End-Stage Renal Disease
Conditions
Keywords
hemodialysis, spironolactone, cardiac fibrosis, diastolic function
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.
Interventions
DRUGSpironolactone
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.
Sponsors
Brigham and Women's Hospital
George Washington University
Vanderbilt University
University of Washington
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Number of Participants With Serum Potassium >6.5 mEq/L | 0 - 40 weeks | The number of participants who had serum potassium \>6.5 mEq/L was assessed by treatment arm. |
| Safety - Participants With Serious Hypotension | 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). |
| Study Drug Tolerability | 0 - 36 weeks | Tolerability is defined as number of participants who experienced permanent study drug discontinuation or dose reduction. |
| Efficacy - Change in Mitral Annular E' Velocity | 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. |
| Feasibility of Conducting a Full-scale Mortality-powered Trial | 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
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | 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 |
| Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | 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') |
| Safety - Number of Participants With Serious Hyperkalemia | 0 - 40 weeks | Number of patients with serious hyperkalemia requiring hospitalization, emergency/unscheduled dialysis or resin therapy |
| Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia | 0 - 40 Weeks | The number of participants who had serum potassium \>6.5 mEq/L or serious hyperkalemia was assessed by treatment arm. |
| Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | 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 |
| Safety - Hyperkalemia Requiring Adjustment in Treatment | 0 - 40 weeks | Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication |
| Safety - Inter- or Intra-dialytic Hypotension | 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 |
| Safety - Cardiovascular Death | 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 |
| Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants will be treated with placebo for 36 weeks.
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. | 51 |
| Spironolactone 12.5 mg Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks.
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. | 27 |
| 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.
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. | 26 |
| 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.
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. | 25 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Change to peritoneal dialysis | 0 | 0 | 1 | 0 |
| Overall Study | Death | 2 | 0 | 2 | 1 |
| Overall Study | Dialysis discontinuation | 0 | 1 | 0 | 0 |
| Overall Study | Kidney transplantation | 2 | 2 | 2 | 0 |
| Overall Study | Transfer to non-participating unit | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Spironolactone 12.5 mg | Spironolactone 25 mg | Spironolactone 50 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 11.5 | 55.1 years STANDARD_DEVIATION 13.6 | 53.3 years STANDARD_DEVIATION 13.5 | 55.5 years STANDARD_DEVIATION 9.8 | 55.5 years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 47 Participants | 24 Participants | 24 Participants | 23 Participants | 118 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 39 Participants | 18 Participants | 18 Participants | 17 Participants | 92 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 7 Participants | 8 Participants | 7 Participants | 5 Participants | 27 Participants |
| Sex: Female, Male Female | 19 Participants | 12 Participants | 7 Participants | 6 Participants | 44 Participants |
| Sex: Female, Male Male | 32 Participants | 15 Participants | 19 Participants | 19 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 51 | 0 / 27 | 2 / 26 | 1 / 25 |
| other Total, other adverse events | 45 / 51 | 24 / 27 | 25 / 26 | 23 / 25 |
| serious Total, serious adverse events | 27 / 51 | 13 / 27 | 13 / 26 | 12 / 25 |
Outcome results
Primary
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
Population: The number of participants analyzed reflects those who had analyzable echocardiogram data at both study time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Efficacy - Change in Mitral Annular E' Velocity | Baseline MA E' | 7.4 cm/second | Standard Deviation 1.7 |
| Placebo | Efficacy - Change in Mitral Annular E' Velocity | Change between baseline - 36 weeks | 0.1 cm/second | Standard Deviation 1.1 |
| Placebo | Efficacy - Change in Mitral Annular E' Velocity | 36 Week MA E' | 7.5 cm/second | Standard Deviation 1.9 |
| Spironolactone 12.5 mg | Efficacy - Change in Mitral Annular E' Velocity | Baseline MA E' | 7.6 cm/second | Standard Deviation 1.8 |
