Trial Outcomes & Findings for Metolazone As Early Add On Therapy For Acute Decompensated Heart Failure (MELT-HF)--A Single Center Pilot Study. (NCT NCT02620384)

NCT ID: NCT02620384

Last Updated: 2019-02-15

Results Overview

Total urinary output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 147 participants
• Primary outcome timeframe: 48 hours
• Results posted on: 2019-02-15

Participant Flow

147 participants from one local institution (inpatient hospital) were enrolled between October 2015 and November 2017

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.

Participant milestones

Measure	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.	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.
Overall Study STARTED	70	73
Overall Study COMPLETED	66	66
Overall Study NOT COMPLETED	4	7

Reasons for withdrawal

Measure	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.	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.
Overall Study Adverse Event	2	1
Overall Study Discharged prior to 2nd dose	2	5
Overall Study Drug shortage prevented 2nd dose	0	1

Baseline Characteristics

Metolazone As Early Add On Therapy For Acute Decompensated Heart Failure (MELT-HF)--A Single Center Pilot Study.

Baseline characteristics by cohort

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.	Total n=132 Participants Total of all reporting groups
Age, Continuous	73.67 years STANDARD_DEVIATION 13.5 • n=5 Participants	71.86 years STANDARD_DEVIATION 12.8 • n=7 Participants	72.77 years STANDARD_DEVIATION 13.1 • n=5 Participants
Sex: Female, Male Female	26 Participants n=5 Participants	29 Participants n=7 Participants	55 Participants n=5 Participants
Sex: Female, Male Male	40 Participants n=5 Participants	37 Participants n=7 Participants	77 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) White	63 Participants n=5 Participants	64 Participants n=7 Participants	127 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	66 participants n=5 Participants	66 participants n=7 Participants	132 participants n=5 Participants
NYHA Class at Enrollment Class 3	28 participants n=5 Participants	25 participants n=7 Participants	53 participants n=5 Participants
NYHA Class at Enrollment Class 4	38 participants n=5 Participants	41 participants n=7 Participants	79 participants n=5 Participants
N-Terminal proBNP Value Upon Admission	10905.6 pg/mL STANDARD_DEVIATION 12749.9 • n=5 Participants	10184.7 pg/mL STANDARD_DEVIATION 11340.1 • n=7 Participants	10545.12 pg/mL STANDARD_DEVIATION 12024.2 • n=5 Participants
Time Difference Qualifying Diuretic and Study Drug Initiation	147.7 minutes STANDARD_DEVIATION 147.7 • n=5 Participants	121.3 minutes STANDARD_DEVIATION 112.9 • n=7 Participants	132.5 minutes STANDARD_DEVIATION 114.3 • n=5 Participants

PRIMARY outcome

Timeframe: 48 hours

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Total urinary output in milliliters (ml) at 48 hours. Measurement timing began with administration of first dose of investigational product, ended 48 hours later.

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Total Urinary Output at 48 Hours	6893.777 Milliliters Standard Deviation 3122.6532	9333.288 Milliliters Standard Deviation 4188.5731

PRIMARY outcome

Timeframe: 48 hours

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

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.

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Fluid Balance at 48 Hours	-4260.762 Mililiters Standard Deviation 2705.8710	-6510.091 Mililiters Standard Deviation 4121.3808

SECONDARY outcome

Timeframe: 48 hours

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Change in weight from the date/time of study enrollment (baseline) and 48 hours.

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Change in Weight First 48 Hours	-3.23227 killograms Standard Deviation 2.538462	-5.93939 killograms Standard Deviation 4.033661

SECONDARY outcome

Timeframe: 6, 12, 24, 36 and 48 hours.

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

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.

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=65 Participants 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.
Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. Baseline	9 score on a scale Standard Deviation .0000	9 score on a scale Standard Deviation .0000
Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. 48 hours	2.295 score on a scale Standard Deviation 1.6640	1.600 score on a scale Standard Deviation 1.5441
Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. 6 hours	6.21 score on a scale Standard Deviation 1.524	5.49 score on a scale Standard Deviation 1.532
Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. 12 hours	4.88 score on a scale Standard Deviation 1.564	3.98 score on a scale Standard Deviation 1.441
Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. 24 hours	3.77 score on a scale Standard Deviation 1.662	2.95 score on a scale Standard Deviation 1.643
Degree of Improvement in Dyspnea at 6, 12, 24, 36 and 48 Hours. 36 hours	2.924 score on a scale Standard Deviation 1.6249	2.123 score on a scale Standard Deviation 1.5663

SECONDARY outcome

Timeframe: 48 hours

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Total dosage loop diuretic in first 48 hours using conversion tool to calculate intravenous Lasix equivalence

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=65 Participants 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.
Total Dose Diuretics First 48 Hours	346.470 Milligrams Standard Deviation 381.9480	350.160 Milligrams Standard Deviation 444.8640

SECONDARY outcome

Timeframe: 48 hours

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Number of Participants with Inotrope administration during first 48 hours following study enrollment.

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Number of Participants With Inotrope Administration During First 48 Hours	9 Participants	4 Participants

SECONDARY outcome

Timeframe: 30 Days

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

All Cause Mortality at 30 Days

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
All Cause Mortality at 30 Days	1 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Inpatient Hospitalization

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Length of hospital stay in days

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Length of Hospital Stay	5.33 days Standard Deviation 4.695	5.44 days Standard Deviation 3.672

OTHER_PRE_SPECIFIED outcome

Timeframe: 30 Days

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

All Cause Readmission Within 30 Days

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
All Cause Readmission Within 30 Days	10 Participants	9 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 30 Days

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Heart Failure Readmission Within 30 Days

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Heart Failure Readmission Within 30 Days	2 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 48 Hours

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Severe electrolyte abnormalities requiring aggressive replacement defined as potassium levels less than 3.0 meq/L during the study.

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Number of Participants With Potassium Electrolyte Abnormality Requiring Replacement	0 Participants	3 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 48 Hours

Population: All participants who received both doses of the investigational product and completed the 48 hour assessments were included in the efficacy analysis.

Number of Participants with severe electrolyte abnormalities requiring aggressive replacement defined as magnesium levels less than 1.5 meq/L during the study.

Outcome measures

Measure	Experimental: Placebo n=66 Participants 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.	Experimental: Metolazone n=66 Participants 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.
Number of Participants With Magnesium Electrolyte Abnormality Requiring Replacement	2 Participants	1 Participants

Adverse Events

Experimental: Placebo

Serious events: 0 serious events

Other events: 13 other events

Deaths: 1 deaths

Experimental: Metolazone

Serious events: 0 serious events

Other events: 15 other events

Deaths: 4 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Experimental: Placebo n=70 participants at risk 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.	Experimental: Metolazone n=72 participants at risk 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.
Cardiac disorders Hypotension Requiring Intervention	8.6% 6/70 • Number of events 6 • 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.	1.4% 1/72 • Number of events 1 • 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.
General disorders Electrolyte abnormalities requiring intervention	2.9% 2/70 • Number of events 2 • 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.	5.6% 4/72 • Number of events 4 • 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.
Renal and urinary disorders Acute Kidney Injury	5.7% 4/70 • Number of events 4 • 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.	13.9% 10/72 • Number of events 10 • 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.
General disorders Hypotention requiring intervention and Acute Kidney Injury	1.4% 1/70 • Number of events 1 • 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.	0.00% 0/72 • 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.

Additional Information

Director of Research Programs

Aultman Hospital

Phone: 330-363-7274

Email: mary.amos@aultman.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place