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

Primary Purpose

End-Stage Renal Disease

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Spironolactone

About this trial

This is an interventional treatment trial for End-Stage Renal Disease focused on measuring hemodialysis, spironolactone, cardiac fibrosis, diastolic function

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

The George Washington University
Brigham and Women's Hospital
Vanderbilt University Medical Center
Kidney Research Institute, University of Washington

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Spironolactone 12.5 mg

Spironolactone 25 mg

Spironolactone 50 mg

Placebo

Arm Description

Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks.

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.

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.

Participants will be treated with placebo for 36 weeks.

Outcomes

Primary Outcome Measures

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.

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).

Study Drug Tolerability

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

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.

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.

Secondary Outcome Measures

Safety - Number of Participants With Serious Hyperkalemia

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

Safety - Hyperkalemia Requiring Adjustment in Treatment

Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication

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

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

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

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

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')

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

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.

Full Information

NCT ID

NCT02285920

First Posted

October 13, 2014

Last Updated

July 16, 2019

Sponsor

University of Pennsylvania

Collaborators

Brigham and Women's Hospital, George Washington University, Vanderbilt University, University of Washington

1. Study Identification

Unique Protocol Identification Number

NCT02285920

Brief Title

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

Acronym

SPin-D

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

November 2014 (undefined)

Primary Completion Date

June 2017 (Actual)

Study Completion Date

July 30, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Pennsylvania

Collaborators

Brigham and Women's Hospital, George Washington University, Vanderbilt University, University of Washington

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

End-Stage Renal Disease

Keywords

hemodialysis, spironolactone, cardiac fibrosis, diastolic function

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

129 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Spironolactone 12.5 mg

Arm Type

Active Comparator

Arm Description

Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks.

Arm Title

Spironolactone 25 mg

Arm Type

Active Comparator

Arm Description

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.

Arm Title

Spironolactone 50 mg

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants will be treated with placebo for 36 weeks.

Intervention Type

Drug

Intervention Name(s)

Spironolactone

Intervention Description

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.

Primary Outcome Measure Information:

Title

Safety - Number of Participants With Serum Potassium >6.5 mEq/L

Description

The number of participants who had serum potassium >6.5 mEq/L was assessed by treatment arm.

Time Frame

0 - 40 weeks

Title

Safety - Participants With Serious Hypotension

Description

Time Frame

0 - 40 weeks

Title

Study Drug Tolerability

Description

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

Time Frame

0 - 36 weeks

Title

Efficacy - Change in Mitral Annular E' Velocity

Description

Time Frame

Baseline to 36 weeks

Title

Feasibility of Conducting a Full-scale Mortality-powered Trial

Description

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 Outcome Measure Information:

Title

Safety - Number of Participants With Serious Hyperkalemia

Description

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

Time Frame

0 - 40 weeks

Title

Safety - Hyperkalemia Requiring Adjustment in Treatment

Description

Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication

Time Frame

0 - 40 weeks

Title

Safety - Inter- or Intra-dialytic Hypotension

Description

Time Frame

0 - 40 weeks

Title

Safety - Cardiovascular Death

Description

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

Time Frame

0 - 40 weeks

Title

Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF)

Description

Secondary outcome measures include other echocardiographic markers of systolic and diastolic function • Change in left ventricular ejection fraction between Baseline and 36 weeks

Time Frame

Baseline - 36 weeks

Title

Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI)

Description

Secondary outcome measures include other echocardiographic markers of systolic and diastolic function, • Change in left ventricular mass index (LVMI) between baseline and 36 weeks

Time Frame

Baseline - 36 weeks

Title

Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E')

Description

Time Frame

Baseline - 36 weeks

Title

Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS)

Description

Secondary outcome measures include other echocardiographic markers of systolic and diastolic function, • Change in myocardial strain and strain rate between baseline and 36 weeks

Time Frame

Baseline - 36 weeks

Title

Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia

Description

The number of participants who had serum potassium >6.5 mEq/L or serious hyperkalemia was assessed by treatment arm.

Time Frame

0 - 40 Weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Laura M Dember, MD

Organizational Affiliation

University of Pennsylvania

Official's Role

Principal Investigator

Facility Information:

Facility Name

The George Washington University

City

Washington

State/Province

District of Columbia

ZIP/Postal Code

20037

Country

United States

Facility Name

Brigham and Women's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02120

Country

United States

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Kidney Research Institute, University of Washington

City

Seattle

State/Province

Washington

ZIP/Postal Code

98104

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

33586138

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.

Results Reference

derived

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

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