| Spironolactone 12.5 mg | Efficacy - Change in Mitral Annular E' Velocity | Change between baseline - 36 weeks | -0.2 cm/second | Standard Deviation 1 |
| Spironolactone 12.5 mg | Efficacy - Change in Mitral Annular E' Velocity | 36 Week MA E' | 7.4 cm/second | Standard Deviation 1.9 |
| Spironolactone 25 mg | Efficacy - Change in Mitral Annular E' Velocity | 36 Week MA E' | 7.7 cm/second | Standard Deviation 1.4 |
| Spironolactone 25 mg | Efficacy - Change in Mitral Annular E' Velocity | Baseline MA E' | 7.8 cm/second | Standard Deviation 1.9 |
| Spironolactone 25 mg | Efficacy - Change in Mitral Annular E' Velocity | Change between baseline - 36 weeks | -0.1 cm/second | Standard Deviation 1.2 |
| Spironolactone 50 mg | Efficacy - Change in Mitral Annular E' Velocity | Baseline MA E' | 7.0 cm/second | Standard Deviation 1.9 |
| Spironolactone 50 mg | Efficacy - Change in Mitral Annular E' Velocity | Change between baseline - 36 weeks | 0.3 cm/second | Standard Deviation 1.6 |
| Spironolactone 50 mg | Efficacy - Change in Mitral Annular E' Velocity | 36 Week MA E' | 7.3 cm/second | Standard Deviation 1.9 |
Primary
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
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Feasibility of Conducting a Full-scale Mortality-powered Trial | Death | 2 Participants |
| Placebo | Feasibility of Conducting a Full-scale Mortality-powered Trial | Change to peritoneal dialysis | 0 Participants |
| Placebo | Feasibility of Conducting a Full-scale Mortality-powered Trial | Study completed | 47 Participants |
| Placebo | Feasibility of Conducting a Full-scale Mortality-powered Trial | Transfer to non-participating facility | 0 Participants |
| Placebo | Feasibility of Conducting a Full-scale Mortality-powered Trial | Dialysis discontinued | 0 Participants |
| Placebo | Feasibility of Conducting a Full-scale Mortality-powered Trial | Kidney transplantation | 2 Participants |
| Spironolactone 12.5 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Change to peritoneal dialysis | 0 Participants |
| Spironolactone 12.5 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Kidney transplantation | 2 Participants |
| Spironolactone 12.5 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Transfer to non-participating facility | 1 Participants |
| Spironolactone 12.5 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Death | 0 Participants |
| Spironolactone 12.5 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Dialysis discontinued | 1 Participants |
| Spironolactone 12.5 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Study completed | 23 Participants |
| Spironolactone 25 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Kidney transplantation | 2 Participants |
| Spironolactone 25 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Change to peritoneal dialysis | 1 Participants |
| Spironolactone 25 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Death | 2 Participants |
| Spironolactone 25 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Dialysis discontinued | 0 Participants |
| Spironolactone 25 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Study completed | 21 Participants |
| Spironolactone 25 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Transfer to non-participating facility | 0 Participants |
| Spironolactone 50 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Study completed | 24 Participants |
| Spironolactone 50 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Kidney transplantation | 0 Participants |
| Spironolactone 50 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Change to peritoneal dialysis | 0 Participants |
| Spironolactone 50 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Transfer to non-participating facility | 0 Participants |
| Spironolactone 50 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Dialysis discontinued | 0 Participants |
| Spironolactone 50 mg | Feasibility of Conducting a Full-scale Mortality-powered Trial | Death | 1 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety - Number of Participants With Serum Potassium >6.5 mEq/L | 9 Participants |
| Spironolactone 12.5 mg | Safety - Number of Participants With Serum Potassium >6.5 mEq/L | 4 Participants |
| Spironolactone 25 mg | Safety - Number of Participants With Serum Potassium >6.5 mEq/L | 4 Participants |
| Spironolactone 50 mg | Safety - Number of Participants With Serum Potassium >6.5 mEq/L | 8 Participants |
Primary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety - Participants With Serious Hypotension | 0 Participants |
| Spironolactone 12.5 mg | Safety - Participants With Serious Hypotension | 2 Participants |
| Spironolactone 25 mg | Safety - Participants With Serious Hypotension | 0 Participants |
| Spironolactone 50 mg | Safety - Participants With Serious Hypotension | 3 Participants |
Primary
Study Drug Tolerability
Tolerability is defined as number of participants who experienced permanent study drug discontinuation or dose reduction.
