LAST-D: L-Arginine and Spironolactone Trial in Dialysis-Dependent ESRD

Sponsor

Brigham and Women's Hospital (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01855334

Collaborator

Massachusetts General Hospital (Other), Beth Israel Deaconess Medical Center (Other), Joslin Diabetes Center (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Cardiovascular disease is the primary cause of death in patients with end stage renal disease (ESRD). New research suggests that the high risk of death may be partly due to high levels of fibrosis and a loss of small blood vessels in the heart of patients with dialysis-dependent ESRD. This study is designed to compare the effects of two different drugs, spironolactone and L-arginine, with placebo on structure and function of the heart in individuals with dialysis-dependent ESRD.

Condition or Disease	Intervention/Treatment	Phase
End Stage Renal Disease Hemodialysis	Drug: Spironolactone Dietary Supplement: L-arginine Drug: Placebo	Phase 4

Detailed Description

We hypothesize that that abnormalities in aldosterone and nitric oxide (NO) homeostasis contribute to the progression of microvascular disease and myocardial fibrosis in ESRD and that agents designed to restore normal aldosterone and NO homeostasis will improve microvascular and diastolic cardiac function in the heart of individuals with dialysis dependent ESRD. We will test 2 specific agents: The mineralocorticoid receptor blocker spironolactone; and L-arginine, an agent which improves NO bioavailability. Two specific aims will be addressed using a prospective, double-blinded, 2x2 factorial trial in dialysis dependent patients with ESRD. Subjects will be randomized to placebo, spironolactone plus placebo, L-arginine plus placebo, or combination spironolactone and L-arginine therapy. Diastolic cardiac function will be assessed using tissue Doppler index (TDI) determined mitral annular velocities (E') on LV echocardiography, and microvascular supply will be assessed using CFR-the ratio of hyperemic to resting myocardial blood flow-measured by positron emission tomography (PET) scans at baseline, 2 weeks and after 9 months of randomized therapy.

This randomized trial of spironolactone and L-arginine will provide important data about the contributions of aldosterone and NO to the pathogenesis of cardiovascular disease in ESRD, will demonstrate the therapeutic potential of L-arginine and spironolactone as as targeted cardiovascular therapies for use in ESRD, and will provide important insights into the underlying pathophysiology of cardiovascular disease in ESRD. The results generated will provide the data needed to design large-scale trials testing whether spironolactone or L-arginine can improve mortality or cardiovascular outcomes in ESRD.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized, Controlled Trial of L-arginine and Spironolactone in Dialysis-dependant End Stage Renal Disease

Anticipated Study Start Date :

Sep 1, 2013

Anticipated Primary Completion Date :

Jul 1, 2018

Anticipated Study Completion Date :

Jul 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Spironolactone + Placebo Spironolactone 25 mg by mouth daily + Placebo L-arginine-liquid formulation by mouth 3 times daily	Drug: Spironolactone Other Names: Aldactone Drug: Placebo
Placebo Comparator: Double Placebo Placebo spironolactone-1 tablet by mouth daily + Placebo L-arginine liquid formulation by mouth 3 times daily	Drug: Placebo
Experimental: Spironolactone + L-arginine Spironolactone 25 mg daily + L-arginine 3 grams orally 3 times daily	Drug: Spironolactone Other Names: Aldactone Dietary Supplement: L-arginine
Experimental: L-arginine + Placebo L-arginine 3 grams by mouth 3 times daily + Placebo spironolactone 1 tablet by mouth daily	Dietary Supplement: L-arginine Drug: Placebo

Outcome Measures

Primary Outcome Measures

Change in coronary Flow Reserve (PET) [Between baseline and 9 months]
Coronary flow reserve will be measured using rest and stress 13N ammonia myocardial positron emission tomography (PET) at baseline and 9 months
Change in left ventricular diastolic function [Between baseline and 9 months]
Left ventricular diastolic function will be measured using mitral annular E' on tissue doppler index echocardiography at baseline and 9 months

Secondary Outcome Measures

Association between coronary flow reserve (CFR) and tissue doppler index (E') [Baseline]
Change in resting myocardial blood flow [Between baseline and 9 months]
Change in left ventricular mass index [Between baseline and 9 months]
Change in coronary vascular resistance [Between 0 and 9 months]
Association between change in coronary flow reserve (CFR) and change in diastolic function-tissue doppler index (E') [Between baseline and 9 months]
Change in early diastolic function (E') [Between baseline and 2 weeks]
Combined cardiovascular safety [Up to 9 months]
Combined rate of death, myocardial infarction, stroke, or hospitalization
Cardiovascular death [Up to 9 months]
Hyperkalemia [Up to 9 months]
Hyperkalemia requiring extra dialysis, adjustment in dialysate potassium, or discontinuation of therapy
Hypotension [Up to 9 months]
Symptomatic or intradialytic hypotension up to 9 months
Change in early coronary flow reserve [Between baseline and 2 weeks]
Change in hyperemic myocardial blood flow [Between baseline and 9 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Chronic dialysis therapy for End Stage Renal Disease
Age 21-85

Exclusion Criteria:

Hyperkalemia requiring unscheduled dialysis within 3 months
Pre-dialysis potassium ≥6.5 meq/L within 3 months
Hypotension defined as SBP <100
Recurrent intra-dialytic hypotension defined as recurrent cramping, light-headedness, or hypotension requiring infusion of saline or other intervention or otherwise limiting ability to achieve dry weight. Or SBP <80
History of myocardial infarction
History of coronary artery bypass surgery
Non revascularized coronary disease >90%
Mitral valve repair or replacement
Severe mitral valve disease
Renal transplant expected within 9 months
Expected survival < 9 months
Pregnant
Prisoners
Unable to provide consent
Allergy to spironolactone or L-arginine
Digitalis use
1st or 2nd degree heart block

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	021114
2	Brigham & Women's Hospital	Boston	Massachusetts	United States	02120
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215