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

Mass General Brigham

Status and phase: Withdrawn; Phase 4

Conditions: Hemodialysis; End Stage Renal Disease

Treatments: Drug: Placebo; Drug: Spironolactone; Dietary Supplement: L-arginine

Study type: Interventional

Funder types: Other

Identifiers

NCT01855334

1R01DK096189

Details and patient eligibility

About

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.

Full 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.

Sex: All

Ages: 18 to 85 years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

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0 participants in 4 patient groups, including a placebo group

Spironolactone + Placebo

Experimental group

Description:

Spironolactone 25 mg by mouth daily + Placebo L-arginine-liquid formulation by mouth 3 times daily

Treatment:

Drug: Placebo

Drug: Spironolactone

Double Placebo

Placebo Comparator group

Description:

Placebo spironolactone-1 tablet by mouth daily + Placebo L-arginine liquid formulation by mouth 3 times daily

Treatment:

Drug: Placebo

Spironolactone + L-arginine

Experimental group

Description:

Spironolactone 25 mg daily + L-arginine 3 grams orally 3 times daily

Treatment:

Drug: Spironolactone

Dietary Supplement: L-arginine

L-arginine + Placebo

Experimental group

Description:

L-arginine 3 grams by mouth 3 times daily + Placebo spironolactone 1 tablet by mouth daily

Treatment:

Drug: Placebo

Dietary Supplement: L-arginine