Clinical trial NCT02585843
Conditions: Heart Failure
Keywords: Heart Failure Mineralocorticoid receptor antagonists Loop diuretic resistance
Sponsor: Columbia University
Start date: 2015-11-01; Completion date: 2017-03-31
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, single-center, double-blind and randomized placebo controlled trial for evaluation of a 7-day 100mg daily dose of spironolactone on weight loss and resolution of signs and symptoms of congestion in outpatients with acute decompensated heart failure (ADHF). Patients who are not responding to their current loop diuretics will be considered for this study. Mineralocorticoid receptor antagonists (MRAs) are recommended as standard of care in management of heart failure (HF) patients. However, recommended doses of MRAs (spironolactone 25mg/daily or eplerenone 50mg/daily) will not have any impact on signs and symptoms of volume overload. Therefore, the proposed study will aim to show the impact of this outpatient regimen to improve diuresis and possible reduction in hospitalization for further diuretic management in HF patients with signs and symptoms of congestion.

Detailed description:
The incidence and prevalence of heart failure (HF) is rising with more than 5 million Americans suffering from this syndrome. Hospitalization rates for acute decompensated heart failure (ADHF) are also remarkably high, exceeding more than 1 million admissions per year. Congestion is the main cause of hospitalization for ADHF. Loop diuretics as the main therapy for decongestion, often are not adequate since many patients with ADHF develop "loop diuretic resistance". These patients will require hospitalization for intravenous diuretic or other advanced decongestion therapies. Thus, novel decongestion therapies are needed to decrease hospital admission rates and subsequent complications of multiple hospitalizations. Hyperaldosteronism, not only is a pivotal pathogenic factor in HF, but also contributes to loop diuretic resistance. Attempts for normalization of circulatory aldosterone with mineralocorticoid receptor antagonists (MRAs), mainly spironolactone, have shown to decrease mortality in HF patients with reduced left ventricular ejection fraction (LVEF). Moreover, MRAs significantly decrease the rate of rehospitalization in both HF with preserved and reduced LVEF. The dose of spironolactone in these trials is 25mg daily. However, this dose does not increase natriuresis (urinary sodium excretion). Natriuresis is achieved with higher doses of MRAs. Therefore, the primary aim of this study is to examine the efficacy of 7-day 100mg daily of spironolactone on weight loss and resolution of signs and symptoms of congestion in patients aged 60 years with ADHF and loop diuretic resistance.

Arms: arm 1: Spironolactone 100mg: 100mg/day of spironolactone (2 capsules), PO (oral) for 7 days arm 2: Spironolactone 25mg: 25mg/day of spironolactone, PO (oral)
Interventions: intervention 1: Spironolactone 100mg intervention 2: Spironolactone 25mg
Intervention descriptions: intervention 1: 2 capsules of study medication consist of 100mg, PO (oral) for 7 days intervention 2: 25mg/day of spironolactone

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
Pilot Study of Natriuretic Versus Standard Doses of Mineralocorticoid Receptor Antagonists in 
Heart Failure and Loop Diuretic Resistance in Outpatients 
NCT: 02585843 
Date 8/30/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Design 
We conducted a pilot, prospective, single-center, double-blind, randomized, placebo controlled 
trial assessing the effects of high dose spironolactone in addition to intensified loop diuretic 
therapy vs. standard medical therapy in outpatients with ADHF. Our primary outcome was 
defined as weight change over the seven day study period.  Based on data from a non-
randomized intervention study, we aimed to recruit a total sample size of 40 subjects to detect 
a difference in our primary outcome of weight loss of 1.5kg difference between treatment and 
control. 
 
On Day 1, all potential subjects were evaluated with complete medical history and physical 
examination, review of home medications, measurement of vital signs and body weight with a 
calibrated scale, serum collection for basic metabolic panel, liver function test, biomarkers of 
congestion, and electrocardiogram. “Imminent hospitalization” was determined by two 
independent HF specialists to assess the need for hospitalization for intravenous diuretics. 
Home MRAs were discontinued and potassium supplementation held if baseline serum 
potassium was >4.0mmol/L. Beta-blockers, ACE-I or angiotenin II receptor blockers were 
continued at home dose. Loop diuretic dosage was increased by two-fold. Patients were seen at 
two office visits in total, baseline at day 1 and final visit on day 7. On day 3, participants had 
serum basic metabolic panel to assess potassium levels and renal function for safety 
assessment.  
 
Intervention 
Enrolled patients were randomly assigned in a 1:1 ratio to high-dose (100mg/day) or standard-
dose (25mg/day) spironolactone treatment groups.  
 
