Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure

Mineralocorticoid receptor antagonist (MRA) therapy is recommended in stable chronic
systolic heart failure (HF) and post-infarction HF patients for improving morbidity and
mortality. MRA therapy in AHF and in high doses is less well studied. The effectiveness and
safety of early high dose MRA therapy in AHF is supported by a single-blind study showing
lower risk of worsening renal function and need for loop diuretics, and improved congestion.
MRA therapy in AHF may improve outcomes by relieving congestion at higher doses through
their natriuretic property, in addition to preventing the deleterious effects of
exacerbation of neuro-hormonal activation by loop diuretics.

This randomized, double blind, placebo-controlled study of high-dose spironolactone vs.
placebo (for patients not receiving MRA at home) or low-dose spironolactone (for patients
already receiving low-dose spironolactone) in AHF, will enroll 360 participants at
approximately 30 clinical centers. After obtaining informed consent, subjects who fulfill
all the inclusion criteria and none of the exclusion criteria will be randomized.
Randomization will be performed by using procedures determined by the Coordinating Center
(CC).

- Patients receiving no MRA therapy at baseline will be randomized to receive either
spironolactone 100 mg or placebo daily for 96 hours.

- Patients already receiving low-dose spironolactone at baseline (12.5 mg or 25 mg daily)
will be randomized to 100 mg or 25 mg spironolactone daily for 96 hours.

Within 24 hours prior to randomization, all study participants will undergo:

- Medical History

- Review of medications including pre-hospital loop diuretics, MRA, and potassium doses

- Physical examination, vital signs and body weight

- Measurement of creatinine, blood urea nitrogen (BUN), and electrolytes

- Dyspnea Relief Assessments (7-point Likert and Visual Analog Scale)

- Serum pregnancy test for all women of childbearing potential

- Collection of samples for measurement of NT-proBNP levels (Core Lab)

Study drug will be initiated as follows:

- Patients receiving no MRA therapy at baseline: 4x25 mg study capsules once daily;
starting dose 100 mg spironolactone or placebo; if dose adjustment is required, active
capsules will be adjusted by pharmacy to achieve the required dose.

- Patients already receiving low-dose spironolactone at baseline: 4x25 mg study capsules
once daily; one capsule containing 25 mg spironolactone and 3x25 mg study capsules
containing spironolactone or placebo; if dose adjustment is required, active capsules
will be adjusted by pharmacy to achieve the required dose.

Patients will be followed every 24 hours following randomization through 96 hours. Study
drug will be administered daily for 96 hours. Study drug administration time is anchored to
time of randomization. Dose adjustments (continue, hold, stop) are permitted according to
serum K+ and renal function.

Assessment at 24 hours post randomization includes: Review of medications, body weight,
fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and
adverse events.

If the 24 hour assessment is also the day of discharge, include:

- Physical exam / Vital signs

- Dyspnea Relief (7-Point Likert and VAS) worksheets

- Biomarkers (NT-proBNP) (Core Lab)

Assessment at 48 hours post randomization includes: Review of medications, physical
exam/vital signs, body weight, fluid intake/urine output, Dyspnea Relief (7-Point Likert and
VAS) worksheets, creatinine, blood urea nitrogen (BUN), and electrolytes, biomarker levels
(NT-proBNP) by Core Lab.

Assessment at 72 hours post randomization includes: Review of medications, body weight,
fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and
adverse events.

If the 72 hour assessment is also the day of discharge, include:

- Physical exam / Vital signs

- Dyspnea Relief (7-Point Likert and VAS) worksheets

- Biomarkers (NT-proBNP) (Core Lab)

Assessment at 96 hours post randomization includes: Review of medications, physical
exam/vital signs, body weight, fluid intake/urine output, creatinine, blood urea nitrogen
(BUN), and electrolytes, Dyspnea Relief (7-Point Likert and VAS), and biomarker levels
(NT-proBNP) by Core Lab.

If patient is clinically euvolemic in less than 96 hours, the investigator may consider
changing loop diuretics to oral dose.

Study drug will be discontinued after 96 hours and further use of MRA will be left to the
treating physician's discretion.

Assessment at Discharge: If discharge occurs after the 96 hour assessment but prior to the
30 day follow-up telephone call,the following will be documented: Medication review
(prescribed medications at the time of discharge), body weight (if available), creatinine,
blood urea nitrogen (BUN), and electrolytes (if available), and adverse events.

Ejection fraction data will be obtained from echocardiogram within 6 months prior to
randomization. Those patients who do not have an echocardiogram recorded within this time
frame will get an echocardiogram, nuclear perfusion study, MRI, or MUGA performed prior to
the 96 hour in-hospital assessment to ascertain ejection fraction.

Follow-up Telephone Call at Day 30: All participants will be contacted by telephone at day
30 (+3 days) following randomization to assess tertiary endpoints, including medication use
and adverse events.

Follow-up Telephone Call at Day 60: All participants will be contacted by telephone at day
60 (+/-3 days) following randomization to assess vital status.

During the consent process, patients will be asked if interested in donating samples and
data for research purposes via a biorepository and/or genetic study. Based on site and IRB
preference, this optional part of the study may be incorporated into the main consent or may
be a separate consent and IRB application.

Inclusion Criteria:

- Male or female patient ≥21 years old

- Admitted to hospital for AHF with at least 1 symptom (dyspnea, orthopnea, or fatigue)
and 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular
congestion on chest radiography) of congestion

- Patient must be randomized within 24 hours of first IV diuretic dose administered for
the current episode of decompensation (regardless of where the diuretic was given
e.g. office, ED, ambulance, hospital etc.)

- Estimated GFR of ≥30 mL/min/1.73m2 determined by the MDRD equation

- Serum K+ ≤5.0 mmol/L at enrollment

- NT-proBNP ≥1000 pg/mL or BNP ≥250 pg/mL, measured within 24h from randomization

- Not on MRA or on low-dose spironolactone (12.5 mg or 25 mg daily) at baseline

Exclusion Criteria:

- Taking eplerenone or >25 mg spironolactone at baseline

- eGFR < 30 ml/min/1.73m2

- Serum K+ >5.0 mmol/L. If a repeat measurement within the enrollment window is <5.0,
the patient can be considered for inclusion.

- Systolic blood pressure <90 mmHg

- Hemodynamically significant arrhythmias or defibrillator shock within 1 week

- Acute coronary syndrome currently suspected or within the past 4 weeks

- Severe liver disease (ALT or AST >3 x normal, alkaline phosphatase or bilirubin >2x
normal)

- Active infection (current use of oral or IV antimicrobial agents)

- Active gastrointestinal bleeding

- Active malignancy other than non-melanoma skin cancers

- Current or planned mechanical circulatory support within 30 days

- Post cardiac transplant or listed for transplant and expected to receive one within
30 days

- Current inotrope use

- Complex congenital heart disease

- Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis,
constrictive pericarditis or tamponade

- Previous adverse reaction to MRAs

- Enrollment in another randomized clinical trial during index hospitalization