Clinical trial NCT02620384
Conditions: Acute Decompensated Heart Failure
Keywords: Metolazone Heart Failure
Sponsor: Aultman Health Foundation
Start date: 2015-10-01; Completion date: 2017-12-29
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: This group will receive all standard heart failure therapy and placebo pill. arm 2: This group will receive all standard heart failure therapy with addition of metolazone.
Interventions: intervention 1: Experimental: Placebo intervention 2: Experimental: Metolazone
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol documents:
Prot_000.pdf: 
MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
Page 1 of 10 
 
 
 
 
MELT-HF 
 
MEtolazone as Early add on Therapy for acute 
decompensated Heart Failure.  
A single center pilot study. 
 
 
Muhammad A. Chaudhry, MD 
 
 
 
 


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
Page 2 of 10 
INTRODUCTION 
Background 
 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.  
 In many cases, a “stepped approach” with oral loop diuretics advancing to intravenous 
and finally combination high dose diuretics is employed.  
PREVIOUS TRIALS 
DOSE( Diuretic strategies in patients with ADHF) Trial 
 Prospective, randomized double blinded trial of 308 patients with ADHF. 
 Showed that high dose diuretics (2.5 times the outpatient daily dose) were associated with 
improved urine output at 72 hours (3575± 2635 in low dose group vs. 4899±3479 in high 
dose group). 
 There was no significant difference between the high and low dose groups in mean 
creatinine change (0.08±0.3 mg per deciliter in high-dose group as compared to 0.04±0.3 
mg per deciliter in low-dose group, P=0.21.  
CARESS-HF (Ultrafiltration in ADHF patients with CRS) Trial 
 Randomized non blinded study of 188 patients with ADHF. 
 High dose loop strategy with stepped addition of metolazone was used. The combination 
approach compared favorably with renal ultrafiltration in patients with acute 
decompensated heart failure. 


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
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 At 96 hours, the mean change in the creatinine level was 0.04±0.53 mg per deciliter in 
drug therapy group, as compared with +0.23±0.70 mg per deciliter in the ultrafiltration 
group (P = 0.003).   
 There was no significant difference in weight loss at 96 hours between patients in the 
pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg 
vs. 5.7±3.9 kg [12.6±8.5 lb], respectively; P = 0.58).  
  There was a higher percentage of serious adverse events in the ultrafiltration group as 
compared with the pharmacologic-therapy group (72% vs. 57%, P = 0.03). 
OBJECTIVES 
THE PRIMARY OBJECTIVE OF THE STUDY IS TO DETERMINE EFFICACY OF 
METOLAZONE AS SYNERGISTIC THERAPY WITH LASIX IN PATIENTS WITH 
ACUTE DECOMPENSATED HEART FAILURE. 
STUDY DESIGN 
 A single center double blinded randomized placebo- controlled pilot study of the addition 
of 5 mg of metolazone per day for a total of 2 doses compared to placebo in patients 
admitted with acute decompensated heart failure (Class III-IV).  
 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. 
ENDPOINTS 
Primary Endpoint 
 Total urinary output and negative fluid balance (in milliliters) at 48 hours following 
initial administration of first intravenous diuretic.  
Secondary Endpoints 
 Change in weight from admission to day 2. 
 Degree of improvement in dyspnea at 6, 12, 24, 36, and 48 hours assessed with Modified 
Borg Scale (1-10) (Appendix 1). 
 All-cause mortality at 30 days. 


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
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 Time difference between diuretic dose and study drug. 
 Total dose of diuretics administered during first 48 hours from administration of first 
intravenous diuretic. 
 Inotrope administration during hospital stay.  
Exploratory Endpoints 
 Length of hospital stay.  
  All cause readmission occurring within 30 days after discharge.  
  Heart failure readmission occurring within 30 days post discharge.  
Safety Endpoints 
 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.  
  Severe hypotension following study drug administration (MAP less than 55 mm of Hg).  
ADVERSE EFFECTS OF INVESTIGATIONAL PRODUCT 
 Hypotension requiring intervention. 
 Electrolyte imbalance requiring intervention. 
 Acute kidney injury defined as a 30% rise from baseline. 
The above adverse effects will be collected on each patient for 48 hours after enrollment in the 
MELT trial. No other adverse events will be reported unless deemed to related to the study by 
the Principal Investigator. 
STUDY PROCEDURES 
 This is a randomized, double blinded, placebo-controlled single center study of at least 
200 patients who are admitted to Aultman Hospital with clinical decompensated Class 
III-IV congestive heart failure.  
 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 doses of study drug will be administered.  The first dose will be given as soon as 
possible following enrollment, but within 6 hours of the first intravenous diuretic 


