Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing

• ClinicalTrials.gov Identifier: NCT03746002
• Recruitment Status: Terminated
• First Posted: November 19, 2018
• Results First Posted: October 22, 2021
• Last Update Posted: October 22, 2021
• Sponsor: University of Maryland, Baltimore
• Information provided by (Responsible Party): Brent Reed, University of Maryland, Baltimore

Study Description

Brief Summary:

The purpose of this study is to examine whether administering metolazone 60 minutes prior to furosemide increases urine output compared with administering metolazone and furosemide concomitantly. Participants will have equal chance of being assigned to each group.

Condition or disease	Intervention/treatment	Phase
Fluid Overload; Heart Failure Acute	Drug: Metolazone 60 minutes prior to furosemide; Drug: Metolazone concurrently with furosemide	Phase 4

Detailed Description:

Diuretic resistance is common among patients with acute decompensated heart failure, and one strategy for overcoming this phenomenon is sequential nephron blockade with loop plus thiazide-type diuretics. Metolazone is an oral thiazide-type diuretic commonly used for this purpose. Due to its delayed absorption, some clinicians suggest that metolazone be given 30-60 minutes prior to the loop diuretic. However, the efficacy and safety of such a strategy has not been investigated despite its added complexity. The purpose of this study is to investigate whether pre-dosing with metolazone confers a difference in efficacy and safety compared to administering it at the same time as furosemide.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective, randomized, open-label, active control pilot study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Diuretic Effect of Metolazone Pre-dosing Versus Concurrent Dosing With Furosemide: a Pilot Study
• Actual Study Start Date: January 1, 2019
• Actual Primary Completion Date: January 10, 2020
• Actual Study Completion Date: January 10, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Metolazone Pre-dosing; Metolazone 5 mg by mouth administered 60 minutes prior to furosemide background therapy (120 - 160 mg intravenous bolus, followed by furosemide 120 - 160 mg intravenous bolus 12 - 24 hours after)	Drug: Metolazone 60 minutes prior to furosemide; All patients will receive furosemide background therapy (furosemide 120 - 160 mg IV bolus dosed twice within a twenty four hour period. Patients will be randomized 1:1 to either metolazone 5 mg tablet dosed 60 minutes prior to first dose of furosemide or metolazone dosed concurrently (within ten minute time frame) with the first dose of furosemide.; Other Name: Zaroxolyn
Active Comparator: Metolazone Concurrent Dosing; Metolazone 5 mg by mouth administered at the same time as furosemide background therapy (120 - 160 mg intravenous bolus, followed by furosemide 120 - 160 mg intravenous bolus 12 - 24 hours after)	Drug: Metolazone concurrently with furosemide; All patients will receive furosemide background therapy (furosemide 120 - 160 mg IV bolus dosed twice within a twenty four hour period. Patients will be randomized 1:1 to either metolazone 5 mg tablet dosed 60 minutes prior to first dose of furosemide or metolazone dosed concurrently (within ten minute time frame) with the first dose of furosemide.; Other Name: Zaroxolyn

Outcome Measures

Primary Outcome Measures :

1. 24-Hour Urine Output [ Time Frame: 24 hours ]
   Total measured urine output in milliliters produced after metolazone dose is given

Secondary Outcome Measures :

1. Change in Total Body Weight [ Time Frame: Baseline and at 12 to 23 hours after metolazone dose ]
   Change in total body weight from baseline value measured prior to metolazone dose to value collected after metolazone dose
2. Change in Serum Creatinine [ Time Frame: Baseline and at 12 to 23 hours after metolazone dose ]
   Change in serum creatinine from baseline value collected prior to metolazone dose to value collected after metolazone dose
3. Acute Kidney Injury [ Time Frame: Baseline and at 12 to 23 hours after metolazone dose ]
   Portion of patients with increase in serum creatinine by ≥ 0.3 mg/dL or ≥ 50% from baseline
4. Hypokalemia [ Time Frame: Baseline and at 12 to 23 hours after metolazone dose ]
   Proportion of patients with potassium level less than 4.0 mEq/L measured after metolazone dose is given
5. Hypomagnesemia [ Time Frame: Baseline and at 12 to 23 hours after metolazone dose ]
   Proportion of patients with magnesium level less than 2.0 mg/dL measured after metolazone dose is given
6. Hyponatremia [ Time Frame: Baseline and at 12 to 23 hours after metolazone dose ]
   Proportion of patients with serum sodium level less than 135 mg/dL measured after metolazone dose is given

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 89 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Admission within 48 hours for acute decompensated heart failure with at least one symptom and one sign of volume overload
• Receipt of loop diuretic prior to admission
• Plan to administer furosemide 120 - 160 mg IV bolus twice daily over the next 24 hours with additional diuresis deemed necessary
• If patient is concurrently administered intravenous vasodilator or inotrope, the dose of vasodilator or inotrope must be stable for 6 hours prior to enrollment with a plan to continue the same dose for the 24 hour duration of this study

Exclusion Criteria:

• Metolazone prescribed prior to admission
• Receipt of continuous intravenous infusion of furosemide
• Cirrhosis or end stage renal disease
• Non-English speaking patients

Contacts and Locations

Locations

United States, Maryland

University of Maryland Medical Center

Baltimore, Maryland, United States, 21201

Sponsors and Collaborators

University of Maryland, Baltimore

Investigators

• Principal Investigator: Brent Reed, PharmD; University of Maryland, College Park

  Study Documents (Full-Text)

Documents provided by Brent Reed, University of Maryland, Baltimore:

Study Protocol and Statistical Analysis Plan  [PDF] August 14, 2018

More Information

Publications:

Ellison DH, Felker GM. Diuretic Treatment in Heart Failure. N Engl J Med. 2017 Nov 16;377(20):1964-1975. doi: 10.1056/NEJMra1703100. No abstract available. Erratum In: N Engl J Med. 2018 Feb 1;378(5):492.

Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010 Nov 2;56(19):1527-34. doi: 10.1016/j.jacc.2010.06.034.

Grosskopf I, Rabinovitz M, Rosenfeld JB. Combination of furosemide and metolazone in the treatment of severe congestive heart failure. Isr J Med Sci. 1986 Nov;22(11):787-90.

Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med. 1991 May 15;114(10):886-94. doi: 10.7326/0003-4819-114-10-886.

• Responsible Party: Brent Reed, Associate Professor, Pharmacy Practice and Science, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT03746002
• Other Study ID Numbers: HP-00082982
• First Posted: November 19, 2018
• Results First Posted: October 22, 2021
• Last Update Posted: October 22, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Brent Reed, University of Maryland, Baltimore:

diuretic; metolazone; furosemide

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Metolazone; Furosemide; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Sodium Potassium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Sodium Chloride Symporter Inhibitors