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

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ClinicalTrials.gov Identifier: NCT02285920
Recruitment Status : Active, not recruiting
First Posted : November 7, 2014
Last Update Posted : July 7, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

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.

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.

Study Design

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
Primary Completion Date : June 2017
Estimated Study Completion Date : September 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

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.


Outcome Measures

Primary Outcome Measures :
  1. Safety [ Time Frame: 0 - 40 weeks ]
    a) The incidence of serum potassium >6.5 mEq/L

  2. Safety [ Time Frame: 0 - 40 weeks ]
    b) The incidence of serious hypotension not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection)

  3. Tolerability [ Time Frame: 0 - 36 weeks ]
    Tolerability will be assessed on the basis of whether participants can continue the assigned dose throughout the entire treatment period. Any reduction in dose of study medication will be considered a failure of primary tolerability.

  4. Efficacy [ Time Frame: 0 - 36 weeks ]
    Change in mitral annular E' velocity will be measured using Tissue Doppler Index (TDI) echocardiography of the left ventricle as a measure of diastolic function and as surrogate measure of left ventricular fibrosis.

  5. Feasibility [ Time Frame: 0 - 40 weeks ]
    An objective of this study is to assess the feasibility of conducting a full-scale mortality-powered trial. Feasibility will be assessed based on recruitment, dropout and loss to follow-up rates.


Secondary Outcome Measures :
  1. Safety [ Time Frame: 0 - 40 weeks ]
    1. Potassium level >6.5 mEq/L
    2. Serious hypotension requiring hospitalization or emergency dept. treatment
    3. Serious hyperkalemia requiring hospitalization, emergency/unscheduled dialysis or resin therapy
    4. Combined incidence of potassium >6.5 mEq/L or serious hyperkalemia requiring hospitalization, emergency/unscheduled dialysis or resin therapy
    5. Treatment-emergent events - combined incidence of death, myocardial infarction, stroke, hospitalizations, potassium greater than 6.5 mEq/L, serious hyperkalemia, serious hypotension
    6. Individual components of the treatment-emergent endpoint
    7. Cardiovascular death
    8. Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication
    9. Proportion of dialysis sessions using 1 mEq/L potassium dialysis solution bath
    10. Within-patient variability in serum potassium concentration
    11. Symptomatic inter- or intra-dialytic hypotension

  2. Efficacy [ Time Frame: 0 - 36 weeks ]

    Secondary outcome measures include other echocardiographic markers of systolic and diastolic function, circulating markers of fibrosis and, in a sub-study, heart rate variability as assessed by Holter monitoring and coronary flow reserve (CFR) as assessed by myocardial positron emission tomography (PET).

    • Change in left ventricular mass index (LVMI) between 0 and 36 weeks
    • Change in ejection fraction between 0 and 36 weeks
    • Change in myocardial strain and strain rate between 0 and 36 weeks
    • Change in cardiac fibrosis markers between baseline and 36 weeks
    • Change in inflammatory markers between baseline and 36 weeks
    • Change in oxidative stress markers between baseline and 36 weeks
    • Change in CFR between baseline and 36 weeks
    • Association between change in CFR and change in E'
    • Heart rate variability
    • Serious arrhythmia


Eligibility Criteria

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
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
Contacts and Locations

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
United States, District of Columbia
The George Washington University
Washington, D.C., 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
Principal Investigator: Laura M Dember, MD University of Pennsylvania
More Information

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT02285920     History of Changes
Other Study ID Numbers: 821193
First Posted: November 7, 2014    Key Record Dates
Last Update Posted: July 7, 2017
Last Verified: July 2017

Keywords provided by University of Pennsylvania:
hemodialysis
spironolactone
cardiac fibrosis
diastolic function

Additional relevant MeSH terms:
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