A Phase 3 interventional study of Experimental: Placebo and Experimental: Metolazone in Acute Decompensated Heart Failure, sponsored by Aultman Health Foundation. Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-02-15.
Sponsored by Aultman Health Foundation · Phase 3, Interventional, and Treatment
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.
5,701 studies on the registry are indexed under Heart Failure; 1,220 are open to participants now.
This study's enrollment of 147 is above the median of 72 across 3,736 interventional studies indexed under Heart Failure.
Browse Heart Failure studies →Aultman Health Foundation is the lead sponsor of 13 studies on the registry; none are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 6 (100%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
This group will receive all standard heart failure therapy and placebo pill.
Drug: Experimental: Placebo
This group will receive all standard heart failure therapy with addition of metolazone.
Drug: 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 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.
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.
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.
Time frame: 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.
Time frame: 48 hours
Change in Weight First 48 Hours
Change in weight from the date/time of study enrollment (baseline) and 48 hours.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 48 hours
All Cause Mortality at 30 Days
All Cause Mortality at 30 Days
Time frame: 30 Days
Length of Hospital Stay
Length of hospital stay in days
Time frame: Inpatient Hospitalization
All Cause Readmission Within 30 Days
All Cause Readmission Within 30 Days
Time frame: 30 Days
Heart Failure Readmission Within 30 Days
Heart Failure Readmission Within 30 Days
Time frame: 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.
Time frame: 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.
Time frame: 48 Hours
147 participants from one local institution (inpatient hospital) were enrolled between October 2015 and November 2017
| Milestone | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Started | 70 | 73 |
| Completed | 66 | 66 |
| Not completed | 4 | 7 |
| Withdrew: Adverse event | 2 | 1 |
| Withdrew: Discharged prior to 2nd dose | 2 | 5 |
| Withdrew: Drug shortage prevented 2nd dose | 0 | 1 |
Total urinary output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later.
| Milliliters | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Total Urinary Output at 48 Hours | 6893.777 ± 3122.6532 | 9333.288 ± 4188.5731 |
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.
| Mililiters | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Fluid Balance at 48 Hours | -4260.762 ± 2705.8710 | -6510.091 ± 4121.3808 |
Change in weight from the date/time of study enrollment (baseline) and 48 hours.
| killograms | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Change in Weight First 48 Hours | -3.23227 ± 2.538462 | -5.93939 ± 4.033661 |
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.
| score on a scale | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Baseline | 9 ± .0000 | 9 ± .0000 |
| 6 hours | 6.21 ± 1.524 | 5.49 ± 1.532 |
| 12 hours | 4.88 ± 1.564 | 3.98 ± 1.441 |
| 24 hours | 3.77 ± 1.662 | 2.95 ± 1.643 |
| 36 hours | 2.924 ± 1.6249 | 2.123 ± 1.5663 |
| 48 hours | 2.295 ± 1.6640 | 1.600 ± 1.5441 |
Total dosage loop diuretic in first 48 hours using conversion tool to calculate intravenous Lasix equivalence
| Milligrams | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Total Dose Diuretics First 48 Hours | 346.470 ± 381.9480 | 350.160 ± 444.8640 |
Number of Participants with Inotrope administration during first 48 hours following study enrollment.
| Participants | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Number of Participants With Inotrope Administration During First 48 Hours | 9 | 4 |
All Cause Mortality at 30 Days
| Participants | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| All Cause Mortality at 30 Days | 1 | 4 |
Length of hospital stay in days
| days | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Length of Hospital Stay | 5.33 ± 4.695 | 5.44 ± 3.672 |
All Cause Readmission Within 30 Days
| Participants | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| All Cause Readmission Within 30 Days | 10 | 9 |
Heart Failure Readmission Within 30 Days
| Participants | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Heart Failure Readmission Within 30 Days | 2 | 4 |
Severe electrolyte abnormalities requiring aggressive replacement defined as potassium levels less than 3.0 meq/L during the study.
| Participants | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement | 0 | 3 |
Number of Participants with severe electrolyte abnormalities requiring aggressive replacement defined as magnesium levels less than 1.5 meq/L during the study.
| Participants | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement | 2 | 1 |
Collected over 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 events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Experimental: Placebo | 1/70 (1.4%) | 0/70 (0%) | 13/70 (18.6%) |
| Experimental: Metolazone | 4/72 (5.6%) | 0/72 (0%) | 15/72 (20.8%) |
| Event | Experimental: Placebo | Experimental: Metolazone |
|---|---|---|
| Acute Kidney InjuryRenal and urinary disorders | 4/70 | 10/72 |
| Hypotension Requiring InterventionCardiac disorders | 6/70 | 1/72 |
| Electrolyte abnormalities requiring interventionGeneral disorders | 2/70 | 4/72 |
| Hypotention requiring intervention and Acute Kidney InjuryGeneral disorders | 1/70 | 0/72 |
Per protocol only participants who receive both doses of investigational product are analyzed
| Age, Continuous(years) | Experimental: Placebo | Experimental: Metolazone | Total |
|---|---|---|---|
| Mean | 73.67 ± 13.5 | 71.86 ± 12.8 | 72.77 ± 13.1 |
| Sex: Female, Male(Participants) | Experimental: Placebo | Experimental: Metolazone | Total |
|---|---|---|---|
| Female | 26 | 29 | 55 |
| Male | 40 | 37 | 77 |
| Race (NIH/OMB)(Participants) | Experimental: Placebo | Experimental: Metolazone | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 3 | 2 | 5 |
| White | 63 | 64 | 127 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Experimental: Placebo | Experimental: Metolazone | Total |
|---|---|---|---|
| United States | 66 | 66 | 132 |
| NYHA Class at Enrollment(participants) | Experimental: Placebo | Experimental: Metolazone | Total |
|---|---|---|---|
| Class 3 | 28 | 25 | 53 |
| Class 4 | 38 | 41 | 79 |
| N-Terminal proBNP Value Upon Admission(pg/mL) | Experimental: Placebo | Experimental: Metolazone | Total |
|---|---|---|---|
| Mean | 10905.6 ± 12749.9 | 10184.7 ± 11340.1 | 10545.12 ± 12024.2 |
| Time Difference Qualifying Diuretic and Study Drug Initiation(minutes) | Experimental: Placebo | Experimental: Metolazone | Total |
|---|---|---|---|
| Mean | 147.7 ± 147.7 | 121.3 ± 112.9 | 132.5 ± 114.3 |
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Aultman Health Foundation