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

Phase 2

Completed

• Conditions: End-Stage Renal Disease
• Interventions: Drug: Spironolactone

• Registration Number: NCT02285920
• Lead Sponsor: University of Pennsylvania

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.

Study Timeline

• Study First Submitted: 2014-10-13
• Study Start: 2014-11
• Study First Submitted QC: 2014-11-04
• Study First Posted: 2014-11-07
• Primary Completion: 2017-06
• Study Completion: 2017-07-30
• Results First Submitted: 2019-02-19
• Status Verified: 2019-07
• Results First Submitted QC: 2019-07-16
• Last Update Submitted: 2019-07-16
• Results First Posted: 2019-07-23
• Last Update Posted: 2019-07-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 129

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

Read More

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

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Spironolactone 12.5 mg	Spironolactone	Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks.
Spironolactone 25 mg	Spironolactone	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.
Spironolactone 50 mg	Spironolactone	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.
Placebo	Spironolactone	Participants will be treated with placebo for 36 weeks.

Primary Outcome Measures

Name	Time	Method
Study Drug Tolerability	0 - 36 weeks	Tolerability is defined as number of participants who experienced permanent study drug discontinuation or dose reduction.
Safety - Participants With Serious Hypotension	0 - 40 weeks	The number of participants experiencing serious hypotension, defined as hypotension requiring hospitalization or ED visit and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection).
Efficacy - Change in Mitral Annular E' Velocity	Baseline to 36 weeks	Change in mitral annular E' velocity measured using Tissue Doppler Index (TDI) echocardiography. Efficacy outcomes were considered exploratory with a goal of detecting signals rather than clearly demonstrating efficacy.
Safety - Number of Participants With Serum Potassium >6.5 mEq/L	0 - 40 weeks	The number of participants who had serum potassium \>6.5 mEq/L was assessed by treatment arm.
Feasibility of Conducting a Full-scale Mortality-powered Trial	0 - 40 weeks	An objective of this study is to assess the feasibility of conducting a full-scale mortality-powered trial. Feasibility assessed based on recruitment, dropout and loss to follow-up rates.

Secondary Outcome Measures

Name	Time	Method
Safety - Hyperkalemia Requiring Adjustment in Treatment	0 - 40 weeks	Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication
Safety - Inter- or Intra-dialytic Hypotension	0 - 40 weeks	Inter- or intra-dialytic hypotension defined as: 1. Inter-dialytic: systolic blood pressure \<90 mm Hg or inter-dialytic hypotension requiring adjustment in anti-hypertensive medications or treatment in a hospital or emergency room.; 2. Intra-dialytic: systolic blood pressure \<80 mm Hg during ≥3 dialysis sessions per 30-day period or treatment for either hypotension or symptoms of hypotension during ≥3 dialysis sessions per 30-day period
Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF)	Baseline - 36 weeks	Secondary outcome measures include other echocardiographic markers of systolic and diastolic function; • Change in left ventricular ejection fraction between Baseline and 36 weeks
Safety - Cardiovascular Death	0 - 40 weeks	Number of Cardiovascular deaths defined as death due to myocardial infarction, congestive heart failure, cardiac valvular disease, arrhythmia, sudden death, stroke, or peripheral arterial disease
Safety - Number of Participants With Serious Hyperkalemia	0 - 40 weeks	Number of patients with serious hyperkalemia requiring hospitalization, emergency/unscheduled dialysis or resin therapy
Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI)	Baseline - 36 weeks	Secondary outcome measures include other echocardiographic markers of systolic and diastolic function,; • Change in left ventricular mass index (LVMI) between baseline and 36 weeks
Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E')	Baseline - 36 weeks	Secondary outcome measures include other echocardiographic markers of systolic and diastolic function,; • E/E' is the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E')
Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS)	Baseline - 36 weeks	Secondary outcome measures include other echocardiographic markers of systolic and diastolic function,; • Change in myocardial strain and strain rate between baseline and 36 weeks
Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia	0 - 40 Weeks	The number of participants who had serum potassium \>6.5 mEq/L or serious hyperkalemia was assessed by treatment arm.

Trial Locations

Locations (4)

Kidney Research Institute, University of Washington; 🇺🇸 Seattle, Washington, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

The George Washington University; 🇺🇸 Washington, District of Columbia, United States