Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD Trial

The primary objective of this study is to characterize the safety and tolerability of
multiple doses of chronic SPL therapy compared with placebo in maintenance hemodialysis
patients and to assess the feasibility of conducting a full-scale, mortality-powered trial of
SPL. The effects of SPL compared with placebo on multiple cardiovascular efficacy parameters
will also be analyzed. The primary efficacy parameter will be the change in the E'
measurement on tissue Doppler echocardiography (TDI) as an index of diastolic function and a
surrogate for myocardial fibrosis. Secondary cardiac parameters of interest that will be
studied in the overall population or in sub-studies include heart rate variability,
circulating markers of fibrosis, and coronary flow reserve (CFR) as an index of microvascular
function. These parameters are designed to broaden insight into the potential effects of SPL
on cardiac structure and function in individuals with dialysis-dependent ESRD and to assess
the feasibility of conducting a full-scale, mortality-powered trial.

Inclusion Criteria:

1. Maintenance hemodialysis therapy for end-stage renal disease

2. Age 18-85 years

3. ≥3 calendar months since dialysis initiation. Note if a patient has been on dialysis
for ≥3 but less than 6 calendar months, there must be no hospitalizations during the 6
weeks prior to screening, and no change in estimated dry weight (EDW) within 2 weeks
of the screening date.

4. For women of childbearing potential, willingness to use a highly effective method of
birth control for up to 4 weeks after the last dose to study drug.

5. Ability to provide informed consent

Exclusion Criteria:

1. Serum potassium ≥6.5 mEq/L within the 3 months prior to screening

2. Serum potassium level ≥6.0 mEq/L within 2 weeks prior to the baseline visit. If a
potassium value is not available through routine clinical care during this 2-week
period a potassium measurement will be performed as a research test.

3. Unscheduled dialysis for hyperkalemia within the 3 months prior to screening

4. Pre-dialysis systolic blood pressure <100 mm Hg within 2 weeks prior to screening or
at the baseline visit

5. 2 or more dialysis sessions within the month prior to screening with either 2
intra-dialytic measurements of systolic blood pressure <80 mm Hg or muscle cramping,
light-headedness, nausea or hypotension requiring infusion of saline or other
intervention directed at hypotension

6. Current dual use of angiotensin converting enzyme inhibitor (ACEI) and angiotensin
receptor blocker (ARB)

7. Current use of digoxin

8. Current use of spironolactone or eplerenone

9. Allergy to spironolactone

10. Inability to maintain dialysis machine blood flow ≥300 mL/min during any of the most
recent 3 dialysis sessions prior to the screening visit as an indicator of vascular
access dysfunction

11. Mitral valve repair or replacement

12. Severe mitral valve disease by echocardiography, coronary angiography or cardiac
magnetic resonance imaging

13. Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another
dialysis unit within 9 months

14. Expected survival <9 months

15. Pregnancy, anticipated pregnancy, or breastfeeding

16. Incarceration

17. Participation in another intervention study