Comparison of Oral Thiazides vs Intravenous Thiazides vs Tolvaptan in Combination With Loop Diuretics for Diuretic Resistant Decompensated Heart Failure
Phase: PHASE4
Conditions: Heart Failure
Sponsor: Vanderbilt University

Comparison of oral thiazides vs intravenous thiazides vs tolvaptan in combination with loop 
diuretics for diuretic resistant decompensated heart failure 
 
 
NCT 02606253 
Document Date 8/31/2019 
 

 
Protocol Version #: 6 
 
1 
Protocol Date: 10/27/2017 
 
 
 
 
 
 
 
 
Comparison of oral thiazides vs intravenous thiazides vs tolvaptan in combination with loop 
diuretics for diuretic resistant decompensated heart failure 
 
Principal Investigator:  
Zachary L. Cox, PharmD 
 
 
 
 
Co-Investigators: 
Rebecca Hung, M.D., Associate Professor 
Department of Cardiovascular Medicine 
Vanderbilt University 
 
Daniel J Lenihan, M.D., Professor  
Department of Cardiovascular Medicine 
Vanderbilt University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Version #: 6 
 
2 
Protocol Date: 10/27/2017 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Risks of Investigational Agents/Devices (side effects) 
7.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
8.0 
Study Withdrawal/Discontinuation 
9.0 
Statistical Considerations 
10.0 
Privacy/Confidentiality Issues 
11.0 
Follow-up and Record Retention 
 
Appendices 
Appendix A: Schedule of Study Assessments 
Appendix B: Patient-Reported Congestion Score 
 

 
Protocol Version #: 6 
 
3 
Protocol Date: 10/27/2017 
1.0 
Background 
 
Loop diuretic therapy is the cornerstone of heart failure (HF) symptom management.  Symptoms 
of fluid retention and congestion are responsible for 90% of HF hospitalizations, and almost all 
(86%- 97%) patients hospitalized for HF receive intravenous (IV) loop diuretics.1,2-4  The 
incidence of diuretic resistance is unknown, given the lack of a consensus definition, but 
resistance is reported to occur in 25-35% of heart failure patients. 5-7 Despite the prevalence of 
loop diuretic use in HF and frequency of diuretic resistance, guidelines by the Heart Failure 
Society of America (HFSA) and the American College of Cardiology Foundation/American 
Heart Association (ACCF/AHA) provide nonspecific guidance on diuretic regimen design in 
response to diuretic resistance. Both guidelines recommend (LOE IIA, Class B) the addition of a 
second type of diuretic (options listed include oral metolazone and intravenous chlorothiazide). 8,9 
As expected, 57% of physician questions about advanced HF management in a recent survey 
concerned diuretic titration.10 
 
Addition of a second diuretic is a common practice to overcome diuretic resistance, despite the 
scarcity of literature to support this practice. A 2010 literature review of combining thiazide and 
loop diuretics found, “The aggregate body of literature is limited by the small size of studies, 
study design with lack of control groups, heterogeneous patient populations, wide variation in 
diuretic regimens, and focus on physiologic rather than clinical outcomes.”11 In addition to lack 
of evidence guiding its use, combination diuretic therapy is further complicated by adverse events 
and costs associated with this practice. Electrolyte derangements are a common adverse effect of 
combination diuretic regimens, predisposing patients to cardiac arrhythmias. 11 Furthermore, each 
agent has it limitations: metolazone is subjected to erratic absorption due to its oral dosage form; 
whereas, intravenous chlorothiazide over comes the absorption issue but is more costly.12-14 
Clearly, a need to better understand the benefits and risk of these therapies exist. 
 
A non-thiazide option, also mentioned in heart failure guidelines for fluid removal, is the oral 
vasopressin 2-receptor antagonist tolvaptan.  This agent could be an equally effective alternative 
to thiazide diuretics with potentially less electrolyte derangement. In the EVEREST (Efficacy of 
Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan) trials the addition of 
30 mg tolvaptan daily was evaluated compared to IV loop diuretics in > 4,000 patients 
hospitalized for ADHF.15 Weight reduction was again seen as early as the 1st day, and weights at 
discharge or day 7 were 0.6 kg lower in trial A and 0.9 kg lower in trial B (p <  .001). Most 
notably, no study reported hypokalemia with the combination of loop diuretics and tolvaptan.15-17 
Another study demonstrated that 80mg furosemide plus 30mg of tolvaptan provided a reducing of 
1.48kg (± 1.14kg) at 48 hours in a small subset of an acute HF population.18 However this study 
was not conducted in patients who had developed diuretic resistance.  
 
Given the importance of adequate decongestion in acute hear failure and the common occurrence 
of loop diuretic resistance, there is a critical need for evidence regarding the optimal selection of 
additional agents to restore diuretic efficacy. 
 
2.0 
Rationale and Specific Aims 
 
Given the sparse amount of data regarding adjunctive diuretic strategies in acute heart failure, this 
study aims to address this gap by providing one of the first prospective trials comparing three 
different medications in addition to loop diuretics. By utilizing a prescriptive algorithm for loop 
diuretic dosing and other medical therapies that alter diuretic response, the study will address 
many of the limitations of previous studies such as the lack of a control group, retrospective 
design, and wide variations of both loop and thiazide diuretic regimens.13, 14 Metolazone will be 

 
Protocol Version #: 6 
 
4 
Protocol Date: 10/27/2017 
employed as the standard-of-care thiazide to mirror current clinical perceptions and to replicate a 
recent landmark diuretic study’s thiazide use.11, 19-20 Our selected sample size will provide 
adequate power to detect clinically meaningful differences in outcomes, a further limitation of 
previous studies. The results of this study have the potential impact practice immediately as it 
will provide the first evidence to guide practitioners on the most appropriate next step to over 
come diuretic resistance. The evidence from the results of this trial would have the potential to be 
included in future guidelines for heart failure management. Finally, this data could generate other 
hypotheses which would serve has the foundation of other studies.   
 
