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Limited resources available to met accrual goal.
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The primary objective of the study is to determine efficacy of metolazone as synergistic therapy with Lasix in patients with acute decompensated heart failure. This will be a single center double blinded randomized placebo- controlled pilot study of the addition of 5 mg of metolazone per day for 2 days compared to placebo in patients admitted with acute decompensated heart failure.
Heart failure is a major source of morbidity, mortality and growing public health cost. In US, the number of congestive heart failure patients is more than 4 million with more than 550,000 new annually reported cases. The annual cost of heart failure management exceeds 35 billion dollars per year.The heart failure readmissions and average length of hospital stay cost approximately $11,000 per patient.
Loop diuretics are used alone in the majority of cases to promote diuresis. An association of increased creatinine and increased risk of renal dysfunction, the cardiorenal syndrome, in the face of high dose loop diuretics has raised questions regarding the safety and toxicity of high dose loop diuretics. While the dose of diuretics is ubiquitous, little data exists to guide their use and many clinicians are uncertain as to when and how to initiate and limit therapy.
Prospective randomized data on large number of decompensated heart failure patients receiving metolazone in addition to standard therapy is scarce and needs further definitive evaluation in terms of clinical outcomes and safety. In many cases, a "stepped approach" with oral loop diuretics advancing to intravenous and finally combination high dose diuretics is employed.
Primary endpoint: Total urinary output and negative fluid balance in millilitres (ml) at 48 hours following first dose of intravenous diuretic.
Secondary endpoints:
This is a single center study of at least 200 patients who are admitted to Aultman Hospital with clinical decompensated congestive heart failure ( NYHA III-IV). It is a double blinded randomized placebo- controlled pilot study of the addition of 5 mg of metolazone per day for 2 days compared to placebo in patients admitted with acute decompensated heart failure. We will compare a strategy of early institution of metolazone with standard of care in patients admitted with decompensated heart failure and volume overload. All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician.
After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. Two additional doses of metolazone within 6 and 24 hours of administration of standard intravenous diuretics will be given to the treatment arm. Patients and physicians will be blinded to the administered drug (metolazone vs placebo).Drug will be distributed by pharmacy when a patient is consented and enrolled in the trial. Specific guidance/recommendations regarding diuretic therapy will be provided (documented in detail below) but will be at the discretion of the treating physician. We will collect data on demographics, co-morbidities, clinical presentations and outcomes with metolazone administration with patient follow up at one week (+3) and 30 (±7) days post discharge.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental: Placebo | Placebo Comparator | This group will receive all standard heart failure therapy and placebo pill. |
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| Experimental: Metolazone | Active Comparator | This group will receive all standard heart failure therapy with addition of metolazone. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Experimental: Placebo | Drug | All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first placebo dose is given within six hours of admininstration of first dose of intravenous diuretic. The second placebo dose is given at 24-hours after the first dose. |
| Measure | Description | Time Frame |
|---|---|---|
| Total Urinary Output at 48 Hours | Total urinary output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later. | 48 hours |
| Fluid Balance at 48 Hours | Difference in value between input and output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later. Fluid balance = Fluid in minus Fluid out. | 48 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Weight First 48 Hours | Change in weight from the date/time of study enrollment (baseline) and 48 hours. | 48 hours |
| Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | Dyspnea assessed at 6, 12, 24, 36 and 48 hours with Modified Borg Scale (1-10). Range is from 1 (very slight) to 10 (maximal) dyspnea. |
| Measure | Description | Time Frame |
|---|---|---|
| Length of Hospital Stay | Length of hospital stay in days | Inpatient Hospitalization |
| All Cause Readmission Within 30 Days | All Cause Readmission Within 30 Days |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Muhammad Chaudhry, MD | Aultman Health Foundation | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aultman Health Foundation | Canton | Ohio | 44710 | United States |
Participants who signed consent but after further evaluation did not to meet inclusion or met one or more exclusion criteria were not included in the analysis. There were four screen failures following consent.
