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

A Randomized, Double Blind Pilot Study Evaluating CLCNKA (Ka Renal Chloride Channel[ClC-Ka]) Polymorphism Effects on Hypertrophy Regression in Caucasian Hypertensive Patients Treated With Eplerenone

This study will consist of middle-aged Caucasian non-failing subjects with high blood pressure who are homozygous for a gene that confers increased risk of developing heart failure, the Glycine 83 variant of the Ka renal chloride channel (ClC-Ka Gly/Gly 83), or middle-aged Caucasian non-failing hypertensive subjects who lack the heart failure risk gene, the wild-type Arginine 83 Ka renal chloride channel (ClC-Ka Arg/Arg 83). Subjects on standard therapy for high blood pressure with an angiotensin converting inhibitor (ACEI) or angiotensin receptor blocker (ARB) will be randomized to additional treatment with eplerenone (an aldosterone antagonist) or placebo, and assessed for changes in echocardiographic left ventricular hypertrophy (LVMI). Secondary endpoints will assess left ventricular remodeling and other echocardiographic variables. The investigators hypothesize that subjects homozygous for the CLCNKA risk allele will have a greater response to eplerenone in terms of reductions in LVMI than those lacking the risk allele.

Study Overview

• Status: Withdrawn
• Conditions: Hypertension
• Intervention / Treatment: Drug: placebo; Drug: Eplerenone

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63108
      • Barnes Jewish Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1; Caucasian hypertensive patients who are homozygous for the ClC-Ka Gly/Gly83 allele	Drug: Eplerenone; Eplerenone 50 mg/day; Other Names: Inspra; aldosterone antagonist
Active Comparator: Arm 2; Caucasian hypertensive patients who are homozygous for ClC-Ka Arg/Arg 83 allele	Drug: Eplerenone; Eplerenone 50 mg/day; Other Names: Inspra; aldosterone antagonist
Placebo Comparator: Arm 3; Caucasian hypertensive patients who are homozygous for ClC-Ka Arg/Arg 83 allele	Drug: placebo; placebo
Placebo Comparator: Arm 4; Caucasian hypertensive patients who are homozygous for the ClC-Ka Gly/Gly83 allele	Drug: placebo; placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in LV mass index (g/m2) in ClC-Ka Gly/Gly83 patients and ClC-Ka Gly/Gly83 patients	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in LV relative wall thickness	6 and 12 months
Change in N-terminal pro-brain natriuretic peptide (NT-proBNP)	6 and 12 months
Change in LV mass index (g/m2)	6 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: University of Pennsylvania
• Investigators: Principal Investigator: Thomas Cappola, MD, University of Pennsylvania; Principal Investigator: Gerald Dorn, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Anticipated): December 1, 2014
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: January 10, 2011
• First Submitted That Met QC Criteria: January 11, 2011
• First Posted (Estimate): January 12, 2011

Study Record Updates

• Last Update Posted (Estimate): June 3, 2015
• Last Update Submitted That Met QC Criteria: June 1, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: heart failure; left ventricular hypertrophy
• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Hypertrophy; Physiological Effects of Drugs; Antihypertensive Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Diuretics, Potassium Sparing; Mineralocorticoid Receptor Antagonists; Eplerenone
• Other Study ID Numbers: CLNCKA-1