L-Arginine and Spironolactone Trial in Dialysis-Dependent ESRD

End Stage Renal Disease Clinical Trial

— LAST-D  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT01855334
• Other study ID #: 1R01DK096189
• Status: Withdrawn
• Phase: Phase 4
• First received: May 14, 2013
• Last updated: May 2, 2017
• Start date: September 2013
• Est. completion date: July 2018

Study information

• Verified date: May 2017
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: July 2018
• Est. primary completion date: July 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• End Stage Renal Disease
• Hemodialysis
• Kidney Diseases
• Kidney Failure, Chronic
• Renal Insufficiency, Chronic

Intervention

Drug:
• Spironolactone

Dietary Supplement:
• L-arginine

Drug:
• Placebo

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Beth Israel Deaconess Medical Center, Joslin Diabetes Center, Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in coronary Flow Reserve (PET)	Coronary flow reserve will be measured using rest and stress 13N ammonia myocardial positron emission tomography (PET) at baseline and 9 months	Between baseline and 9 months
Primary	Change in left ventricular diastolic function	Left ventricular diastolic function will be measured using mitral annular E' on tissue doppler index echocardiography at baseline and 9 months	Between baseline and 9 months
Secondary	Association between coronary flow reserve (CFR) and tissue doppler index (E')		Baseline
Secondary	Change in resting myocardial blood flow		Between baseline and 9 months
Secondary	Change in left ventricular mass index		Between baseline and 9 months
Secondary	Change in coronary vascular resistance		Between 0 and 9 months
Secondary	Association between change in coronary flow reserve (CFR) and change in diastolic function-tissue doppler index (E')		Between baseline and 9 months
Secondary	Change in early diastolic function (E')		Between baseline and 2 weeks
Secondary	Combined cardiovascular safety	Combined rate of death, myocardial infarction, stroke, or hospitalization	Up to 9 months
Secondary	Cardiovascular death		Up to 9 months
Secondary	Hyperkalemia	Hyperkalemia requiring extra dialysis, adjustment in dialysate potassium, or discontinuation of therapy	Up to 9 months
Secondary	Hypotension	Symptomatic or intradialytic hypotension up to 9 months	Up to 9 months
Secondary	Change in early coronary flow reserve		Between baseline and 2 weeks
Secondary	Change in hyperemic myocardial blood flow		Between baseline and 9 months