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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02285920
Recruitment Status : Completed
First Posted : November 7, 2014
Results First Posted : July 23, 2019
Last Update Posted : July 23, 2019
Sponsor:
Collaborators:
Brigham and Women's Hospital
George Washington University
Vanderbilt University
University of Washington
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
End-Stage Renal Disease Drug: Spironolactone Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 129 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent End-Stage Renal Disease (ESRD) (SPin-D) Trial
Study Start Date : November 2014
Actual Primary Completion Date : June 2017
Actual Study Completion Date : July 30, 2017

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Safety - Number of Participants With Serum Potassium >6.5 mEq/L [ Time Frame: 0 - 40 weeks ]
    The number of participants who had serum potassium >6.5 mEq/L was assessed by treatment arm.

  2. Safety - Participants With Serious Hypotension [ Time Frame: 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).

  3. Study Drug Tolerability [ Time Frame: 0 - 36 weeks ]
    Tolerability is defined as number of participants who experienced permanent study drug discontinuation or dose reduction.

  4. Efficacy - Change in Mitral Annular E' Velocity [ Time Frame: 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.

  5. Feasibility of Conducting a Full-scale Mortality-powered Trial [ Time Frame: 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 :
  1. Safety - Number of Participants With Serious Hyperkalemia [ Time Frame: 0 - 40 weeks ]
    Number of patients with serious hyperkalemia requiring hospitalization, emergency/unscheduled dialysis or resin therapy

  2. Safety - Hyperkalemia Requiring Adjustment in Treatment [ Time Frame: 0 - 40 weeks ]
    Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication

  3. Safety - Inter- or Intra-dialytic Hypotension [ Time Frame: 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

  4. Safety - Cardiovascular Death [ Time Frame: 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

  5. Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) [ Time Frame: 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


  6. Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) [ Time Frame: 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


  7. Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') [ Time Frame: 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')


  8. Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) [ Time Frame: 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


  9. Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia [ Time Frame: 0 - 40 Weeks ]
    The number of participants who had serum potassium >6.5 mEq/L or serious hyperkalemia was assessed by treatment arm.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02285920


Locations
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United States, District of Columbia
The George Washington University
Washington, District of Columbia, United States, 20037
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02120
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
United States, Washington
Kidney Research Institute, University of Washington
Seattle, Washington, United States, 98104
Sponsors and Collaborators
University of Pennsylvania
Brigham and Women's Hospital
George Washington University
Vanderbilt University
University of Washington
Investigators
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Principal Investigator: Laura M Dember, MD University of Pennsylvania
  Study Documents (Full-Text)

Documents provided by University of Pennsylvania:
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT02285920    
Other Study ID Numbers: 821193
First Posted: November 7, 2014    Key Record Dates
Results First Posted: July 23, 2019
Last Update Posted: July 23, 2019
Last Verified: July 2019
Keywords provided by University of Pennsylvania:
hemodialysis
spironolactone
cardiac fibrosis
diastolic function
Additional relevant MeSH terms:
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Kidney Diseases
Kidney Failure, Chronic
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents