High-dose Aldosterone Antagonist for Acute Decompensated Heart Failure
Conditions: Acute Decompensated Heart Failure
Sponsor: The University of Texas Health Science Center at San Antonio

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vSept3-2014 
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COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Official Study Title: High-dose Aldosterone antagonist for Acute Decompensated 
Heart Failure 
 
NCT number: NCT 02823626 
 
IRB Approval Date: 06-09-17 
 
Unique Protocol ID: HSC20160252H 
 
 
 

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Protocol Template Form 
 
Item 1 UTHSCSA 
Tracking Number 
HSC20160252H 
 
Item 2 Abstract / Project Summary 
Provide a succinct and accurate description of the proposed 
research. State the purpose/aims. Describe concisely the research 
design and methods for achieving the stated goals. This section 
should be understandable to all members of the IRB, scientific and 
non-scientific.   
DO NOT EXCEED THE SPACE PROVIDED. 
Purpose/Objectives: Primary Aims  
1: Evaluate the safety of high-dose spironolactone in combination of Patiromer in acute decompensated heart 
failure patients.  
2: Evaluate the efficacy of high-dose spironolactone in combination of Patiromer in causing volume loss and 
symptom relief in patients with ADHF treated with high-dose spironolactone.   
 
Secondary Aims  
1: Evaluate the effect of high-dose spironolactone on urinary sodium excretion and renal function.  
 
Research Design/Plan: We propose a prospective exploratory single-arm, open-label pilot study to assess the 
safety and efficacy of high dose spironolactone in combination with Patiromer in patients hospitalized with 
decompensation of chronic heart failure who shows sign of resistance of loop diuretics. Patients admitted with 
decompensated heart failure will be identified from the inpatient cardiology and internal medicine services.  
Methods: Study Protocol 
Pre-screening: Patients meeting the inclusion and exclusion criteria will be approached to participate in the 
study. Informed consent will be taken at this time. These patients will receive intravenous loop diuretic per the 
discretion of treating physician and will be closely followed for weight loss and symptoms relief.  
Screening: The patients who don’t respond as measured by symptoms relief or <0.5 kg weight loss/day  
a) Despite furosemide ≥ 160 mg IV total daily dose or equivalent dose of torsemide or bumetanide. (1 mg 
bumetanide = 10 mg torsemide = 20 mg furosemide). OR 
b) After 48 hours of admission irrespective of diuretic dose. 
will be considered for the study intervention. Patients who have not participated in the pre-screening phase and 
do not respond adequately to furosemide >160 mg iv daily dose will directly be enrolled into active intervention 
part of the study. 
Intervention (High-Dose Spironolactone + Patiromer): Patients will be initiated on spironolactone 100 mg 
orally once daily along with patiromer 8.4 gm orally (if serum K >4.3 meq/L). The dose of loop diuretic will stay 
same during rest of the study period. On day 2, the dose of spironolactone will be titrated to 200 mg orally once 
a day depending on the diuretic response and lab results. Serum potassium and magnesium will be monitored 
twice a day. An EKG will be performed any time electrolytes are out of range. The dose of patiromer will be 
increased to 16.8 gm in patients with potassium levels exceeding 5.5 meq/L; or it will be held for serum K <4.3 
mEq/L. Treatment will continue till patients achieve euvolemia or get discharged. Euvolemia is defined as 
resolution of symptoms and signs of volume overload.   
Treatment Failures: Patients will be considered high dose spironolactone failure if they do not achieve a net 
negative body weight after a minimum of 5 days. High-dose spironolactone may be stopped anytime per the 
discretion of the treating physician.  The patients that do not respond to high-dose spironolactone are 
considered treatment failures and will be included in the primary endpoint analysis. 
Concomitant Medications/diet:  Patient taking concomitant heart failure medications such as ACEi, ARB 
and/or beta-blockers are to be continued throughout the study as tolerated.  If these medications have not 
been administered at the time of randomization, timing and sequence of the starting ACEi, ARB or beta-
blockers will be left to the discretion of the treating physician. All the patients will be prescribed low Na 
(<1.5gm/day) and low potassium (50-75 mEq/day) diet. 
Clinical Relevance: Insert response here 
 

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Item 3 
Background 
 
Describe past experimental 
and/or clinical findings 
leading to the formulation 
of your study.   
For research involving 
unapproved drugs, describe 
animal and human studies.   
For research that involves 
approved drugs or devices, 
describe the FDA approved 
uses of this drug/device in 
relation to your protocol. 
Congestive heart failure currently affects an estimated 6.6 million adults in the United 
States and ADHF accounts for ~ 1 million hospitalizations yearly1. The main focus in 
the management of ADHF is on therapies directly responsible for removal of excess 
sodium and water. The most widely used therapy at present is higher than usual dose 
of oral or intravenous loop diuretics including furosemide, torsemide and bumetanide 
alone or in combination with thiazide like diuretics including chlorthalidone, 
hydrochlorthiazide or metolazone. However, resistance to the natriuretic effect and 
declining kidney function during diuresis are common occurrences. The mechanisms 
behind these relationships are complex and patient specific. The heart failure patients 
have severe underlying secondary hyperreninemic and hyperaldosteronism state due 
to reduced effective arterial blood volume (EABV) as a result of decreased cardiac 
output2. Long-term loop diuretic use causes further RAAS activation by inhibiting 
sodium chloride transport at the macula densa and relative volume depletion as a result 
of failure to transfer the fluid from interstitium to vascular compartment at an acceptable 
rate. In addition, chronic use of loop diuretics causes enhanced sodium chloride co-
transporter expression at distal collecting tubules leading to increased sodium 
absorption at this site resulting in resistance to natriuretic effect3. Addition of thiazide 
like diuretics overcomes the later problem; however, relative volume depletion causing 
further RAAS activation and excessive proximal tubular and collecting duct sodium 
absorption remains an issue.   
 
Recently many other strategies including extracorporeal ultrafiltration and human 
recombinant low dose B-type natriuretic peptide – nesiritide have been used for 
removal of excessive fluid in addition to or in place of diuretics4,5. However, none of 
these therapies have shown to be more beneficial than loop diuretics. In addition, blood 
based extracorporeal ultrafiltration requires use of invasive device and anti-coagulation. 
The possible explanation for failure to achieve the better outcomes with the above 
strategies is similar to the use of loop diuretic, i.e. further stimulation of neurohumoral 
system and RAAS by either rapid fluid removal or vasodilating property, respectively.  
 
Item 4 
Purpose and rationale 
Insert purpose, objectives 
and research 
questions/hypotheses here. 
 If you cut and paste from 
another document, make 
sure the excerpted material 
answers the question 
Patients with CHF and cirrhosis share the same pathophysiology of arterial underfilling 
due to either decreased cardiac output or splanchnic vasodilatation respectively, 
resulting in stimulation of the sympathetic nervous system (SNS) and RAAS3. 
Subsequent hyperaldosteronism causes sodium retention and contributes to volume 
accumulation in both cirrhosis and HF. High-doses of aldosterone antagonists 
(spironolactone up to 400 mg/day) is a standard therapy to achieve negative sodium 
balance in cirrhotic patients6. However, in HF a low-dose aldosterone antagonist 
(spironolactone 25 mg/day) is recommended since it was shown to decrease mortality 
through anti-fibrosis action. Of note, this low dose of spironolactone does not have 
natriuretic effect7. Given that severe neurohormonal activation and hyperaldosteronism 
as a result of heart failure and further enhanced by loop diuretic is the 
pathophysiological basis of sodium retention and loop diuretic resistance in patients 
with ADHF similar to cirrhotic patients, neutralizing the effects of aldosterone with 
natriuretic doses of aldosterone antagonists may be a potential option to treat these 
patients8. In this regard, in a small trial of 6 avidly sodium retaining patients with heart 
failure, spironolactone 200 mg BID caused a marked increase in sodium excretion and 
indeed led to sodium balance over a few days with a clinically negligible rise in serum 
potassium concentration9. In another study, 81% of the patients with severe heart 
failure, who were resistant to high-dose loop diuretics (10 mg of bumetanide) and 
captopril, responded with increased natriuresis with the use of 100 mg/day 
spironolactone10. 
 