Specific Aims 
1. Compare the 48-hour weight change of either intravenous chlorothiazide or oral tolvaptan 
compared to standard-of-care oral metolazone when combined with standardized loop diuretic 
dosing for diuretic resistance in acute heart failure 
Current heart failure guidelines recommend addition of a thiazide diuretic, listing either oral 
metolazone or intravenous chlorothiazide, to loop diuretic therapy as strategy to overcome loop 
diuretic resistance. At equipotent doses, these two therapies differ 250 fold in cost. To date, no 
prospective trial has compared the efficacy of these two commonly utilized therapies. We expect 
intravenous chlorothiazide will not provide an increase in clinically meaningful weight loss at 48 
hours compared to oral metolazone.  
Tolvaptan, an oral vasopressin 2 receptor antagonist, could restore diuretic efficacy when used in 
combination with loop diuretics. While the safety of this combination has been established in the 
EVEREST trials, tolvaptan has been formally studied in a limited capacity as combination 
therapy to restore loop diuretic resistance. From this sparse data, we expect oral tolvaptan will 
provide equal weight loss at 48 hours compared to metolazone.  
 
2. Compare the adverse effects of electrolyte depletion and renal function changes between 
intravenous chlorothiazide or oral tolvaptan compared to standard-of-care oral metolazone when 
combined with standardized loop diuretic dosing for diuretic resistance in acute heart failure 
Hypokalemia is a common adverse effect of combining a thiazide and loop diuretic, increasing 
the risk of atrial and ventricular arrhythmias in a population who is already at high risk. We 
expect intravenous chlorothiazide will require equivalent cumulative potassium repletion at 48 
hours compared to oral metolazone. Hypokalemia as not been reported with the combination of 
tolvaptan and loop diuretics, likely due to tolvaptan’s distinctive mechanism of action. We expect 
tolvaptan will require less cumulative potassium repletion at 48 hours compared to oral 
metolazone. This potential benefit could provide tolvaptan a unique advantage for combination 
diuretic therapy in environments when electrolyte monitoring cannot be routinely performed or in 
patients with frequent arrhythmic events.  
 
3. Pharmacoeconomic analysis of the direct costs of intravenous chlorothiazide or oral tolvaptan 
compared to standard-of-care oral metolazone when combined with standardized loop diuretic 
dosing for diuretic resistance in acute heart failure 
The average wholesale price for one dose of each agent according to Redbook online is $1.50, 
$357, and $375 for metolazone 5mg tablet, chlorothiazide 500mg vial, and tolvaptan 30mg tablet 
respectively. We will perform a direct cost analysis including drug cost and other therapy-related 
costs. We expect both intravenous chlorothiazide and oral tolvaptan to have higher direct costs 
compared to metolazone. We expect the reduction in electrolyte repletion and accompanying 
adverse event treatment will reduce the cost difference of tolvaptan tablets compared to 
metolazone tablets.  
 
 
 

 
Protocol Version #: 6 
 
5 
Protocol Date: 10/27/2017 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
Criteria for inclusion will be: 
• Age of 18 years or older  
• Hospital admission for hypervolemic decompensated heart failure complicated by loop 
diuretic resistance.  
o Hypervolemia will be diagnosed by the admitting provider as either (i) 
pulmonary artery catheterization with a pulmonary capillary wedge pressure 
greater than 19mmHg plus a systemic physical exam finding of hypervolemia 
(peripheral edema, ascites, or pulmonary edema on auscultation) or (ii) in the 
absence of pulmonary artery catheterization data 2 of the following signs or 
symptoms: peripheral edema ascites, jugular venous pressure > 10mmHg, or 
pulmonary edema on chest x-ray.  
o Loop diuretic resistance is defined as a provider decision to pursue combination 
diuretic therapy because of failure to reach provider defined adequate diuresis 
(can not exceed urine output of 2 L in past 12 hours) despite receipt of an 
intravenous loop diuretic dose of a furosemide equivalent of at least 240mg/day 
over at least the past 12 hours (40mg furosemide = 20mg torsemide = 1mg 
bumetanide).  
• Standard-of-care monitoring, including 24 hour telemetry monitoring on an inpatient 
ward and a basic metabolic panel laboratory assessment twice daily during the study 
period.  
 
Exclusion Criteria 
Candidates will be excluded if they meet any of the following criteria at the time of enrollment: 
• 
Decision to pursue hemodialysis by a nephrologist 
• 
estimated glomerular filtration rate by the MDRD equation < 15ml/min/m2 
• 
systolic blood pressure < 85mmHg 
• 
pregnancy* or breastfeeding 
• 
serum potassium < 3.0mEq/L 
• 
serum sodium > 145mEq/L or < 130mEq/L 
• 
severe malnutrition 
• 
advanced liver disease 
• 
inability to perform standing weights 
• 
inability to collect and measure urine with either a foley catheter or urine collection 
containers 
• 
concomitant therapy with strong CYP3A4 inhibitors/inducers (systemic ketoconazole, 
clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir, nefozodone, 
rifampin, rifabutin, rifapentin, phenytoin, phenobarbital, carbamazepine, St. John’s 
Wort), p-glycoprotein inhibitors (cyclosporine, erythromycin, tacrolimus, dronedarone, 
quinidine, or verapamil) 
• 
non-study diuretics (spironolactone doses >75mg/day, eplerenone > 75mg/day, non-study 
thiazides or loop diuretics, or systemic acetazolamide, triamterene, or amiloride therapy) 
• 
Thiazide mediation administered in the previous 24 hours prior to randomization 
 
*Pregnancy: In women of childbearing age who are not in menopause per patient report during 
screening, a serum pregnancy test will be ordered and negative prior to enrollment. 
 