147 participants from one local institution (inpatient hospital) were enrolled between October 2015 and November 2017
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental: Placebo | This group will receive all standard heart failure therapy and placebo pill. Experimental: Placebo: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first placebo dose is given within six hours of admininstration of first dose of intravenous diuretic. The second placebo dose is given at 24-hours after the first dose. |
| FG001 | Experimental: Metolazone | This group will receive all standard heart failure therapy with addition of metolazone. Experimental: Metolazone: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first dose of metolazone is given within six hours of admininstration of first dose of intravenous diuretic The second dose of metolazone is given 24-hours after the first dose. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Per protocol only participants who receive both doses of investigational product are analyzed
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| ID | Title | Description |
|---|---|---|
| BG000 | Experimental: Placebo | This group will receive all standard heart failure therapy and placebo pill. Experimental: Placebo: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first placebo dose is given within six hours of admininstration of first dose of intravenous diuretic. The second placebo dose is given at 24-hours after the first dose. |
| Units | Counts |
|---|---|
| Participants |
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| 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 | Total Urinary Output at 48 Hours | Total urinary output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later. | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Mean | Standard Deviation | Milliliters | 48 hours |
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Serious and non-serious adverse effects will be collected for the first 48 hours following enrollment in the MELT trial. No other adverse events are reported unless deemed to related to the study by the Principal Investigator. All cause mortality was assessed and reported for all patients at the 30 day timepoint following study enrollment. Study design did not require collection of mortality data past the 30 day timepoint.
Non-serious adverse effects collected were: Hypotension requiring intervention, electrolyte imbalance requiring intervention and acute kidney injury defined as 30% rise in creatinine over baseline. Per study design All-Cause Mortality, Serious Adverse Events and Non-Serious adverse events reporting include all subjects who received at least one dose of study drug per. Note: Per protocol only patients receiving both doses of study drug were included in primary and secondary measures analysis.
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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 | Experimental: Placebo | This group will receive all standard heart failure therapy and placebo pill. Experimental: Placebo: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first placebo dose is given within six hours of admininstration of first dose of intravenous diuretic. The second placebo dose is given at 24-hours after the first dose. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension Requiring Intervention | Cardiac disorders | Non-systematic Assessment | Hypotension Requiring Intervention defined as MAP less than 55 |
Recruitment ended early due to limited resources,however all protocol directed measures were completed for all enrolled. I&O was measured and recorded manually which introduces room for error.BORG assessment timing not exact due to limited resources.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director of Research Programs | Aultman Hospital | 330-363-7274 | mary.amos@aultman.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 17, 2017 | Dec 5, 2018 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Dec 4, 2018 | Dec 5, 2018 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| Experimental: Metolazone | Drug | All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first dose of metolazone is given within six hours of admininstration of first dose of intravenous diuretic The second dose of metolazone is given 24-hours after the first dose. |
|
| 6, 12, 24, 36 and 48 hours. |
| Total Dose Diuretics First 48 Hours | Total dosage loop diuretic in first 48 hours using conversion tool to calculate intravenous Lasix equivalence | 48 hours |
| Number of Participants With Inotrope Administration During First 48 Hours | Number of Participants with Inotrope administration during first 48 hours following study enrollment. | 48 hours |
| All Cause Mortality at 30 Days | All Cause Mortality at 30 Days | 30 Days |
| 30 Days |
| Heart Failure Readmission Within 30 Days | Heart Failure Readmission Within 30 Days | 30 Days |
| Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement | Severe electrolyte abnormalities requiring aggressive replacement defined as potassium levels less than 3.0 meq/L during the study. | 48 Hours |
| Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement | Number of Participants with severe electrolyte abnormalities requiring aggressive replacement defined as magnesium levels less than 1.5 meq/L during the study. | 48 Hours |
| Drug shortage prevented 2nd dose |
|
| BG001 | Experimental: Metolazone | This group will receive all standard heart failure therapy with addition of metolazone. Experimental: Metolazone: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first dose of metolazone is given within six hours of admininstration of first dose of intravenous diuretic The second dose of metolazone is given 24-hours after the first dose. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| NYHA Class at Enrollment | Class I: Patients with cardiac disease but no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II (Mild) Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in above symptoms Class III (Moderate) Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes above symptoms. Class IV (Severe) Inability to carry on any physical activity without symptoms, may be present at rest. | Number | participants |