Time frame: 0 - 36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Study Drug Tolerability | 16 Participants |
| Spironolactone 12.5 mg | Study Drug Tolerability | 5 Participants |
| Spironolactone 25 mg | Study Drug Tolerability | 6 Participants |
| Spironolactone 50 mg | Study Drug Tolerability | 8 Participants |
Secondary
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
Time frame: Baseline - 36 weeks
Population: The number of participants analyzed reflects those who had analyzable echocardiogram data at both study time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Baseline | 68.9 percent ejection fraction | Standard Deviation 4 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF 36-Week | 70.7 percent ejection fraction | Standard Deviation 3.1 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Change | 1.8 percent ejection fraction | Standard Deviation 4.1 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF 36-Week | 66.9 percent ejection fraction | Standard Deviation 9.9 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Change | 1.0 percent ejection fraction | Standard Deviation 4.7 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Baseline | 65.9 percent ejection fraction | Standard Deviation 8.5 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Baseline | 66.0 percent ejection fraction | Standard Deviation 11.4 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Change | -0.7 percent ejection fraction | Standard Deviation 7.3 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF 36-Week | 65.3 percent ejection fraction | Standard Deviation 13.9 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Change | 1.3 percent ejection fraction | Standard Deviation 3.7 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF Baseline | 68.2 percent ejection fraction | Standard Deviation 5.8 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF) | LVEF 36-Week | 69.5 percent ejection fraction | Standard Deviation 6.3 |
Secondary
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
Time frame: Baseline - 36 weeks
Population: The number of participants analyzed reflects those who had analyzable echocardiogram data at both study time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Baseline | -17.2 % of myocardial shortening | Standard Deviation 2.8 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Change | -0.8 % of myocardial shortening | Standard Deviation 2.3 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS 36-week | -18.1 % of myocardial shortening | Standard Deviation 2.8 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Baseline | -16.7 % of myocardial shortening | Standard Deviation 3.3 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Change | -0.3 % of myocardial shortening | Standard Deviation 3.3 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS 36-week | -17.0 % of myocardial shortening | Standard Deviation 3.3 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS 36-week | -17.0 % of myocardial shortening | Standard Deviation 3.9 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Baseline | -17.2 % of myocardial shortening | Standard Deviation 4.2 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Change | 0.2 % of myocardial shortening | Standard Deviation 2.7 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Baseline | -17.4 % of myocardial shortening | Standard Deviation 3 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS Change | -0.7 % of myocardial shortening | Standard Deviation 2.9 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS) | LVGLS 36-week | -18.2 % of myocardial shortening | Standard Deviation 3 |
Secondary
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
Time frame: Baseline - 36 weeks
Population: The number of participants analyzed reflects those who had analyzable echocardiogram data at both study time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Baseline | 105.2 g/m^2 | Standard Deviation 25.2 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Change | -10.4 g/m^2 | Standard Deviation 11.9 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI 36-Week | 94.8 g/m^2 | Standard Deviation 22.4 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Baseline | 115.5 g/m^2 | Standard Deviation 26.7 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Change | -10.9 g/m^2 | Standard Deviation 18.1 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI 36-Week | 104.6 g/m^2 | Standard Deviation 27 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI 36-Week | 109.1 g/m^2 | Standard Deviation 30.5 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Baseline | 116.4 g/m^2 | Standard Deviation 26.9 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Change | -7.3 g/m^2 | Standard Deviation 21 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Baseline | 106.3 g/m^2 | Standard Deviation 29.2 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI Change | -9.8 g/m^2 | Standard Deviation 9.3 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI) | LVMI 36-Week | 96.5 g/m^2 | Standard Deviation 25.7 |
Secondary
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')
Time frame: Baseline - 36 weeks
Population: The number of participants analyzed reflects those who had analyzable echocardiogram data at both study time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Baseline | 10.7 ratio | Standard Deviation 5.8 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Change | 0.9 ratio | Standard Deviation 3.6 |
| Placebo | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' 36-Week | 11.5 ratio | Standard Deviation 7 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Baseline | 11.8 ratio | Standard Deviation 6.2 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Change | 0.4 ratio | Standard Deviation 4.4 |
| Spironolactone 12.5 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' 36-Week | 12.2 ratio | — |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' 36-Week | 10.6 ratio | Standard Deviation 3.9 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Baseline | 9.2 ratio | Standard Deviation 5 |
| Spironolactone 25 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Change | 1.4 ratio | Standard Deviation 2.2 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Baseline | 12.5 ratio | Standard Deviation 5.6 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' Change | -0.6 ratio | Standard Deviation 4 |
| Spironolactone 50 mg | Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E') | E/E' 36-Week | 11.9 ratio | Standard Deviation 5.5 |
Secondary
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
Time frame: 0 - 40 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety - Cardiovascular Death | 1 Participants |
| Spironolactone 12.5 mg | Safety - Cardiovascular Death | 0 Participants |
| Spironolactone 25 mg | Safety - Cardiovascular Death | 2 Participants |
| Spironolactone 50 mg | Safety - Cardiovascular Death | 1 Participants |
Secondary
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.