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
Page 5 of 10 
administration. This will be considered Day 0.  The second dose will be administered 24 
hours after the first dose of study drug. This will be considered Day 1.  Patients and 
physicians will be blinded to the administered drug (metolazone vs. placebo). In the event 
of unforeseen circumstances the patient does not receive both doses of study drug (i.e. 
early discharge or emergent surgery), they will be deemed inevaluable. See Analysis 
Populations section below.  
 Study drug assignment will be randomized and distributed by a delegated pharmacist 
after the 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 within seven (±3) days 
and 30 (±7) days post discharge.  
 BMP, magnesium and CBC will be collected daily or as clinically indicated at the 
discretion of the treating physician..  
 BNP will be collected on admission and Day 2. For the first ten (10) patients, a BNP will 
be collected at discharge.   
 Patients will be preferred to have an indwelling urinary catheter to collect accurate output 
measurements. If patient agreeable, the catheter will be placed upon enrollment unless 
already in place. Total urinary output will be measured at 48 hours after from 
administration of first intravenous diuretic.  
 Daily intake, urine output and standing weights will be measured for the entire length of 
the hospital stay.  The total urine output and negative fluid balance will be measured at 
48 hours from administration of first intravenous diuretic (primary endpoint). 
 Total dose of diuretics administered in both groups will be monitored and compared with 
total urine output at 48 hours (primary endpoint). Urine output will be adjusted based on 
total loop diuretic dose beginning from administration of first intravenous diuretic 
(analysis of covariance). 
 Study drug will be administered as soon as possible after enrollment in the study and this 
will be conveyed clearly to the emergency staff prior to starting the study to avoid 
unnecessary delays. The time interval between the administration of loop diuretic and the 
dose of study drug will be tracked as well and adjustments made accordingly in the final 
analysis. 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
 Age 18 years or older  


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
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 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 or equal to 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 defined as mean arterial pressure (MAP) less than 55 
 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  
Subject Population 
Recruitment 
 At least 200 patients who are admitted with acute decompensated heart failure will be 
identified in the Emergency Room, Outpatient Clinic, 4 South, or Cardiac Care Unit.  
 Patients included in the study will receive standard heart failure therapy including but not 
restricted to 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.  


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
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 For the participating patients, they will be recommended to at least receive their (total 
daily outpatient dose of furosemide) x1.25 intravenously. 
  With equivalent conversion which would be 2:1 for torsemide and Lasix and 40:1 for 
bumex and Lasix, we will give at least 1.25 x intravenous dose of Lasix if they are taking 
torsemide or bumex as part of their outpatient regimen.  
 If enrolled in the study, the first dose of study drug will be given as soon as possible 
following enrollment, but within 6 hours of the first IV dose diuretics.  The second dose 
will be administered 24 hours after the first dose of study drug.. 
 Electrolytes will be repleted per the treating physician.  
 Drug administration will be held in patients with severe hypotension (MAP less than 55). 
STATISTICAL ANALYSIS 
Statistical Methods 
 Power Analysis: In the DOSE trial urine output at 72 hours was 4200ml with a standard 
deviation of 3200 ml.  
 With 1:1 randomization, there is a power of more than 80% to detect a difference of 
3000-4000 ml between the groups at 48 hours and at least 200 patients will be enrolled to 
achieve statistical significance. 
 The demographics to the two groups will be compared with Fischer’s exact T-test to 
ensure the validity of the randomization.  
 Primary and secondary outcomes will be collected and compared with the Student’s T-
test.  
 Appropriate subgroup analyses will be done and outcomes will be presented by Kaplan 
Meier plots. 
Analysis Populations 
 The Evaluable Population for the primary, secondary, and exploratory endpoints will 
include all randomized subjects who receive both doses of the study drug, and complete 
the 48 hour evaluation period. The efficacy analysis will be based on the Evaluable 
Population. 
 If a patient does not receive both doses of study drug or complete the 48 hour evaluation 
period they will be considered inevaluable, however, this will not be classified as a 
protocol deviation.  
 The Safety Endpoints will include all randomized subjects who receive at least one dose 
of the study drug.  


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
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Data and Safety Monitoring 
A data safety monitoring committee will be assigned to review each case for eligibility, 
adherence to the protocol, occurrence of adverse events, and accuracy of data. This will be 
completed on a regular basis. The first review will be conducted after enrolling the first 100 
patients. Regular reviews will be scheduled at increments of 50 randomized patients until 
enrollment goals are met. Unscheduled random chart audits will also be performed to ensure data 
integrity. Any deficiencies found during these reviews will be addressed and reported to 
necessary parties. 
All study related data will be anonymized and secured via password access being strictly 
confidential to the investigators. The stored data will be kept in locked cabinets at all times with 
limited access.  


