week study, and each subject will receive placebo or active drug in a random order. At the end of week 8, treatment arm for each subject will be blindly switched. Biomarker levels will be drawn 3 times (baseline, week 8, and week 16) during the study period for each subject. | 16 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events in patients treated with spironolactone as compared to placebo. | Safety and tolerability of spironolactone as compared to placebo in PAH. | 16 week | 
| Change in six-minute walk distance from baseline to week 8 and week 16. |  | 16 week | 
| Composite end-point | Composite end-point predefined as greater than 10% increase in walk distance, improvement by at least one functional class and absence of clinical worsening. Clinical worsening will be defined as hospitalization for worsening PAH, all-cause death, addition of prostacyclin therapy, lung transplantation, or atrial septostomy. | 16 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Edema, Potassium Sparing Diuretics, Right-sided heart failure