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

Primary Purpose

Hypertension

Status

Withdrawn

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Eplerenone

placebo

About this trial

This is an interventional treatment trial for Hypertension focused on measuring left ventricular hypertrophy, heart failure

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Caucasians with hypertension who are homozygous for the ClC-Ka Gly/Gly83 and the ClC-Ka Arg/Arg 83 allele.
Male or non-pregnant female aged 40 to 80 years.
Hypertension, defined as currently taking high blood pressure medications or not on medications but having SDP >140 or DBP >90.
Ejection fraction > 50% by any method within 6 months of the screening visit.
The Investigator must obtain written informed consent before the subject is screened for the study.
Subject should be on stable dose of ACE or ARB at moderate dosing for at least 4 weeks before randomization.

Exclusion Criteria:

History of heart failure with preserved or depressed ejection fraction.
Creatinine clearance of < 45 mL/min based on the Cockcroft-Gault formula (Appendix C).
Pregnancy
Life expectancy less than 12 months.
Planned cardiac surgery or percutaneous cardiac intervention within 3 months.
Serum potassium >5.5 mEq/L.
History of hyperkalemia (K>6.0 mEq/L) with eplerenone or spironolactone.
Myocardial infarction or stroke within 3 months of screening.
Evidence of clinical instability (hypotension, arrhythmias, unstable angina etc.).
Subjects on or requiring K-sparing diuretics or spironolactone.
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
Known hypersensitivity to eplerenone or spironolactone.
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.
Psychoses or behavioral conditions that in the opinion of the Investigator would limit study compliance.
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.

Sites / Locations

Barnes Jewish Hospital
Hospital of the University of Pennsylvania

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Arm 1

Arm 2

Arm 3

Arm 4

Arm Description

Caucasian hypertensive patients who are homozygous for the ClC-Ka Gly/Gly83 allele

Caucasian hypertensive patients who are homozygous for ClC-Ka Arg/Arg 83 allele

Caucasian hypertensive patients who are homozygous for the ClC-Ka Gly/Gly83 allele

Outcomes

Primary Outcome Measures

Change in LV mass index (g/m2) in ClC-Ka Gly/Gly83 patients and ClC-Ka Gly/Gly83 patients

Secondary Outcome Measures

Change in LV relative wall thickness

Change in N-terminal pro-brain natriuretic peptide (NT-proBNP)

Change in LV mass index (g/m2)

Full Information

NCT ID

NCT01275352

First Posted

January 10, 2011

Last Updated

June 1, 2015

Sponsor

Washington University School of Medicine

Collaborators

University of Pennsylvania

1. Study Identification

Unique Protocol Identification Number

NCT01275352

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2015

Overall Recruitment Status

Withdrawn

Why Stopped

Lack of funding

Study Start Date

December 2011 (undefined)

Primary Completion Date

December 2014 (Anticipated)

Study Completion Date

June 2015 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Washington University School of Medicine

Collaborators

University of Pennsylvania

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension

Keywords

left ventricular hypertrophy, heart failure

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Factorial Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1

Arm Type

Active Comparator

Arm Description

Caucasian hypertensive patients who are homozygous for the ClC-Ka Gly/Gly83 allele

Arm Title

Arm 2

Arm Type

Active Comparator

Arm Description

Caucasian hypertensive patients who are homozygous for ClC-Ka Arg/Arg 83 allele

Arm Title

Arm 3

Arm Type

Placebo Comparator

Arm Description

Caucasian hypertensive patients who are homozygous for ClC-Ka Arg/Arg 83 allele

Arm Title

Arm 4

Arm Type

Placebo Comparator

Arm Description

Caucasian hypertensive patients who are homozygous for the ClC-Ka Gly/Gly83 allele

Intervention Type

Drug

Intervention Name(s)

Eplerenone

Other Intervention Name(s)

Inspra, aldosterone antagonist

Intervention Description

Eplerenone 50 mg/day

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

placebo

Primary Outcome Measure Information:

Title

Change in LV mass index (g/m2) in ClC-Ka Gly/Gly83 patients and ClC-Ka Gly/Gly83 patients

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Change in LV relative wall thickness

Time Frame

6 and 12 months

Title

Change in N-terminal pro-brain natriuretic peptide (NT-proBNP)

Time Frame

6 and 12 months

Title

Change in LV mass index (g/m2)

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Caucasians with hypertension who are homozygous for the ClC-Ka Gly/Gly83 and the ClC-Ka Arg/Arg 83 allele. Male or non-pregnant female aged 40 to 80 years. Hypertension, defined as currently taking high blood pressure medications or not on medications but having SDP >140 or DBP >90. Ejection fraction > 50% by any method within 6 months of the screening visit. The Investigator must obtain written informed consent before the subject is screened for the study. Subject should be on stable dose of ACE or ARB at moderate dosing for at least 4 weeks before randomization. Exclusion Criteria: History of heart failure with preserved or depressed ejection fraction. Creatinine clearance of < 45 mL/min based on the Cockcroft-Gault formula (Appendix C). Pregnancy Life expectancy less than 12 months. Planned cardiac surgery or percutaneous cardiac intervention within 3 months. Serum potassium >5.5 mEq/L. History of hyperkalemia (K>6.0 mEq/L) with eplerenone or spironolactone. Myocardial infarction or stroke within 3 months of screening. Evidence of clinical instability (hypotension, arrhythmias, unstable angina etc.). Subjects on or requiring K-sparing diuretics or spironolactone. 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 Known hypersensitivity to eplerenone or spironolactone. 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. Psychoses or behavioral conditions that in the opinion of the Investigator would limit study compliance. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Thomas Cappola, MD

Organizational Affiliation

University of Pennsylvania

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Gerald Dorn, MD

Organizational Affiliation

Washington University School of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Barnes Jewish Hospital

City

St. Louis

State/Province

Missouri

ZIP/Postal Code

63108

Country

United States

Facility Name

Hospital of the University of Pennsylvania

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

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