 

 
Protocol Version #: 6 
 
6 
Protocol Date: 10/27/2017 
4.0 
Enrollment/Randomization 
 
We will conduct a single center, randomized, double-blind, double-dummy, parallel design trial 
comparing oral metolazone, intravenous chlorothiazide, and oral tolvaptan in combination with 
loop diuretics in patients hospitalized for hypervolemic acute heart failure. The duration of the 
study will be 48 hours from the first dose of the study thiazide or tolvaptan medication. 
Vanderbilt University Medical center will be the study site. IRB approval will be obtained from 
the Vanderbilt Univeristy Medical Center IRB.  
 
All patients will provide informed consent prior to enrollment. After enrollment, all patients will 
be randomized in a 1:1:1 fashion at VUMC using a random number table in the investigational 
drug services pharmacy. The investigational pharmacists will perform randomization, and 
investigators will be blinded to the treatment arm.  
 
 
5.0 
Study Procedures 
 
5.1 Background and Standard of Care Therapies 
All patients will be started on a 2L/day fluid restriction and a 2g/day sodium restriction. 
Decisions regarding the initiation, titration, or discontinuation of standard heart failure 
medications (ACEI, ARB, Aldosterone Antagonists, Beta Blockers, digoxin, hydralazine, 
nitrates) are left to the discretion of the treating physicians.  All electrolyte repletion, loop diuretic 
dose titration, and concomitant therapies to enhance diuresis if needed will be utilized at the 
provider’s discretion.  
To prevent confounding heterogeneity in the diuretic treatment approach, a stepped care 
algorithm similar to the CARRESS-HF19 trial will be utilized for loop diuretics, both initial doses 
and subsequent dose changes, and for concomitant inotropes and vasodilators. The stepped care 
algorithm and the initial diuretic treatment regimen are delineated in Study Flow Diagram below. 
A minimum furosemide equivalent dose of 580mg/24hrs (100mg IV bolus + 20mg/hr infusion 
rate) must be ordered at enrollment. 
 
5.2 Randomization 
All patients will be randomized in a 1:1:1 fashion at VUMC using an electronic randomization 
tool embedded in REDCAP.  Patients will be randomized to either: 
1) intravenous chlorothiazide 500mg IV Q12H + an oral placebo capsule Q12H  
2) intravenous placebo infusion Q12H + a capsule containing oral metolazone 5mg PO 
Q12H  
3) intravenous placebo infusion Q12H + a capsule containing oral tolvaptan 30mg once 
daily and placebo capsule in the evening dose.  
 
(Relative potency21, 22: Metolazone 100 fold more potent than chlorothiazide)  
 
 
 
 
 
 
 
 
 
 

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Protocol Version #: 6 
Protocol Date: 10/27/2017 
8
5.3 Blinding 
This study will be double blinded. Blinding will be performed by the enrolling site’s 
investigational drug service pharmacy. A double-dummy strategy will prevent investigators from 
knowing the treatment arm during observation.  
 
5.4 Study Outcomes 
The primary outcome will be 48-hour standing scale weight change (kg) from enrollment among 
the metolazone, intravenous chlorothiazide, and tolvaptan arms, using metolazone group as the 
comparator group for all other groups.  
Secondary outcomes, using metolazone as the comparator group for each, will be: 
• 
48 hour net urine output (mls) 
• 
mean change in serum creatinine, blood urea nitrogen, and eGFR at 24 hours, 48hours, 
and at hospital discharge 
• 
mean change in diuretic efficiency at 24 and 48 hours from baseline value at enrollment 
• 
mean change in serum potassium at 24 and 48 hours from baseline value at enrollment 
• 
mean change in serum sodium at 24 hours, 48hrs, and at discharge from baseline value at 
enrollment 
• 
cumulative dose of potassium (mEq) and magnesium (g) supplementation administered at 
24 and 48 hours 
• 
incidence of severe hypokalemia 
• 
need for escalation in study-directed loop diuretic therapy at 24 and 48 hours 
• 
addition of vasoactive or inotropic medication at 24 and 48 hours 
• 
Treatment failure (definition below) 
• 
Patient-scored congestion visual analog scale score at baseline, 24 and 48 hours 
(Appendix B) 
• 
new cardiac arrhythmias (atrial and ventricular) during the study period 
• 
receipt of inotropic therapy, dopamine, or nitroglycerin; requirement of ultrafiltration or 
hemodialysis during index hospitalization 
• 
in-hospital mortality 
• 
pharmacoeconomic analysis of the direct costs in each arm including the cost of:  
o study medication 
o additional non-trial protocol laboratory analysis cost related to monitoring of 
electrolytes 
o treatment of study medication related adverse effects (arrhythmias, hypotension, 
electrolyte repletion) 
o escalation of loop diuretic therapy doses 
o addition of additional therapies for suboptimal diuresis (inotropic therapy, 
vasodilators) 
o new initiation of renal replacement therapies (hemodialysis or ultrafiltration) 
• 
Spot urinary electrolytes and diuretic urine concentration 
• 
Pharmacokinetics and pharmacodynamics of the diuretics in the urine and blood 
• 
Fractional excretion of sodium 
 
