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

University of Pennsylvania129 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

129

Conditions

End-Stage Renal Disease

Interventions

SpironolactoneDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 85 Years

Medical Language ↔ Plain English

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

Locations (4)

The George Washington University

Washington D.C., District of Columbia, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Kidney Research Institute, University of Washington

Seattle, Washington, United States

Outcomes

Primary Outcomes

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.

Time frame: 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).

Time frame: 0 - 40 weeks

Study Drug Tolerability

Tolerability is defined as number of participants who experienced permanent study drug discontinuation or dose reduction.

Time frame: 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.

Time frame: 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.

Time frame: 0 - 40 weeks

Secondary Outcomes

Safety - Number of Participants With Serious Hyperkalemia

Number of patients with serious hyperkalemia requiring hospitalization, emergency/unscheduled dialysis or resin therapy

Time frame: 0 - 40 weeks

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.