CLCNKA (Ka Renal Chloride Channel[ClC-Ka]) Polymorphism Effects on Hypertrophy Regression

The screening phase will involve identifying Caucasian hypertensive patients who are
homozygous for the ClC-Ka Gly/Gly83 and the ClC-Ka Arg/Arg 83 allele. All patients will be
on background therapy with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin
receptor blocker (ARB) at least mid range dosing. If patient is not at recommended dose of
ACE or ARB they must be titrated up and be stable on a midrange dose of ACEI or ARB for at
least 4 weeks before they can be entered into the study. There will be 2 treatment phases.
Phase 1 will be up to 4 weeks in duration and will consist of randomization to one table of
eplerenone (25 mg) or matching placebo. On week 2 the patient will be up titrated to two
tablets of eplerenone (50 mg) or matching placebo, to achieve a target dose of 50 mg of
eplerenone. If the patient cannot tolerate two tablets of eplerenone or matching placebo
they can be down titrated to one tablet of eplerenone or matching placebo. The target BP on
study medication is < 130/80 mmHg. After the patients have been up titrated to the
maximally tolerated dose of study medication, the background hypertension therapy can be
adjusted to reach the target BP of < 130/80 mmHg by the end of week 4. Phase 2 will be 52
weeks in duration to assess the effects of placebo or eplerenone on LV hypertrophy. Serum
potassium will be monitored throughout the study, and if necessary, doses of eplerenone will
be titrated down as necessary.

Inclusion Criteria:

1. Caucasians with hypertension who are homozygous for the ClC-Ka Gly/Gly83 and the
ClC-Ka Arg/Arg 83 allele.

2. Male or non-pregnant female aged 40 to 80 years.

3. Hypertension, defined as currently taking high blood pressure medications or not
on medications but having SDP >140 or DBP >90.

4. Ejection fraction > 50% by any method within 6 months of the screening visit.

5. The Investigator must obtain written informed consent before the subject is screened
for the study.

6. Subject should be on stable dose of ACE or ARB at moderate dosing for at least 4
weeks before randomization.

Exclusion Criteria:

1. History of heart failure with preserved or depressed ejection fraction.

2. Creatinine clearance of < 45 mL/min based on the Cockcroft-Gault formula (Appendix
C).

3. Pregnancy

4. Life expectancy less than 12 months.

5. Planned cardiac surgery or percutaneous cardiac intervention within 3 months.

6. Serum potassium >5.5 mEq/L.

7. History of hyperkalemia (K>6.0 mEq/L) with eplerenone or spironolactone.

8. Myocardial infarction or stroke within 3 months of screening.

9. Evidence of clinical instability (hypotension, arrhythmias, unstable angina etc.).

10. Subjects on or requiring K-sparing diuretics or spironolactone.

11. Concomitant use of potent inhibitors of CYP3A4 including ketoconazole, itraconazole,
nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir or any drug
noted in the Contraindications, Warnings or Precautions sections of their labeling to
be potent CYP3A4 inhibitors

12. Known hypersensitivity to eplerenone or spironolactone.

13. Evidence of current alcohol or drug abuse Severe organic disorders or surgery or
disease of the gastrointestinal tract that in the opinion of the Investigator may
interfere in the absorption and elimination of the study drug.

14. Psychoses or behavioral conditions that in the opinion of the Investigator would
limit study compliance.

15. Subjects who have received any investigational medication or used any investigational
device within 30 days prior to first dose of study drug or subjects actively
participating in any investigational drug or device study.