5.5 Study Definitions 
• 
Urine output: Total urine volume (ml) from time of study enrollment to 48 hours 
• 
Hypokalemia: Serum potassium value < 3.5mEq/L  
• 
Severe Hypokalemia: Serum potassium value < 3.0mEq/L 
• 
Hyponatremia: Serum sodium value < 135mEq/L  

Protocol Version #: 6 
Protocol Date: 10/27/2017 
9
• 
Severe Hyponatremia: Serum sodium value < 130mEq/L and a decrease of 5mEq/L or 
more from enrollment serum sodium 
• 
Overcorrection of serum sodium: increase in serum sodium from baseline by >12mEq/L 
in 24 hours, increase in >8mEq/L in 12 hours, or receipt of intravenous fluids because of 
symptoms of overcorrection of serum sodium regardless of the numerical rise 
• 
Hypomagnesiemia: Serum magnesium value < 2mEq/L  
• 
Diuretic efficiency = 24hr urine output/ 24hr Lasix equivalents in milligrams 
• 
Weight: Standing weight on the same scale as used for baseline weight measurement 
• 
New Atrial Arrhythmia: A “new” diagnosis of atrial arrhythmia (includes atrial 
fibrillation, atrial flutter, ectopic atrial tachycardia) lasting > 30 seconds OR any atrial 
arrhythmia which causes hemodynamic instability (MAP < 60 and requiring intervention) 
• 
New Ventricular Arrhythmia: Ventricular tachycardia lasting longer than 30 seconds, or 
frequent non-sustained VT causing hemodynamic instability with MAP < 60 mmHg 
requiring intervention or > 1 intra-cardiac defibrillation or external cardiac defibrillation 
shock or ventricular fibrillation requiring defibrillation 
• 
Hypotension: SBP < 85 for 2 repeated measurements within 30 minutes or lasting at least 
30 minutes or symptomatic hypotension necessitating clinical intervention (defined as 
vasopressor support, intravenous fluid boluses, or initiation of inotropes) 
• 
Treatment failure: Patients requiring additional non-study diuretic (spironolactone doses 
>75mg/day, eplerenone > 75mg/day, non-study thiazides (at a dose of metolazone 2.5mg 
or greater equivalence) or loop diuretics, or systemic acetazolamide (for diuretic 
indication), triamterene, or amiloride therapy) at any time during the 48-hour 
randomization period. These patients will be considered treatment failures for the purpose 
of analysis of the primary endpoint and all secondary endpoints.  
• 
Patients whose cardiologist adds inotropic or vasodilator medications will not be 
considered treatment failures. Patients who require an increase in the loop diuretic 
regimen will also not be considered treatment failures.  
• 
Medication costs will be defined as the Redbook average wholesale price at the time of 
the trial to reduce inter-institutional price differences and improve external validity of the 
analysis. 
 
5.6 Study Outcome Timeline 
Day 1: Baseline standing weight, BMP every 12 hours, urine collection, 20ml blood collection 
dyspnea score.  
Day 2: 24 hour urine collection/quantification, BMP every 12 hours, 24 hour standing weight, 
20ml blood collection, 24 hour dyspnea score, receipt of non-study diuretics, need of new 
inotropes or vasodilators 
Day 3: 48 urine collection/quantification, 48 hour standing weight, 20ml blood collection, 48 
hour dyspnea score, receipt of non-study diuretics, need of new inotropes or vasodilators.  
End of study. 
Day 30 (+/- 2 days): Telephone contact for the following events in past 30 days: 
• 
ER visits and reason for visits 
• 
Hospitalizations and reason for hospitalizations 
• 
Serious adverse events 
 
5.7 Research Blood, Plasma, and Urine Collection 
We will collect 20 ml of blood (10ml of serum and 10ml of plasma) at baseline (after consent), at 
24 hours, and at 48 hours/study conclusion. We will serially collect urine produced during the 
study period for analysis. Analyses will include fractional excretion of sodium, diuretic 
pharmacokinetics/dynamics, and measures of hemoconcentration.   

