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

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.

Study Overview

• Status: Terminated
• Conditions: Acute Decompensated Heart Failure
• Intervention / Treatment: Drug: Experimental: Placebo; Drug: Experimental: Metolazone

Detailed Description

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:

1. Change in weight from admission to day 2.
2. Degree of improvement in dyspnea at 6,12, 24,36, and 48 hours assessed with Modified Borg Scale (1-10)
3. All cause mortality at 30 days.

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.

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Canton, Ohio, United States, 44710
      • Aultman Health Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 years or older
• Current hospitalization for chronic congestive heart failure with admission up to 48 hours prior to inclusion.
• Chronic heart failure will be defined as requiring treatment for a minimum of 30 days prior to current admission, NYHA Class III or IV at the time of hospitalization, and left ventricular ejection fraction less than 40% within one year or evidence of heart failure with preserved ejection fraction and evidence of diastolic dysfunction on echocardiogram.
• Admitted with clinical decompensated heart failure based on history, physical exam, and parameters indicating extracellular volume expansion such as including JVP ≥ 8 cm of water and 1+ or greater peripheral edema
• Is able to be dosed with study medication within six (6) hours of first dose of IV diuretics

Exclusion Criteria:

• Baseline severe hypotension (Mean arterial pressure < 55 mm Hg)
• Creatinine clearance less than 20 ml/min or creatinine greater than 2.5 mg/dl.
• Serum sodium less than 128 meq/L.
• Serum Potassium < 3.0 meq/L.
• Known adverse reaction to metolazone
• Inability to take oral medications
• Severe Aortic Stenosis (AVA < 0.8cm2)
• History of Hypertrophic obstructive cardiomyopathy
• Metastatic Carcinoma per history
• Severe COPD, FEV < 1L
• Severe dyspnea requiring prolonged CPAP,BIPAP or intubation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Experimental: Placebo; This group will receive all standard heart failure therapy and placebo pill.	Drug: 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.
Active Comparator: Experimental: Metolazone; 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 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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.	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

Other Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Aultman Health Foundation
• Investigators: Principal Investigator: Muhammad Chaudhry, MD, Aultman Health Foundation

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): November 29, 2017
• Study Completion (Actual): December 29, 2017

Study Registration Dates

• First Submitted: December 1, 2015
• First Submitted That Met QC Criteria: December 1, 2015
• First Posted (Estimate): December 3, 2015

Study Record Updates

• Last Update Posted (Actual): February 15, 2019
• Last Update Submitted That Met QC Criteria: January 24, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Heart Failure; Metolazone
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Metolazone
• Other Study ID Numbers: 2015.03.26.F2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No