Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent End-Stage Renal Disease (ESRD) (SPin-D) Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 129
- 试验地点
- 4
- 主要终点
- Study Drug Tolerability
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Spironolactone 12.5 mg
Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks.
干预措施: Spironolactone (Drug)
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.
干预措施: Spironolactone (Drug)
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.
干预措施: Spironolactone (Drug)
Placebo
Participants will be treated with placebo for 36 weeks.
干预措施: Spironolactone (Drug)
结局指标
主要结局
Study Drug Tolerability
时间窗: 0 - 36 weeks
Tolerability is defined as number of participants who experienced permanent study drug discontinuation or dose reduction.
Safety - Participants With Serious Hypotension
时间窗: 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).
Efficacy - Change in Mitral Annular E' Velocity
时间窗: 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.
Safety - Number of Participants With Serum Potassium >6.5 mEq/L
时间窗: 0 - 40 weeks
The number of participants who had serum potassium \>6.5 mEq/L was assessed by treatment arm.
Feasibility of Conducting a Full-scale Mortality-powered Trial
时间窗: 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.
次要结局
- Safety - Hyperkalemia Requiring Adjustment in Treatment(0 - 40 weeks)
- Safety - Inter- or Intra-dialytic Hypotension(0 - 40 weeks)
- Efficacy - Secondary Cardiac Outcome Measure - Left Ventricular Ejection Fraction (LVEF)(Baseline - 36 weeks)
- Safety - Cardiovascular Death(0 - 40 weeks)
- Safety - Number of Participants With Serious Hyperkalemia(0 - 40 weeks)
- Efficacy - Secondary Cardiac Outcome Measures Left Ventricular Mass Index (LVMI)(Baseline - 36 weeks)
- Efficacy - Secondary Cardiac Outcome Measures - Ratio of Mitral Peak Velocity to Diastolic Mitral Annular Velocity (E/E')(Baseline - 36 weeks)
- Efficacy - Secondary Cardiac Outcome Measures - Left Ventricular Global Longitudinal Strain (LVGLS)(Baseline - 36 weeks)
- Safety - Combined Incidence of Potassium >6.5 mEq/L or Serious Hyperkalemia(0 - 40 Weeks)