Randomization, Allocation and Blinding 
Randomization was stratified by sex and EF<45% in blocks of size 4. 2 by 2 randomization was 
performed via computer model generated by a study investigator. Allocations were concealed 
via the locked research pharmacy and the research team was blinded to treatment arm. All 
treatment medications were labeled in a blinded fashion. Subjects received 2 capsules per day 
(if standard dose: 25mg and placebo, if high dose: two 50mg) dispended in vials of 2 capsules.    
 
Study Endpoints 
The primary endpoint for the study was defined as change in total body weight at day 7 of the 
study period. Multiple secondary endpoints from day 1 to 7 were assessed. These included a) 
changes in dyspnea assessment scores; Visual Analogue Scale and 7-Likert scale, b) signs of 
congestion (i.e. JVP, peripheral edema and respiratory rales), c) 6MWT, d) serum and urinary 
creatinine, sodium, potassium and plasma aldosterone and renin activity and biomarkers of 
congestion and neurohormonal activation, e) furosemide equivalent of treatment loop diuretics 
doses, e) hospitalization at 30-, 60- and 90-days.  
 
Six-minute walk test was performed per American Thoracic Society guidelines, along with Borg 
scores for dyspnea and fatigue at day 1 and 7. Serum and urinary creatinine, potassium, and 
sodium, plasma aldosterone and renin activity, and pro-BNP were assessed at days 1 and 7. 


Other biomarkers of peripheral congestion (CD146), inflammation (interleukin-6, tumor 
necrosis factor-, endothelin-1) oxidative stress (isoprostane) and endothelial activation 
(vascular cell adhesion molecule-1) were assessed at day 1 and 7 and analyzed by ELISA or LC-
MS.  
 
A data monitoring committee of two independent cardiologists was established to evaluate 
safety, with a pre-specified stopping rule for harm but not for efficacy. Safety endpoints 
included changes in serum creatinine levels, eGFR, and the incidence of hyperkalemia during 
the 7 day treatment period. Safety was assessed by tracking adverse events including new or 
worsening renal dysfunction, and hyperkalemia. Serious adverse events were defined as death 
and all-cause hospitalization. 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
Pilot Study of Natriuretic Versus Standard Doses of Mineralocorticoid Receptor Antagonists in 
Heart Failure and Loop Diuretic Resistance in Outpatients 
NCT: 02585843 
Date 8/30/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Endpoints 
The primary endpoint for the study was defined as change in total body weight at day 7 of the 
study period. Multiple secondary endpoints from day 1 to 7 were assessed. These included a) 
changes in dyspnea assessment scores; Visual Analogue Scale and 7-Likert scale, b) signs of 
congestion (i.e. JVP, peripheral edema and respiratory rales), c) 6MWT, d) serum and urinary 
creatinine, sodium, potassium and plasma aldosterone and renin activity and biomarkers of 
congestion and neurohormonal activation, e) furosemide equivalent of treatment loop diuretics 
doses, e) hospitalization at 30-, 60- and 90-days.  
 
Six-minute walk test was performed per American Thoracic Society guidelines, along with Borg 
scores for dyspnea and fatigue at day 1 and 7. Serum and urinary creatinine, potassium, and 
sodium, plasma aldosterone and renin activity, and pro-BNP were assessed at days 1 and 7. 
Other biomarkers of peripheral congestion (CD146), inflammation (interleukin-6, tumor 
necrosis factor-, endothelin-1) oxidative stress (isoprostane) and endothelial activation 
(vascular cell adhesion molecule-1) were assessed at day 1 and 7 and analyzed by ELISA or LC-
MS.  
 
A data monitoring committee of two independent cardiologists was established to evaluate 
safety, with a pre-specified stopping rule for harm but not for efficacy. Safety endpoints 
included changes in serum creatinine levels, eGFR, and the incidence of hyperkalemia during 
the 7 day treatment period. Safety was assessed by tracking adverse events including new or 
worsening renal dysfunction, and hyperkalemia. Serious adverse events were defined as death 
and all-cause hospitalization. 
 
Statistical Analysis 
Statistical analyses were performed using SPSS version 23. Continuous variables are presented 
as mean  SD (or median with IQR if not following normal distribution) and categorical variables 
were summarized as counts (percentages). The 2 test or Fisher’s exact test (when cell counts 
were small) were used to compare categorical variables. Paired t-tests and the Wilcoxon rank 
sum test was used to compare continuous variables pre vs. post intervention within treatment 
arms. ANOVA was performed to compare continuous variables post-intervention. P< 0.05 
considered statistically significant for all comparisons.