Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD Trial (SPin-D)

University of Pennsylvania

Status and phase: Completed; Phase 2

Conditions: End-Stage Renal Disease

Treatments: Drug: Spironolactone

Study type: Interventional

Funder types: Other

Identifiers

NCT02285920

821193

Details and patient eligibility

About

The SPin-D Trial is a phase II randomized, double-blind, placebo-controlled, multi-center study of spironolactone (SPL) for patients with hemodialysis-dependent end-stage renal disease.

Full description

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.

Enrollment: 129 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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129 participants in 4 patient groups, including a placebo group

Spironolactone 12.5 mg

Active Comparator group

Description:

Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks.

Treatment:

Drug: Spironolactone

Spironolactone 25 mg

Active Comparator group

Description:

Participants will initiate treatment at 12.5 mg daily for 2 weeks at which time the dose will be increased to 25 mg daily for a total treatment time of 36 weeks.

Treatment:

Drug: Spironolactone

Spironolactone 50 mg

Active Comparator group

Description:

Participants will initiate treatment at 12.5 mg daily for 2 weeks at which time the dose will be increased to 25 mg daily for 2 weeks, and increased to 50 mg daily for a total treatment time of 36 weeks.

Treatment:

Drug: Spironolactone

Placebo

Placebo Comparator group

Description:

Participants will be treated with placebo for 36 weeks.

Treatment:

Drug: Spironolactone