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
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Appendix 1: Modified Borg Scale 
SCALE 
SEVERITY 
0 
No Breathlessness* At All 
0.5 
Very Very Slight (Just Noticeable) 
1 
Very Slight 
2 
Slight Breathlessness 
3 
Moderate 
4 
Some What Severe 
5 
Severe Breathlessness 
6 
 
7 
Very Severe Breathlessness 
8 
 
9 
Very Very Severe (Almost Maximum) 
10 
Maximum 
 
Appendix 2:  New York Heart Association (NYHA) Heart Failure Classification 
Class Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest.  If any physical activity is undertaken, discomfort increases. 


MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] 
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References 
1. Bart BA, Goldsmith SR, Lee KL, Redfield MM, Felker GM, O'Connor CM, Chen HH, 
Rouleau JL, Givertz MM, Semigran MJ, Mann D, Deswal A, Bull DA, Lewinter MM, 
Braunwald E. Cardiorenal rescue study in acute decompensated heart failure: rationale 
and design of CARRESS-HF, for the Heart Failure Clinical Research Network. J Card 
Fail. 2012 Mar;18(3):176-82. doi: 10.1016/j.cardfail.2011.12.009.  
2. Croft JB, Giles WH, Pollard RA, et al.Heart failure survival among older adults in the 
United States: a poor prognosis for an emerging epidemic in the Medicare population. 
Arch Intern Med. 1999; 159(5):505–510.  
3. G. Michael Felker, M.D., M.H.S., Kerry L. Lee, Ph.D., David A. Bull, M.D., Margaret 
M. Redfield, M.D., Lynne W. Stevenson, M.D., Steven R. Goldsmith, M.D., Martin M. 
LeWinter, M.D., Anita Deswal, M.D., M.P.H., Jean L. Rouleau, M.D., Elizabeth O. Ofili, 
M.D., M.P.H., Kevin J. Anstrom, Ph.D., Adrian F. Hernandez, M.D., Steven E. McNulty, 
M.S., Eric J. Velazquez, M.D., Abdallah G. Kfoury, M.D., Horng H. Chen, M.B., B.Ch., 
Michael M. Givertz, M.D., Marc J. Semigran, M.D., Bradley A. Bart, M.D., Alice M. 
Mascette, M.D., Eugene Braunwald, M.D., and Christopher M. O'Connor, M.D. for the 
NHLBI Heart Failure Clinical Research Network. Diuretic Strategies in Patients with 
Acute Decompensated Heart Failure. N Engl J Med 2011; 364:797-805March 3, 
2011DOI: 10.1056/NEJMoa1005419.  
4. Graves EJ. National Hospital Discharge Survey: annual summary, 1992.Vital Health Stat 
13. 1994 Oct; (119):1-63. 2. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, 
Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP; ADHERE Scientific 
Advisory Committee and Investigators. Characteristics and outcomes of patients 
hospitalized for heart failure in the United States: rationale, design, and preliminary 
observations from the first 100,000 cases in the Acute Decompensated Heart Failure 
National Registry (ADHERE). Am Heart J. 2005 Feb;149(2):209-16.  
5. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. 
Heart disease and stroke statistics— 2009 update: a report from the American Heart 
Association Statistics Committee and Stroke Statistics Subcommittee ,Circulation 
2009;119(3):e21–181. 
6. O’Connell JB, Bristow MR: Economic impact of heart failure in the United States: Time 
for a different approach. J Hean Lung Transplant 1994; 13: s 107-S 1 I2. 
7. Rosenberg J, Gustafsson F, Galatius S, Hildebrandt PR. Combination therapy with 
metolazone and loop diuretics in outpatients with refractory heart failure: an 
observational study and review of the literature. Cardiovasc Drugs Ther. 2005 
Aug;19(4):301-6.  
 

SAP_001.pdf: 
MELT-HF  NCT02620384 
MEtolazone as Early add on Therapy for acute decompensated Heart 
Failure.  
A single center pilot study.  
Muhammad A. Chaudhry, MD
STATISTICAL ANALYSIS (UPDATED 12/4/2018) 
Statistical Methods  
Power Analysis: In the DOSE trial urine output at 72 hours was 4200ml with a 
standard deviation of 3200 ml. 
 With 1:1 randomization, there is a power of more than 80% to detect a 
difference of 3000-4000 ml between the groups at 48 hours and at least 200 
patients will be enrolled to achieve statistical significance.  
 The demographics to the two groups were compared with Student’s T test for 
continuous variables and Chi Square for categorical variables. There were no 
significant differences in age, gender, race or NYHA enrollment.  
Primary and secondary outcomes were compared with Student’s T tests and 
Repeated Measures ANOVA (for longitudinal data) with between subjects 
variable.