Time frame: 0 - 40 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia | 13 Participants |
| Spironolactone 12.5 mg | Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia | 5 Participants |
| Spironolactone 25 mg | Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia | 5 Participants |
| Spironolactone 50 mg | Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia | 10 Participants |
Secondary
Safety - Hyperkalemia Requiring Adjustment in Treatment
Hyperkalemia requiring adjustment in dialysate potassium concentration, or discontinuation of study medication
Time frame: 0 - 40 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety - Hyperkalemia Requiring Adjustment in Treatment | 13 Participants |
| Spironolactone 12.5 mg | Safety - Hyperkalemia Requiring Adjustment in Treatment | 2 Participants |
| Spironolactone 25 mg | Safety - Hyperkalemia Requiring Adjustment in Treatment | 5 Participants |
| Spironolactone 50 mg | Safety - Hyperkalemia Requiring Adjustment in Treatment | 7 Participants |
Secondary
Safety - Inter- or Intra-dialytic Hypotension
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
Time frame: 0 - 40 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Safety - Inter- or Intra-dialytic Hypotension | Inter-dialytic hypotension only | 3 Participants |
| Placebo | Safety - Inter- or Intra-dialytic Hypotension | Intra-dialytic hypotension only | 20 Participants |
| Placebo | Safety - Inter- or Intra-dialytic Hypotension | Inter- & intra-dialytic hypotension | 3 Participants |
| Placebo | Safety - Inter- or Intra-dialytic Hypotension | No inter- or intra-dialytic hypotension | 25 Participants |
| Spironolactone 12.5 mg | Safety - Inter- or Intra-dialytic Hypotension | Intra-dialytic hypotension only | 9 Participants |
| Spironolactone 12.5 mg | Safety - Inter- or Intra-dialytic Hypotension | Inter- & intra-dialytic hypotension | 3 Participants |
| Spironolactone 12.5 mg | Safety - Inter- or Intra-dialytic Hypotension | No inter- or intra-dialytic hypotension | 14 Participants |
| Spironolactone 12.5 mg | Safety - Inter- or Intra-dialytic Hypotension | Inter-dialytic hypotension only | 1 Participants |
| Spironolactone 25 mg | Safety - Inter- or Intra-dialytic Hypotension | Inter- & intra-dialytic hypotension | 5 Participants |
| Spironolactone 25 mg | Safety - Inter- or Intra-dialytic Hypotension | Intra-dialytic hypotension only | 8 Participants |
| Spironolactone 25 mg | Safety - Inter- or Intra-dialytic Hypotension | No inter- or intra-dialytic hypotension | 12 Participants |
| Spironolactone 25 mg | Safety - Inter- or Intra-dialytic Hypotension | Inter-dialytic hypotension only | 1 Participants |
| Spironolactone 50 mg | Safety - Inter- or Intra-dialytic Hypotension | No inter- or intra-dialytic hypotension | 6 Participants |
| Spironolactone 50 mg | Safety - Inter- or Intra-dialytic Hypotension | Intra-dialytic hypotension only | 14 Participants |
| Spironolactone 50 mg | Safety - Inter- or Intra-dialytic Hypotension | Inter-dialytic hypotension only | 0 Participants |
| Spironolactone 50 mg | Safety - Inter- or Intra-dialytic Hypotension | Inter- & intra-dialytic hypotension | 5 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Safety - Number of Participants With Serious Hyperkalemia | 6 Participants |
| Spironolactone 12.5 mg | Safety - Number of Participants With Serious Hyperkalemia | 2 Participants |
| Spironolactone 25 mg | Safety - Number of Participants With Serious Hyperkalemia | 0 Participants |
| Spironolactone 50 mg | Safety - Number of Participants With Serious Hyperkalemia | 7 Participants |