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

Study Overview
=================
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.

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

Conditions
-----------------
End-Stage Renal Disease

Intervention / Treatment
-----------------
* Drug: Spironolactone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Maintenance hemodialysis therapy for end-stage renal disease Age 18-85 years ≥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. 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. Ability to provide informed consent Exclusion Criteria: Serum potassium ≥6.5 mEq/L within the 3 months prior to screening 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. Unscheduled dialysis for hyperkalemia within the 3 months prior to screening Pre-dialysis systolic blood pressure <100 mm Hg within 2 weeks prior to screening or at the baseline visit 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 Current dual use of angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) Current use of digoxin Current use of spironolactone or eplerenone Allergy to spironolactone 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 Mitral valve repair or replacement Severe mitral valve disease by echocardiography, coronary angiography or cardiac magnetic resonance imaging Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another dialysis unit within 9 months Expected survival <9 months Pregnancy, anticipated pregnancy, or breastfeeding Incarceration Participation in another intervention study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Spironolactone 12.5 mg<br>Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks. | Drug: Spironolactone<br>* 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.<br>|
| Active Comparator: Spironolactone 25 mg<br>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<br>* 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.<br>|
| Active Comparator: Spironolactone 50 mg<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Participants will be treated with placebo for 36 weeks. | Drug: Spironolactone<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hemodialysis, spironolactone, cardiac fibrosis, diastolic function