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However, main issue with the use of spironolactone, especially along with the use of 
angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers 
(ARB), is the development of hyperkalemia. If used in conjunction with adequate doses 
of loop diuretics, the renal potassium retaining properties of aldosterone antagonists is 
counterbalanced by potassium-losing effect of loop diuretics by increasing the distal 
sodium delivery. Nonetheless, hyperkalemia is the most common reason for withdrawl 
for aldosterone antagonists. Patiromer, a nonabsorbed potassium binder, is a new FDA 
approved agent and has been shown to normalize serum potassium in patients with 
CKD and hyperkalemia on RAAS inhibitor in both outpatient as well inpatient setting. 
When given to hospitalized CKD patients with sustained modertate to severe 
hyperkalemia receiving at least one RAAS inhibitor while consuming a 60 mEq/day 
potassium diet in the controlled environment, single dose of patiromer caused a 
significant reduction in mean serum potassium by 7 hour. Mean serum potassium 
continued to decrease and after a second dose of patiromer fell to <5.5 mEq/l by 20 h. 
By 24 h, more than 80% of patients had a serum potassium <5.5 mEq/l. At 48 h, after 
four doses of patiromer, mean serum potassium had fallen by 0.75mEq/l, and more 
than 90% of patients had serum potassium values <5.5mEq/l. Over the entire study, 
mean serum potassium did not increase before the next dose of patiromer15. 
 
 
 
Item 5 
Study Population(s) Being Recruited 
 
In your recruitment plan, how many 
different populations of prospective 
subjects do you plan to target? 
Provide number:        
 
 
 
Identify the criteria for inclusion: 
 
 
Identify the criteria for exclusion: 
e.g., a population can be individuals 
with type 2 diabetes controlled with diet 
and/or a population of healthy controls.  
Or a population can be individuals 
attending an education program, etc. 
 
List each different population on a 
separate row and provide a short 
descriptive label:   
(e.g., normal-healthy, diabetics, 
parents, children, etc.) 
 
To add rows use copy & paste 
Insert response here 
1. Patients  18 years old  
2. Hospitalized with history of 
chronic heart failure and at 
least one symptom (dyspnea, 
orthopnea or edema) and one 
sign (rales, peripheral edema, 
ascites, 
or 
radiographic 
pulmonary edema or pleural 
effusion)  
3. Women of child bearing age 
with negative urine pregnancy 
test 
 
1. Acute coronary syndrome  
2. Patients with a baseline eGFR 
< 
30 
ml/min 
by 
MDRD 
equation 
3. Baseline 
potassium 
concentration ≥ 5.5 mEq/L 
4. Requirement for intravenous 
vasodilators 
or 
inotropic 
agents 
5. Systemic infection 
6. Patients 
with 
concomitant 
end-stage liver disease 
7. Hemodynamically 
significant 
uncorrected valvular disease  

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8. Patients 
with 
pulmonary 
embolism  
9. Patients with high output heart 
failure  
10. Pregnant patients 
 
Insert response here 
Insert response here 
Insert response here 
 
 
Item 6 
Research Plan / Description of the Research Methods a.  Provide a comprehensive narrative describing the research methods.   
Provide the plan for data analysis (include as applicable the sample size calculation). 
 
Step-by-Step Methods:  
Pre-screening: Patients meeting the inclusion and exclusion criteria will be approached to participate 
in the study. Informed consent will be taken at this time. These patients will receive intravenous loop 
diuretic per the discretion of treating physician and will be closely followed for weight loss and 
symptoms relief.  
 
Screening: The patients who don’t respond as measured by symptoms relief or <0.5 kg weight 
loss/day  
a) Despite furosemide ≥ 160 mg IV total daily dose or equivalent dose of torsemide or 
bumetanide. (1 mg bumetanide = 10 mg torsemide = 20 mg furosemide). OR 
b) After 48 hours irrespective of diuretic dose. 
 
will be considered for the study intervention. Patients who have not participated in the pre-screening 
phase and do not respond adequately to furosemide >160 mg iv daily dose will directly be enrolled 
into active intervention part of the study. 
 
