Official Title: “A Comparison of Hydrochlorothiazide and Metolazone in Combination With Furosemide in Congestive Heart Failure Patients”

The purpose of this research study is to compare the effectiveness of hydrochlorothiazide or metolazone in combination with furosemide. Patients with heart failure suffer from swelling because of too much fluid in the body. Furosemide, hydrochlorothiazide, and metolazone are all water pills used to treat the swelling. For most patients, taking furosemide alone is successful. However, sometimes patients need to add another water pill. Doctors usually add either metolazone or hydrochlorothiazide. It is not clear which water pill is better when added to furosemide. The purpose of this study is to determine which water pill when added to furosemide is the best at reducing excess fluid in the body.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Crossover Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2009

Objective: To establish which combination of diuretics is the most effective in promoting diuresis in congestive heart failure patients. Secondary Objectives: To determine the duration of action of furosemide as monotherapy and in combination with either hydrochlorothiazide or metolazone. To determine the effect of diuretic combination therapy on neurohormonal activation. Background: Diuretic resistance occurs when a potent diuretic drug, such as furosemide, is given in therapeutic doses and fails to reduce extracellular fluid volume to the desired level in an edematous patient. Studies have shown that metolazone and hydrochlorothiazide have demonstrated a synergistic response when used in combination with furosemide in congestive heart failure patients. The current guidelines for treating diuretic resistance in congestive heart failure patients recommend the metolazone-furosemide combination. However, there is no evidence to conclude that this combination is superior to hydrochlorothiazide-furosemide in increasing diuresis. Methods:

Randomized, double-blind, crossover study to compare the efficacy of hydrochlorothiazide and metolazone in combination with stable doses of furosemide in 13 patients with congestive heart failure. The primary endpoint will be change in urinary output. Secondary endpoints will be changes in weight, neurohormones (angiotensin II, catecholamines, brain natriuretic peptide, aldosterone), and electrocardiographic parameters of ventricular instability. Study procedures will be performed at the UNM General Clinical Research Center. Patients will be hospitalized for 2 separate 4-day admissions, separated by a 1-week washout period. At each admission each patient will receive furosemide in combination with either metolazone or hydrochlorothiazide (metolazone for one admission and hydrochlorothiazide for the other).

Following administration of combination therapy, blood and urine samples will be collected throughout the day to chart the onset and magnitude of effect of each treatment regimen.

Various hemodynamic, renal, endocrine, and neurohormonal parameters will be assesed as will the effect of each combination treatment on ventricular instability using 12-lead electrocardiography. Data will be analyzed using ANOVA to compare changes from baseline and the Student t-test to analyze intertreatment differences.

All statistical analysis will be performed using SAS v6.12.

Intervention(s) in this Clinical Trial

• Drug: metolazone or hydrochlorothiazide
  • The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Patients will be randomized to receive either metolazone or HCTZ in a randomized, double-blind, placebo controlled crossover trial. The patients will receive the alternative medication if The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.
• Active Comparator: 2
  • Patients will be randomized to receive either metolazone or HCTZ in a randomized, double-blind, placebo controlled crossover trial. The patients will receive the alternative medication if The specific dose of hydrochlorothiazide will be determined by the individual's creatinine clearance. A creatinine clearance of 30-50 mL/min will indicate a dose of 50 mg per day. A creatinine clearance of > 50 mL/min will indicate a dose of 25 mg per day.5 If metolazone is added to their regimen, the specific dose will be determined using the equivalence ratio of 5 mg metolazone to 50 mg hydrochlorothiazide.

Primary Measures

• The primary endpoint will be change in urinary output.
  • Time Frame: 4 days
    Safety Issue?: No

Secondary Measures

• Secondary endpoints will be changes in weight, neurohormones (angiotensin II, catecholamines, brain natriuretic peptide, aldosterone), and electrocardiographic parameters of ventricular instability.
  • Time Frame: 4 days
    Safety Issue?: Yes

Inclusion Criteria:

• Age >18 years
• Diagnosis of chronic congestive heart failure with an ejection fraction ≤45%
• Currently on a stable regimen of furosemide consisting of a daily dose of at least 80 mg for at least two weeks.
• Patients receiving ACE-inhibitors and/or beta-blockers must be taking these medications for at least two weeks in stable doses.

Exclusion Criteria:

• Renal dysfunction (serum creatinine >2 mg/dl or creatinine clearance of <30 ml/min as calculated by the Cockroft and Gault equation)
• Hepatic dysfunction (AST and ALT >3 times the upper limit of the normal)
• Hypokalemia (<4.0 mg/dl)
• Concomitant treatment with any diuretic other than furosemide (with the exception of spironolactone).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of New Mexico

Overall Clinical Trial Officials and Contacts

Overall Contact: Joe R. Anderson, PharmD 505-272-3664 janderson@salud.unm.edu

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00690521

Study ID Number: HRRC 03-477

ClinicalTrials.gov Identifier: NCT00690521

Health Authority: United States: Institutional Review Board