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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Hemodialysis; End Stage Renal Disease
• Intervention / Treatment: Drug: Placebo; Drug: Spironolactone; Dietary supplement: L-arginine

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 Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02120
      • Brigham & Women's Hospital
    • Boston, Massachusetts, United States, 021114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Spironolactone + Placebo; Spironolactone 25 mg by mouth daily + Placebo L-arginine-liquid formulation by mouth 3 times daily	Drug: Placebo; Drug: Spironolactone; Other Names: Aldactone
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	Drug: Placebo; Dietary supplement: L-arginine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Combined rate of death, myocardial infarction, stroke, or hospitalization	Up to 9 months
Cardiovascular death		Up to 9 months
Hyperkalemia	Hyperkalemia requiring extra dialysis, adjustment in dialysate potassium, or discontinuation of therapy	Up to 9 months
Hypotension	Symptomatic or intradialytic hypotension up to 9 months	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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Massachusetts General Hospital; Beth Israel Deaconess Medical Center; Joslin Diabetes Center

Publications and helpful links

General Publications

• Hasegawa T, Nishiwaki H, Ota E, Levack WM, Noma H. Aldosterone antagonists for people with chronic kidney disease requiring dialysis. Cochrane Database Syst Rev. 2021 Feb 15;2(2):CD013109. doi: 10.1002/14651858.CD013109.pub2.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2013
• Primary Completion (ANTICIPATED): July 1, 2018
• Study Completion (ANTICIPATED): July 1, 2018

Study Registration Dates

• First Submitted: May 14, 2013
• First Submitted That Met QC Criteria: May 14, 2013
• First Posted (ESTIMATE): May 16, 2013

Study Record Updates

• Last Update Posted (ACTUAL): May 4, 2017
• Last Update Submitted That Met QC Criteria: May 2, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Cardiovascular disease; ESRD; coronary flow reserve; Dialysis; spironolactone; L-arginine; diastolic function; myocardial perfusion
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic; 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: 1R01DK096189