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

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

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.

Study Overview

• Status: Completed
• Conditions: End-Stage Renal Disease
• Intervention / Treatment: Drug: Spironolactone

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 Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • The George Washington University
  • Massachusetts
    • Boston, Massachusetts, United States, 02120
      • Brigham and Women's Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Kidney Research Institute, University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Spironolactone 12.5 mg; Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks.	Drug: Spironolactone; The trial will be conducted in 2 phases - a dose escalation phase (6 weeks) and a treatment phase (30 weeks). At the end of the dose escalation phase, participants will continue treatment based on the randomized dose assignment for an additional 30 weeks (treatment phase) such that the total duration of study medication is 36 weeks.
Active Comparator: Spironolactone 25 mg; 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.	Drug: Spironolactone; The trial will be conducted in 2 phases - a dose escalation phase (6 weeks) and a treatment phase (30 weeks). At the end of the dose escalation phase, participants will continue treatment based on the randomized dose assignment for an additional 30 weeks (treatment phase) such that the total duration of study medication is 36 weeks.
Active Comparator: Spironolactone 50 mg; 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.	Drug: Spironolactone; The trial will be conducted in 2 phases - a dose escalation phase (6 weeks) and a treatment phase (30 weeks). At the end of the dose escalation phase, participants will continue treatment based on the randomized dose assignment for an additional 30 weeks (treatment phase) such that the total duration of study medication is 36 weeks.
Placebo Comparator: Placebo; Participants will be treated with placebo for 36 weeks.	Drug: Spironolactone; The trial will be conducted in 2 phases - a dose escalation phase (6 weeks) and a treatment phase (30 weeks). At the end of the dose escalation phase, participants will continue treatment based on the randomized dose assignment for an additional 30 weeks (treatment phase) such that the total duration of study medication is 36 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - Number of Participants With Serum Potassium >6.5 mEq/L	The number of participants who had serum potassium >6.5 mEq/L was assessed by treatment arm.	0 - 40 weeks
Safety - Participants With Serious Hypotension	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).	0 - 40 weeks
Study Drug Tolerability	Tolerability is defined as number of participants who experienced permanent study drug discontinuation or dose reduction.	0 - 36 weeks
Efficacy - Change in Mitral Annular E' Velocity	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.	Baseline to 36 weeks
Feasibility of Conducting a Full-scale Mortality-powered Trial	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.	0 - 40 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - Number of Participants With Serious Hyperkalemia	Number of patients with serious hyperkalemia requiring hospitalization, emergency/unscheduled dialysis or resin therapy	0 - 40 weeks
Safety - Hyperkalemia Requiring Adjustment in Treatment	Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication	0 - 40 weeks
Safety - Inter- or Intra-dialytic Hypotension	Inter- or intra-dialytic hypotension defined as: 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.; 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	0 - 40 weeks
Safety - Cardiovascular Death	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	0 - 40 weeks
Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF)	Secondary outcome measures include other echocardiographic markers of systolic and diastolic function • Change in left ventricular ejection fraction between Baseline and 36 weeks	Baseline - 36 weeks
Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI)	Secondary outcome measures include other echocardiographic markers of systolic and diastolic function, • Change in left ventricular mass index (LVMI) between baseline and 36 weeks	Baseline - 36 weeks
Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E')	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')	Baseline - 36 weeks
Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS)	Secondary outcome measures include other echocardiographic markers of systolic and diastolic function, • Change in myocardial strain and strain rate between baseline and 36 weeks	Baseline - 36 weeks
Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia	The number of participants who had serum potassium >6.5 mEq/L or serious hyperkalemia was assessed by treatment arm.	0 - 40 Weeks

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Brigham and Women's Hospital; University of Washington; Vanderbilt University; George Washington University
• Investigators: Principal Investigator: Laura M Dember, MD, University of Pennsylvania

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): July 30, 2017

Study Registration Dates

• First Submitted: October 13, 2014
• First Submitted That Met QC Criteria: November 4, 2014
• First Posted (Estimate): November 7, 2014

Study Record Updates

• Last Update Posted (Actual): July 23, 2019
• Last Update Submitted That Met QC Criteria: July 16, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: hemodialysis; spironolactone; diastolic function; cardiac fibrosis
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: 821193