Protocol Version #: 6 
Protocol Date: 10/27/2017 
10
6.0 Risks 
This study will evaluate the addition of an oral thiazide, intravenous thiazide, or tolvaptan to 
augment intravenous loop diuretic therapy in patients with hypervolemic decompensated heart 
failure and diuretic resistance to adequately dosed loop diuretic monotherapy. Augmentation of 
loop diuretic therapy with a second diuretic (commonly a thiazide) is considered the standard-of-
care in diuretic resistance and is endorsed by the AHA/ACCF and HFSA guidelines.8,9   
Tolvaptan 
Several large scale clinical trials have demonstrated the safety of tolvaptan in patients with 
hypervolemic decompensated heart failure, including in those without hyponatremia. The 
EVEREST study evaluated 4,133 patients with decompensated heart failure randomized to 
placebo or tolvaptan for 60 days. The in-hospital serious adverse event rate was similar between 
tolvaptan (6.5%) and placebo (5.5%). The most common adverse effects of tolvaptan in these 
trials have been thirst (16%), dry mouth (8.4%), and polyuria. Hypernatermia occurred in 1.7% of 
tolvaptan patients vs 0.5% of placebo patients. Acute kidney injury, hypotension, and potassium 
derangements are not associated with tolvaptan therapy. As our duration of study is only 48 
hours, it is not anticipated that study participation will be associated with increased risks beyond 
standard diuresis augmentation with a thiazide. 
Hypernatremia/Over-correction of Serum Sodium 
While hyponatremia is not the target population of this study, patients with a serum sodium range 
of 130-145mEq/L are eligible to participate. Relative to the thiazide arm, patients with 
hyponatremia randomized to tolvaptan are at the unique, albeit rare, risk of over-correction of 
serum sodium. Overcorrection of sodium is commonly defined as an increase in serum sodium by 
more than 12mEq/L in 24 hours. Overcorrection of serum sodium is most likely to occur when 
the serum sodium is < 125mEq/L at baseline, which is an exclusion criterion of our study.  The 
SALT studies included patients with hyponatremia (serum sodium < 135mEq/L) from various 
disease states, including heart failure.  Only 5 patients (2.2%) of patients experienced a rise if 
serum sodium > 12mEq/L during any 24 hour time period, on a dose of 15mg to 60mg a day of 
tolvaptan. No patients experiencing this rapid correction and no patients in EVEREST developed 
osmotic demyelination syndrome (ODS). The FDA package insert for tolvaptan records that cases 
of ODS have occurred in post-marketing surveillance. In our study, we will only randomize 20 
patients to tolvaptan, calculating to 1-2 patients with hyponatremia being randomized to 
tolvaptan. The low rate of overcorrection in literature, small sample size, exclusion criteria 
(sodium < 130mEq/L, advanced liver disease, severe malnutrition), short duration of therapy in 
our trial, and twice daily serum sodium monitoring makes the risk of a patient experiencing 
overcorrection of serum sodium low in our study. All patients will be hospitalized for the duration 
of the study and will be monitored for neurologic symptoms.  
To minimize this risk, patients who are at highest risk of ODS at enrollment (serum sodium < 
130mEq/L) will receive a serum sodium assessment 12 hours after the first dose of study diuretic. 
If the serum sodium increases > 8mEq/L from baseline at 12 hours, the will receive protocolized 
management to prevent ODS.  
1) Intravenous D5W at 3ml/kg/hr  
2) Repeat serum sodium every 2 hours 
3) Neurologic monitoring for symptoms such as speech disturbances, altered mental status, 
and seizure activity 
4) D5W and every 2 hour serum sodium labs will be continued until the serum sodium is < 
8mEq/L above baseline sodium  
Patients will continue the loop diuretic therapy during this protocol. If the patient does not 
develop symptoms of ODS and responds to intravenous D5W therapy by hour 18 (6 hours after 
first serum sodium), they will be eligible for the scheduled second study diuretic dose at 24 hours. 
Patients experiencing any neurologic symptoms or who do not respond to intravenous D5W 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
11
therapy by hour 18 (6 hours after first serum sodium) will not be eligible for repeat study 
medication administration. All patients will be followed per the study protocol through Day 30.  
Hepatic toxicity 
Hepatotoxicity occurred in 3 patients in the TEMPO study, which evaluated the effects of 
Tolvaptan 60-120mg daily in a polycystic kidney disease patient population. In all 3 patients, the 
hepatic toxicity occurred after 3 months of therapy and resolved with tolvaptan discontinuation. 
Our study protocol will exclude patients with advanced liver disease, consistent with the updated 
FDA package labeling recommendations, and will administer a lower dose for only 48 hours.  
 
 
Thiazides (Metolazone or Chlorothiazide) 
In accordance with previous trials evaluating combination thiazide and loop diuretics (DOSE, 
CARRESS-HF), the metabolic risks include gout, hypokalemia, and hyponatremia. The risks 
include: hyponatremia, hypokalemia, gout flare/attack, and cardiac arrhythmias. In the 
CARRESS-HF study, ultrafiltration was compared to a step-wise diuretic protocol in 188 patients 
with hypervolemic, decompensated heart failure and worsening renal function. Of the 94 patients 
in the diuretic arm, 46% of participants received metolazone therapy. Only 3 (3%) patients 
experienced an electrolyte disorder, which included hypokalemia, hyponatremia, and 
hyperuricemia.  Arrhythmic events were not specifically reported. A retrospective comparison of 
intravenous and oral thiazide diuretics found the rate of hypokalemia, defined as a serum 
potassium < 4mEq/L, to be 71% in the oral thiazide group and 83% in the intravenous thiazide 
group.14 Given the small size of previous combination diuretic studies, incidence rates of gout 
attacks and cardiac arrhythmias have not been quantified and are not provided in package 
labeling.11 Our study will minimize hypokalemia and hyponatremia by monitoring the serum 
potassium and sodium every 12 hours during the study period. Electrolyte replacement will be 
performed at the discretion of the attending cardiologist, in accordance with standard of care 
practice.  
 
7.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants 
or Others 
 
A Serious Adverse Event (SAE) is an adverse event that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires prolongation of hospitalization which is not specifically required by the 
protocol nor is it elective 
• 
Results in permanent impairment of a body function or permanent damage to a body 
structure 
• 
Requires medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure 
Additionally, important medical events that may not result in death, be life-threatening, 
or prolong hospitalization may be considered SAEs when they jeopardize the patient or require 
medical or surgical intervention to prevent one of the serious outcomes listed above.  Example of 
such medical events include: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in prolonged 
hospitalization, or the development of drug dependency or drug abuse. Medical and scientific 
judgment must be exercised when classifying events as serious. 
 
The determination of adverse event severity rests on medical judgment of a medically qualified 
investigator. The severity of SAEs will be graded using the following definitions: 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
12
• 
Mild: awareness of sign, symptom, or event, but easily tolerated; 
• 
Moderate: discomfort enough to cause interference with usual activity and may warrant 
intervention; 
• 
Severe: incapacitating with inability to do usual activities or significantly affects clinical 
status, and warrants intervention. 
 