Intervention (High-Dose Spironolactone + Patiromer): Patients will be initiated on spironolactone 
100 mg orally once daily along with patiromer 8.4 gm orally (if serum K >4.3 meq/L). The dose of loop 
diuretic will stay same during rest of the study period. On day 2, the dose of spironolactone will be 
titrated to 200 mg orally once a day depending on the diuretic response and lab results. Serum 
potassium and magnesium will be monitored twice a day. An EKG will be performed any time 
electrolytes are out of range.  The dose of patiromer will be increased to 16.8 gm in patients with 
potassium levels exceeding 5.5 meq/L; or it will be held for serum K <4.3 mEq/L. Treatment will 
continue till patients achieve euvolemia or get discharged. Euvolemia is defined as resolution of 
symptoms and signs of volume overload. 
 
Patients will be followed till achievement of euvolemia or discharge. Daily assessment will be done for 
symptoms, and signs of volume overload including shortness of breath, orthopnea, paroxysmal 
nocturnal dyspnea, abdominal bloating, lower extremity edema, JVD, and body weight changes.  
Serum chemistry will be assessed twice a day and urine electrolytes once a day. Neurohormonal 
analysis will be done at the pre-screening, and at the end of the study duration.  
 
Primary Safety measures:  
1) Incidence of hyperkalemia as defined by serum K >5.5 meq/day. 
2) Incidence of hypokalemia as defined by serum <3.5 meq/day 
3) Renal function: assessed by daily serum creatinine 
 
Primary Efficacy measures:  
1) Weight loss: using same calibrated scale every day in hospital gown. 
2) Symptom relief: assessed using a 5-point Likert scale describing magnitude of shortness of 
breath while the patient is in the supine position. 
 
Secondary Efficacy measures:  

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1) Urine sodium excretion: assessed by FENa% 
2) Urine Sodium/Potassium ratio as a biomarker of aldosterone activity 
 
 
Data Analysis Plan: This is a pilot exploratory study to assess safety and efficacy of high dose 
spironolactone with patiromer to find the sample size for large randomized study.  
A previous study utilizing combination of loop diuretics and high dose spironolactone had generated 
mean weight loss of 4.49±1.51 kg compared to 0.57±1.14 kg16. Given that this weight loss seems 
inflated, a mean weight loss of 2 ± 1.3 kg with two-sided t-testing, and a significance level of 5%, 
provides a power of 90% with 20 subjects [PASS Version 08.0.8, NCSS, Kaysville Utah 2008]. 
Assuming that loop diuretics resistance will be seen in 50% of the patients and there will be some lost 
to FU during active intervention period, we propose to pre-screen at least 300 subjects to enroll 60 
subjects with the goal to have at least 20-30 completers in active intervention arm.  
 
Item 7 Risks Section: 
Complete the following table to describe the risks of all research procedures listed in Step 2, Institutional Form (items 28-34).  Do not list risks of Routine care 
procedures here.  
 ☒ N/A, Risks are described in the informed consent document – do not complete this table. 
Research procedures 
 
example: 
• 
History and physical 
• 
Questionnaire 
• 
Laboratory tests 
 
Add or delete rows as needed 
Risks 
 
List the reasonably expected risks 
under the following categories as appropriate: 
Insert procedure here 
Serious and likely; 
o Insert risk here or enter "none" 
Serious and less likely; 
o Insert risk here or enter "none" 
Serious and rare; 
o Insert risk here or enter "none" 
Not serious and likely; 
o Insert risk here or enter "none" 
Not serious and less likely 
o Insert risk here or enter "none" 
Insert procedure here 
Serious and likely; 
o Insert risk here or enter "none" 
Serious and less likely; 
o Insert risk here or enter "none" 
Serious and rare; 
o Insert risk here or enter "none" 
Not serious and likely; 
o Insert risk here or enter "none" 
Not serious and less likely 
o Insert risk here or enter "none" 
Insert procedure here 
Serious and likely; 
o Insert risk here or enter "none" 
Serious and less likely; 
o Insert risk here or enter "none" 
Serious and rare; 
o Insert risk here or enter "none" 
Not serious and likely; 
o Insert risk here or enter "none" 
Not serious and less likely 
o Insert risk here or enter "none"