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| N-Terminal proBNP Value Upon Admission | Mean | Standard Deviation | pg/mL |
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| Time Difference Qualifying Diuretic and Study Drug Initiation | Time difference between the first diuretic administered following presentation (Qualifying Diuretic) and the first dose of Study Drug | Mean | Standard Deviation | minutes |
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| OG001 | Experimental: Metolazone | This group will receive all standard heart failure therapy with addition of metolazone. Experimental: Metolazone: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first dose of metolazone is given within six hours of admininstration of first dose of intravenous diuretic The second dose of metolazone is given 24-hours after the first dose. |
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| Primary | Fluid Balance at 48 Hours | Difference in value between input and output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later. Fluid balance = Fluid in minus Fluid out. | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Mean | Standard Deviation | Mililiters | 48 hours |
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| Secondary | Change in Weight First 48 Hours | Change in weight from the date/time of study enrollment (baseline) and 48 hours. | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Mean | Standard Deviation | killograms | 48 hours |
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| Secondary | Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. | Dyspnea assessed at 6, 12, 24, 36 and 48 hours with Modified Borg Scale (1-10). Range is from 1 (very slight) to 10 (maximal) dyspnea. | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Mean | Standard Deviation | score on a scale | 6, 12, 24, 36 and 48 hours. |
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| Secondary | Total Dose Diuretics First 48 Hours | Total dosage loop diuretic in first 48 hours using conversion tool to calculate intravenous Lasix equivalence | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Mean | Standard Deviation | Milligrams | 48 hours |
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| Secondary | Number of Participants With Inotrope Administration During First 48 Hours | Number of Participants with Inotrope administration during first 48 hours following study enrollment. | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Count of Participants | Participants | 48 hours |
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| Secondary | All Cause Mortality at 30 Days | All Cause Mortality at 30 Days | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Count of Participants | Participants | 30 Days |
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| Other Pre-specified | Length of Hospital Stay | Length of hospital stay in days | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Mean | Standard Deviation | days | Inpatient Hospitalization |
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| Other Pre-specified | All Cause Readmission Within 30 Days | All Cause Readmission Within 30 Days | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Count of Participants | Participants | 30 Days |
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| Other Pre-specified | Heart Failure Readmission Within 30 Days | Heart Failure Readmission Within 30 Days | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Count of Participants | Participants | 30 Days |
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| Other Pre-specified | Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement | Severe electrolyte abnormalities requiring aggressive replacement defined as potassium levels less than 3.0 meq/L during the study. | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Count of Participants | Participants | 48 Hours |
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| Other Pre-specified | Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement | Number of Participants with severe electrolyte abnormalities requiring aggressive replacement defined as magnesium levels less than 1.5 meq/L during the study. | All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis. | Posted | Count of Participants | Participants | 48 Hours |
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| 1 |
| 70 |
| 0 |
| 70 |
| 13 |
| 70 |
| EG001 | Experimental: Metolazone | This group will receive all standard heart failure therapy with addition of metolazone. Experimental: Metolazone: All patients will receive standard heart failure therapy, including but not restricted to diuretics, digoxin, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, beta blockers, aldosterone antagonists, hydralazine, and/or nitrates, at the discretion of the treating physician. After informed consent is obtained, patients will be randomized 1:1 to the treatment arm or placebo arm. The first dose of metolazone is given within six hours of admininstration of first dose of intravenous diuretic The second dose of metolazone is given 24-hours after the first dose. | 4 | 72 | 0 | 72 | 15 | 72 |
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| Electrolyte abnormalities requiring intervention | General disorders | Non-systematic Assessment | Severe electrolyte abnormalities requiring aggressive replacement defined as potassium levels less than 3.0 meq/L or magnesium levels less than 1.5 meq/L during the study. |
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| Acute Kidney Injury | Renal and urinary disorders | Systematic Assessment | Acute kidney injury defined as a 30% rise in creatinine from baseline. |
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| Hypotention requiring intervention and Acute Kidney Injury | General disorders | Non-systematic Assessment | Hypotention defined as MAP < 50 and AKI defined as 30% increase in creatinine over baseline. |
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| 12 hours |
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| 24 hours |
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| 36 hours |
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| 48 hours |
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