7.1 Assessment of Causality  
A medically-qualified investigator must assess the relationship of any SAE to the use of study 
drug, based on available information, using the following guidelines: 
Possibly Related - There is a reasonable possibility that the adverse event may have been caused 
by the study drug. The temporal relationship of the adverse event to study drug administration 
makes a causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide sufficient explanation for the observed event. 
Not Possibly Related- It is unlikely that the event was caused by the study drug. The temporal 
relationship of the adverse event to the study drug administration makes causal relationship 
unlikely and other drugs, therapeutic interventions or underlying conditions provide a more likely 
explanation for the event. 
Expectedness - The expectedness of an adverse event or suspected adverse reaction shall be 
determined according to the package insert for U.S. marketed furosemide and tolvaptan. Any AE 
that is not identified in nature, severity, or specificity in the current U.S. package insert is 
considered unexpected. Events described in the U.S. package insert as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but not specifically 
mentioned as occurring with the particular drug under investigation are considered unexpected. 
 
7.2 Reporting of SAE 
All serious adverse events occurring from randomization through the 30 day follow-up period 
will be collected. The Site Investigator is responsible for monitoring the safety of patients 
enrolled into the study. The following adverse events are anticipated, disease related-events in 
patients with decompensated heart failure however they should still be reported on the Serious 
Adverse Event form in the REDCAP Database (some may require reporting as study endpoints): 
• 
New Atrial Arrhythmia: A “new” diagnosis of atrial arrhythmia (includes atrial 
fibrillation, atrial flutter, ectopic atrial tachycardia) lasting > 30 seconds OR any atrial 
arrhythmia which causes hemodynamic instability (MAP < 60 and requiring intervention) 
• 
New Ventricular Arrhythmia: Ventricular tachycardia lasting longer than 30 seconds, or 
frequent non-sustained VT causing hemodynamic instability with MAP < 60 mmHg 
requiring intervention or > 1 intra-cardiac defibrillation or external cardiac defibrillation 
shock or ventricular fibrillation requiring defibrillation 
• 
Hypotension: SBP < 85 for 2 repeated measurements within 30 minutes or lasting at least 
30 minutes or symptomatic hypotension necessitating clinical intervention (defined as 
vasopressor support, intravenous fluid boluses, or initiation of inotropes) 
• 
Myocardial infarction: a cardiac event including an elevation in troponin above baseline 
with our without ECG changes that is judged to be a myocardial infarction by the treating 
attending cardiologist 
• 
Cardiac arrest: any ventricular arrhythmic or pulseless electrical event that requires 
immediate life-sustaining medical therapies 
• 
Acute renal failure: A rise is serum creatinine of 1mg/dl or more from the baseline serum 
creatinine in the 48 hour treatment period 
• 
Acute renal failure requiring dialysis: an acute renal failure event that began during the 
48 hour study period and necessitates new hemodialysis during the hospitalization 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
13
• 
Worsening heart failure: the need for rescue therapy (additional open label loop diuretic, 
spironolactone doses >75mg/day, eplerenone > 75mg/day, non-study thiazides (at a dose 
of metolazone 2.5mg or greater equivalence), systemic acetazolamide (for diuretic 
indication), triamterene, amiloride, ultrafiltration, hemodialysis, or mechanical 
circulatory or respiratory support) in the 48 hour treatment period 
• 
Death 
• 
Metabolic SAE (during 48 hour treatment period): 
o Severe Hypokalemia: Serum potassium value < 3.0mEq/L 
o Severe Hyponatremia: Serum sodium value < 130mEq/L and a decrease of 
5mEq/L or more from enrollment serum sodium 
o Overcorrection of serum sodium: increase in serum sodium from baseline by 
>12mEq/L in 24 hours, increase in >8mEq/L in 12 hours, or receipt of 
intravenous fluids because of symptoms of overcorrection of serum sodium 
regardless of the numerical rise 
o Hyperkalemia: serum potassium value > 5.5mEq/L  
o Gout: acute gout attack requiring treatment with an anti-inflammatory agent 
 
All serious adverse events must be recorded in the Serious Adverse Event Record of the 
patient’s REDCAP database. All serious adverse events should be monitored until stabilization or 
resolution. 
 
Reporting to Local IRB. Investigators are also responsible for promptly reporting unexpected 
adverse events (serious and non serious) to their reviewing IRB in accordance with local 
requirements. The Vanderbilt investigational site will report DSM reports to the Vanderbilt IRB 
annually at the time of continuing review at a minimum. If 5 unexpected SAES occur, the trial 
will be temporarily halted and the Vanderbilt IRB will be informed. After review, the study will 
resume if the IRB approves continuation with or without alterations in the study protocol. 
 
 
Reporting to the Industry Sponsor 
The investigator will notify the Sponsor within 24 hours of being notified of any SAE.  
The investigator will also notify the Sponsor of any pregnancy during the study period within 3 
days of being notified. For all non-serious adverse events, the investigator will notify the Sponsor 
of all events as a line item list at the end of the study.  
 
7.3 Study Termination 
The study may be terminated based on review of serious adverse events and unexpected events. If 
5 unexpected SAEs occur this will trigger a temporary halt to the study until additional review of 
these events is conducted by the PI and IRB. 
 
8.0 Study Withdrawal/Discontinuation 
A patient may withdraw at the study at anytime. The patient will inform the site investigator of 
their desire to withdraw. All study-based therapy will stop at this point, and the attending 
cardiologist will perform any further care. All study data collected to that time point will be 
included in the analysis. The withdrawal reason will be documented.  
The site investigator will withdraw patients requiring therapy for overcorrection of serum sodium 
who experience any neurologic symptoms or who do not respond to intravenous D5W therapy 
within 6 hours. All patients will be followed per the study protocol through Day 30. 
 
