EWISE: Study of Eplerenone in Women With Chest Pain, Coronary Vascular Dysfunction and Evidence of Myocardial Ischemia

INDICATION: Coronary Vascular Dysfunction (Endothelial Dysfunction and/or Microvascular
angina).

OBJECTIVES: To investigate effects of aldosterone blockade (eplerenone) on coronary vascular
function.

PATIENT POPULATION: Women who meet the National Heart, Lung and Blood Institute-sponsored
WISE (Women Ischemia Syndrome Evaluation) study criteria of chest discomfort, coronary
vascular dysfunction and undergoing evaluation for myocardial ischemia in the absence of
significant coronary artery stenosis.

STUDY DESIGN: A prospective, randomized, double blind placebo-controlled, comparative trial
of eplerenone, given in the presence of a renin-angiotensin blocker (ACE-I or ARB in the case
of ACE-I intolerance).

TREATMENT: Eplerenone 25mg titrated to 50mg as tolerated per day versus placebo for four
months

PRIMARY EFFICACY PARAMETER(S): Epicardial coronary artery endothelial function at Week 16
(adjusted for baseline treatment group and site by treatment interaction variables) comparing
the eplerenone group to the placebo group.

SECONDARY EFFICACY PARAMETERS: Microvascular coronary endothelial function at Week 16
(adjusted for baseline treatment group and site by treatment interaction variables) comparing
the eplerenone group to the placebo group.

OTHER EFFICACY PARAMETERS:

- Coronary flow reserve

- Chest discomfort as measured by the Seattle Angina Questionnaire

- DASI

SAFETY PARAMETERS: Blood pressure, pulse rate and frequency and occurrence of adverse events.
The latter will include serum K and Creatinine.

STATISTICAL RATIONALE AND ANALYSIS: A statistical rationale for the number of patients in the
study has been provided. Interim analyses are planned after 10 patients have completed
treatment in each group.

ANTICIPATED TOTAL NUMBER OF PATIENTS: 50 (25 per treatment group).

ANTICIPATED NUMBER OF PATIENTS AT EACH SITE: Approximately 13.

PARTICIPATING SITES: University of Florida (Carl Pepine, MD), Emory University (Arshed
Quyyumi, MD), Rhode Island Hospital (Barry Sharaf, MD), and Mayo Clinic (Amir Lerman, MD).
There is an existing relationship between the first 3 sites and the Mayo Clinic site is
familiar with all necessary protocol procedures and is anxious to participate. The University
of Florida will serve as the main contracting site.

Inclusion Criteria:

- Non-pregnant women with chest discomfort who are 21 to 75 years of age and from
diverse racial/ethnic groups.

- Suspected ischemic heart disease (IHD) but no severe coronary stenosis (> 50% diameter
reduction) on coronary angiography used to qualify for WISE.

- Endothelial dysfunction, defined as failure to dilate to intracoronary acetylcholine
(< 5% increase in mean lumen diameter).

- If possible, patients should be taking stable, maximally tolerated dose of either an
angiotensin-converting enzyme inhibitor [ACEI] (or an angiotensin II receptor blocker
[ARB] if ACEI intolerant)

Exclusion Criteria:

- Women who are breast-feeding or who are pregnant. Women of childbearing potential may
be enrolled but must agree not to become pregnant during the course of the study and
must practice a method of birth control considered reliable by the investigator. If
established on hormonal contraceptives for more than 3 months, patients will be
allowed to participate provided that this therapy remains constant throughout the
study. If a patient becomes pregnant or begins breast-feeding during the study, she
must be withdrawn immediately.

- Acute ischemic syndrome defined as acute myocardial infarction [MI] (by enzyme or
electrocardiogram [ECG] criteria) or unstable angina within 1 month of entry.

- Uncontrolled moderate hypertension: sitting blood pressure > 160/95mmHg with
measurements recorded on at least 2 occasions (for blood pressure control patients
must first be stabilized, preferably with a diuretic, and remain on that dosing
regimen throughout participation in the study).

- Severe heart failure defined as New York Heart Association (NYHA) Class III or IV on
treatment.

- Coronary revascularization by either coronary artery bypass grafting (CABG) or
percutaneous transluminal coronary angioplasty (PTCA) or stent placement.

- Conditions likely to influence outcomes independent of IHD: severe lung, renal
(creatinine >1.8 or creatinine clearance [CrCl] ≤ 50ml/min) or hepatic disease;
surgically uncorrected significant congenital or valvular heart disease; and other
diseases likely to be fatal or require frequent hospitalizations within the next six
months.

- Adherence or retention reasons: recent alcoholism or drug abuse; psychiatric illness
including severe depression; dementia; active participation in any other research
trial other than WISE; or unwilling to complete follow-up evaluations including repeat
testing.

- Hypersensitivity to any medications to be used in the study

- Documented obstructive hypertrophic cardiomyopathy.

- Aortic stenosis (valve area < 1.5cm).

- Left ventricular (LV) dysfunction (ejection fraction <= 35%).

- History of significant cocaine or amphetamine abuse.

- Serum potassium > 5.0meq/l at baseline

- Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone,
troleandomycin, clarithromycin, ritonavir, nelfinavir)

- Intolerance to ACEI and ARB medications

- Use of potassium supplements or potassium sparing diuretics