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

Effects of Spironolactone on Collagen Metabolism in Pulmonary Arterial Hypertension

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.

Study Overview

• Status: Unknown
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Spironolactone; Drug: Placebo

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 Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Zeenat Safdar, MD; Phone Number: 713-798-2400; Email: safdar@bcm.edu
• Study Contact Backup: Name: Gwendolyn Goodloe; Phone Number: 713-798-2400; Email: gmb@bcm.edu

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: sugar pill

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Zeenat Safdar, MD, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Anticipated): July 1, 2015
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: November 3, 2011
• First Submitted That Met QC Criteria: November 7, 2011
• First Posted (Estimate): November 9, 2011

Study Record Updates

• Last Update Posted (Estimate): May 8, 2015
• Last Update Submitted That Met QC Criteria: May 6, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Potassium Sparing Diuretics; Right-sided heart failure; Edema
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: H24178; K23HL093214 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No