Clinical trial NCT02285920: Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD Trial
Official title: Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent End-Stage Renal Disease (ESRD) (SPin-D) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: End-Stage Renal Disease
Keywords: hemodialysis
spironolactone
cardiac fibrosis
diastolic function
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Brigham and Women's Hospital
name: George Washington University
name: Vanderbilt University
name: University of Washington
First posted: 2014-11-07
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety - Number of Participants With Serum Potassium >6.5 mEq/L
timeFrame: 0 - 40 weeks
measure: Safety - Participants With Serious Hypotension
timeFrame: 0 - 40 weeks
measure: Study Drug Tolerability
timeFrame: 0 - 36 weeks
measure: Efficacy - Change in Mitral Annular E' Velocity
timeFrame: Baseline to 36 weeks
measure: Feasibility of Conducting a Full-scale Mortality-powered Trial
timeFrame: 0 - 40 weeks
Secondary outcomes:
measure: Safety - Number of Participants With Serious Hyperkalemia
timeFrame: 0 - 40 weeks
measure: Safety - Hyperkalemia Requiring Adjustment in Treatment
timeFrame: 0 - 40 weeks
measure: Safety - Inter- or Intra-dialytic Hypotension
timeFrame: 0 - 40 weeks
measure: Safety - Cardiovascular Death
timeFrame: 0 - 40 weeks
measure: Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF)
timeFrame: Baseline - 36 weeks
measure: Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI)
timeFrame: Baseline - 36 weeks
measure: Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E')
timeFrame: Baseline - 36 weeks
measure: Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS)
timeFrame: Baseline - 36 weeks
measure: Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia
timeFrame: 0 - 40 Weeks
Other outcomes:
Locations:
city: Washington
country: United States
facility: The George Washington University
state: District of Columbia
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Seattle
country: United States
facility: Kidney Research Institute, University of Washington
state: Washington
Study officials:
affiliation: University of Pennsylvania
name: Laura M Dember, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.