9.0 Statistical Considerations 
9.1 Sample Size 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
14
The study will have a sample size of 60 patients, equally allocated to the three study treatment 
groups. 
 
9.2 Power Analysis 
We have collaborated with Department of Biostatistics at Vanderbilt University Medical Center 
to employ the best statistical methods that allow our study to be realistic and achievable. Power 
calculations are difficult because of the lack of prospective trials comparing combination diuretic 
therapy and the numerous flaws in the methods of these previous studies. We will utilize change 
in weight as the primary outcome because weight change has been utilized as a primary efficacy 
outcome in landmark heart failure diuretic trials (CARRESS-HF19) and has less standard 
deviation than net urine output. In previous studies standard deviation of weight loss changes 
between groups varied with an approximate value of 1.6kg.14, 23 If the minimum clinically 
meaningful difference in the experimental and control means is 1.5kg, we will be able to reject 
the null hypothesis that the population means of the experimental and control groups are equal 
with 82.3% power.   The Type I error probability associated with this test of this null hypothesis 
is 0.05.  
 
9.3 Statistical Methods 
We will utilize an intention-to-treat analysis for the primary outcome. We will also perform a per-
protocol analysis for the primary outcome in patients completing the 48-hour treatment period 
without missing study doses. Metolazone will be the comparator arm, against which both 
chlorothiazide and tolvaptan treatment arms will be individually compared. Parametric 
continuous variables will be presented as mean (standard deviation) and non-parametric 
continuous variables will be presented as median (interquartile range). Nominal data will be 
presented as the number (percentage). We will employ a student’s t test for the independent 
continuous primary outcome variable and other secondary outcomes using metolazone as the 
comparison group for both intravenous chlorothiazide and oral tolvaptan. For secondary 
outcomes, of which metolazone will again be the comparison group, fisher’s exact test will be 
used for secondary outcomes that are nominal data. A two tailed p-value of less than or equal to 
0.05 will be considered significant. 
 
10.0 
Privacy/Confidentiality Issues 
 
All study protocols and procedures will be submitted to the site’s Institutional Review Board for 
approval. All data collected will be stored in a secure REDCAP database, accessible only by key 
study personnel. The following identifying information will be collected: age, medical record 
number, admission date, and discharge date. Patient-reported congestion score surveys will be de-
identified, using a study identification number. All patient-reported congestion score surveys and 
consent forms and will be stored in a locked cabinet in the site investigator's office. For statistical 
analyses, all identifying information will be removed. Candidates aged > 89 years will be 
condensed into a category of age greater than or equal to 90 years of age to protect their identity.   
 
11.0 
Follow-up and Record Retention 
 
This study is anticipated to last 12 months. All records will be stored in a secure REDCAP 
database.  
 
 
 
 
 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
15
 
 
 
 
 
References 
1. Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW. Temporal trends in 
clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 
to 2004: findings from Acute Decompensated Heart Failure National Registry 
(ADHERE). Am Heart J 2007;153:1021-8. 
2. AbrahamWT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, et 
al. In-hospital mortality in patients with acute decompensated heart failure requiring 
intravenous vasoactive medications: an analysis from the Acute Decompensated Heart 
Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57-64. 
3.  Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et 
al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the 
EVEREST Outcome Trial. JAMA 2007;297:1319-31. 
4. CuffeMS, CaliffRM,AdamsKF, Benza R,Bourge R,ColucciWS,et al. Short-term 
intravenous milrinone for acute exacerbation of chronic heart failure: a randomized 
controlled trial. JAMA 2002;287:1541-7. 
5. Neuberg GW, Miller AB, O'Connor CM, Belkin RN, Carson PE, et al. Diuretic resistance 
predicts mortality in patients with advanced heart failure. Am Heart J 2002;144:31-8. 
 
6. Yilmaz MB1, Gayat E, Salem R, Lassus J, Nikolaou M et al. Impact of diuretic dosing on 
mortality in acute heart failure using a propensity-matched analysis. European Journal of 
Heart Failure (2011) 13, 1244–1252. 
 
