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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Hypertension	Drug: Spironolactone; Drug: Placebo	Phase 4

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	50 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Effects of Spironolactone on Collagen Metabolism in Pulmonary Arterial Hypertension
Study Start Date :	July 2011
Estimated Primary Completion Date :	July 2015
Estimated Study Completion Date :	December 2015

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Spironolactone; Drug: Spironolactone Drug: Placebo	Drug: Spironolactone; 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.; Other Name: Aldactone
Experimental: Placebo; Drug: Placebo Drug: Spironolactone	Drug: Placebo; 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.; Other Name: sugar pill

Outcome Measures

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Primary Outcome Measures :

1. Change in biomarker levels in the spironolactone treated as compared to placebo treated group. [ Time Frame: 16 week ]
   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.

Secondary Outcome Measures :

1. Number of adverse events in patients treated with spironolactone as compared to placebo. [ Time Frame: 16 week ]
   Safety and tolerability of spironolactone as compared to placebo in PAH.
2. Change in six-minute walk distance from baseline to week 8 and week 16. [ Time Frame: 16 week ]
3. Composite end-point [ Time Frame: 16 week ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Zeenat Safdar, MD	713-798-2400	safdar@bcm.edu
Contact: Gwendolyn Goodloe	713-798-2400	gmb@bcm.edu

Locations

United States, Texas
Baylor College of Medicine	Recruiting
Houston, Texas, United States, 77030

Sponsors and Collaborators

Baylor College of Medicine

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:	Zeenat Safdar, MD	Baylor College of Medicine

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Zeenat Safdar, Associate Professor of Medicine, Baylor College of Medicine
ClinicalTrials.gov Identifier:	NCT01468571 History of Changes
Other Study ID Numbers:	H24178; K23HL093214 ( U.S. NIH Grant/Contract )
First Posted:	November 9, 2011
Last Update Posted:	May 8, 2015
Last Verified:	May 2015

Keywords provided by Zeenat Safdar, Baylor College of Medicine:

Potassium Sparing Diuretics; Right-sided heart failure; Edema

Additional relevant MeSH terms:

Hypertension; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Spironolactone	Mineralocorticoid Receptor Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Diuretics, Potassium Sparing; Diuretics; Natriuretic Agents