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Insufficient rate of patient enrollment/accrual.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metolazone Pre-dosing | Active Comparator | 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) |
|
| Metolazone Concurrent Dosing | Active Comparator | 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metolazone 60 minutes prior to furosemide | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 24-Hour Urine Output | Total measured urine output in milliliters produced after metolazone dose is given | 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Total Body Weight | Change in total body weight from baseline value measured prior to metolazone dose to value collected after metolazone dose | Baseline and at 12 to 23 hours after metolazone dose |
| Change in Serum Creatinine |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Brent Reed, PharmD | University of Maryland, College Park | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Maryland Medical Center | Baltimore | Maryland | 21201 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29141174 | Background | 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. | |
| 21029871 | Background | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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) 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. |
| FG001 | 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) 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 24-Hour Urine Output | Total measured urine output in milliliters produced after metolazone dose is given | Posted | Mean | Standard Deviation | mL | 24 hours |
|
24 hours after metolazone dose (no greater than 48 hours after enrollment)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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) 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment | Defined as an increase in serum creatinine by 0.3 mg/dL or more, or 50% or more from baseline |
This study was terminated early due to slow enrollment, resulting in an inadequate sample size.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Brent Reed | University of Maryland School of Pharmacy | 410-706-1452 | breed@rx.umaryland.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 14, 2018 | Sep 25, 2021 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D004487 | Edema |
| ID | Term |
|---|---|
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D008788 | Metolazone |
| D005665 | Furosemide |
| ID | Term |
|---|---|
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013450 | Sulfones |
| D013457 |
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Prospective, randomized, open-label, active control pilot study
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|
|
| Metolazone concurrently with furosemide | Drug | 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. |
|
|
Change in serum creatinine from baseline value collected prior to metolazone dose to value collected after metolazone dose
| Baseline and at 12 to 23 hours after metolazone dose |
| Acute Kidney Injury | Portion of patients with increase in serum creatinine by ≥ 0.3 mg/dL or ≥ 50% from baseline | Baseline and at 12 to 23 hours after metolazone dose |
| Hypokalemia | Proportion of patients with potassium level less than 4.0 mEq/L measured after metolazone dose is given | Baseline and at 12 to 23 hours after metolazone dose |
| Hypomagnesemia | Proportion of patients with magnesium level less than 2.0 mg/dL measured after metolazone dose is given | Baseline and at 12 to 23 hours after metolazone dose |
| Hyponatremia | Proportion of patients with serum sodium level less than 135 mg/dL measured after metolazone dose is given | Baseline and at 12 to 23 hours after metolazone dose |
| 3793436 | Background | 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. |
| 2014951 | Background | 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. |
| BG001 | 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) 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Left ventricular ejection fraction | Mean | Standard Deviation | % |
|
| Serum creatinine | Mean | Standard Deviation | mg/dL |
|
| Serum sodium | Mean | Standard Deviation | mmol/L |
|
| Systolic blood pressure | Mean | Standard Deviation | mm Hg |
|
| Total daily dose loop diuretic prior to admission (in oral furosemide equivalents) | Mean | Standard Deviation | mg/day |
|
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) 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. |
|
|
| Secondary | Change in Total Body Weight | Change in total body weight from baseline value measured prior to metolazone dose to value collected after metolazone dose | Posted | Mean | Standard Deviation | kg | Baseline and at 12 to 23 hours after metolazone dose |
|
|
|
| Secondary | Change in Serum Creatinine | Change in serum creatinine from baseline value collected prior to metolazone dose to value collected after metolazone dose | Posted | Mean | Standard Deviation | mg/dL | Baseline and at 12 to 23 hours after metolazone dose |
|
|
|
| Secondary | Acute Kidney Injury | Portion of patients with increase in serum creatinine by ≥ 0.3 mg/dL or ≥ 50% from baseline | Posted | Count of Participants | Participants | Baseline and at 12 to 23 hours after metolazone dose |
|
|
|
| Secondary | Hypokalemia | Proportion of patients with potassium level less than 4.0 mEq/L measured after metolazone dose is given | Posted | Count of Participants | Participants | Baseline and at 12 to 23 hours after metolazone dose |
|
|
|
| Secondary | Hypomagnesemia | Proportion of patients with magnesium level less than 2.0 mg/dL measured after metolazone dose is given | Posted | Count of Participants | Participants | Baseline and at 12 to 23 hours after metolazone dose |
|
|
|
| Secondary | Hyponatremia | Proportion of patients with serum sodium level less than 135 mg/dL measured after metolazone dose is given | Posted | Count of Participants | Participants | Baseline and at 12 to 23 hours after metolazone dose |
|
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|
| 0 |
| 1 |
| 0 |
| 1 |
| 1 |
| 1 |
| EG001 | 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) 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. | 0 | 2 | 0 | 2 | 1 | 2 |
|
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| Sulfur Compounds |
| D052999 | Quinazolinones |
| D011799 | Quinazolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D013424 | Sulfanilamides |
| D000814 | Aniline Compounds |
| D000588 | Amines |