7. Testani JM1, Cappola TP, Brensinger CM, Shannon RP, Kimmel SE. Interaction between 
loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart 
failure. JACC 2011;58:375-382. 
8. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, et al. 
HFSA 2010 comprehensive heart failure practice guideline. J Card Fail 2010;16:e1-194. 
9. Yancy CW, Jessup M, Bozkurt B, Masoudi FA, Butler J, McBride PE, et al. 2013 
ACCF/AHA guideline for the management of heart failure: a report of the American 
College of Cardiology Foundation/American Heart Association Task Force on Practice 
Guidelines. J Am Coll Cardiol 2013;62:1495-539. 
10. Shah MR, Stevenson LW. Searching for evidence: Refractory questions in advanced 
heart failure. J Card Fail 2004;10:210-8. 
11. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type 
diuretics in heart failure. J Am Coll Cardiol 2010;56:1527-34. 
12. Metolazone [package insert]. Morgantown: Mylan Pharmaceuticals; 2004. 
13. Michael Moranville, Suji Choi, Jennifer Hogg, Jonathan D. Rich Metolazone Versus 
Chlorothiazide as Add-On Therapy to Loop Diuretics in Patients with Acute 
Decompensated Heart Failure and Renal Insufficiency; 2013 HFSA abstract. Journal of 
Cardiac Failure Vol. 19 No. 8S August 2013.  
14. Kissling K, Pickworth KK. Comparison of the Effects of Combination Diuretic Therapy 
with Oral Hydrochlorothiazide or Intravenous Chlorothiazide in Patients Receiving 
Intravenous Furosemide Therapy for the Treatment of Heart Failure. Pharmacotherapy. 
2014;34(8):882–887. 
15. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J,Zampino M, et al. 
Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: 
results from a double-blind, randomized trial. Circulation 2003;107:2690-6. 
16. Udelson JE, Bilsker M, Hauptman PJ, Sequeira R, Thomas I, O’Brien T, et al. A 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
16
multicenter, randomized, double-blind, placebo-controlled study of tolvaptan 
monotherapy compared to furosemide and the combination of tolvaptan and furosemide 
in patients with heart failure and systolic dysfunction. J Card Fail 2011;17:973-81. 
17. Gheorghiade M, Konstam MA, Burnett JC, Grinfeld L, Maggioni AP, Swedberg K, et al. 
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients 
hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 
2007;297:1332-43. 
18. Udelson JE, Bilsker M, Hauptman PJ, et al. A Multicenter, Randomized, Double-blind, 
Placebo-controlled Study of Tolvaptan Monotherapy Compared to Furosemide to the 
Combinations of Tolvaptan and Furosmide in Patients with Heart Failure and Systolic 
Dysfunction. J Cardiac Failure 2011; 17:973-981.18 
19. Bart BA, Goldsmith SR, Lee KL, Redfield MM, Felker GM, O'Connor CM, et al. 
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;18(3):176-82. 
20. Sica DA. Metolazone and Its Role in Edema Management. CHF. 2003;9:100-105. 
21. Goodman & Gillman’s The Pharmacological Basis of Therapeutics 12th edition. 
22. Borhani NO. Chlorothiazide and hydrochlorothiazide: a comparative study of their 
hypotensive, saluretic, and hyperuricemic action. Ann Intern Med 1960;53:342–58. 
23. Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diuretic 
treatment in severe heart failure: a randomized controlled trial. Br Heart J. 1994;71:146-
150. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
17
 
 
 
 
 
Appendix A: Schedule of Study Assessments 
 
Screen 
Baseline 12 hrs 
24hrs 
36 hrs 
48 hrs 
Day 30 
(Phone 
Call) 
Informed Consent 
x 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
x 
 
 
 
 
 
 
Screening 
electrolytes, renal 
function, liver 
function, pregnancy 
status if applicable 
x 
 
 
 
 
 
 
Vital Signs 
x 
x 
x 
x 
x 
x 
 
Standing Weight 
 
x 
 
x 
 
x 
 
Current 
Cardiovascular 
Medications 
 
x 
 
x 
 
x 
 
Loop diuretic 
regimen evaluation 
x 
x 
 
x 
 
x 
 
BMP 
x 
x 
x 
x 
x 
x 
 
Biobank blood  
 
x 
 
x 
 
x 
 
Biobank plasma 
 
x 
 
x 
 
x 
 
Urine Collection 
x 
x 
x 
x 
x 
x 
 
Congestion Score 
Assessment 
 
x 
 
x 
 
x 
 
Adverse Event 
Assessment 
 
 
 
x 
 
x 
 
Outcomes 
Assessment 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
18
 
 
 
 
 
Appendix B: Patient-Reported Congestion Score 
This score will be done at enrollment and repeated at 24 and 48 hours.  
 
 
 
 
 
 
 
 
 
 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
19
 
 
 
 
Appendix C: 30-Day Follow up Telephone Call Script 
The site investigator will perform this phone call at 30 ± 2 days after enrollment.  
 
Hello, my name is Dr. (name) from (Medical Center). I am calling to briefly follow up 
with you about the research study you participated in during your recent hospitalization 
for heart failure approximately one month ago. The study compared 3 different types of 
fluid removal medications in combination with furosemide (Lasix) and was called 
“Comparison of oral thiazides versus intravenous thiazides versus tolvaptan in 
combination with loop diuretics for diuretic resistant decompensated heart failure”.  
 
Do you have time now to complete the brief post-study survey that was mentioned to you 
at the start of the study? It should take no more than 5 minutes of your time. Thank you 
for your participation. 
 
If subject has deceased since discharge 
I am very sorry for your loss. It is important that we ask 3 simple questions to understand 
this unfortunate event. Could you please tell me: 
• Date of death 
• Cause of death 
• Location of death 
o Out-of-hospital 
o In-hospital 
▪ Initial reason for hospitalization 
 
If subject is alive 
Since your discharge from (Medical Center) on (Discharge Date), have you experienced 
any of the following events? 
1. Admission to any hospital? 
a. Admission reason: 
i. Heart failure 
ii. Heart rhythm issue 
iii. Low blood pressure 
iv. Heart attack 
v. Cardiac arrest 
vi. Kidney failure 
1. Was dialysis required? 
vii. Other (free text) 
 
2. Gone to any emergency room? 
a. Reason for emergency room visit: 
i. Heart failure 
ii. Heart rhythm issue 

Protocol Version #: 6 
Protocol Date: 10/27/2017 
20
iii. Low blood pressure 
iv. Heart attack 
v. Cardiac arrest 
vi. Kidney failure 
vii. Other (free text) 
 
3. Any other serious health event? 
a. Document event if so 
 
This ends your participation in this research study. Thank you very much for your 
participation in this research study and for your time today. Your participation is helping 
our medical team understand how to treat patients with heart failure better. Do you have 
any other questions at this time? 
 
Goodbye. 
 
End of Script 
 
 

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