Tolvaptan For Worsening Outpatient Heart Failure: Role of Copeptin In Identifying Responders

This study will be a randomized, double blind, positive control, multi-center clinical trial
enrolling patients who present in the outpatient setting with signs and symptoms consistent
with worsening congestive heart failure. The sample size for the study is 40 patients.
Candidates for the study will be identified by screening outpatients presenting with
worsening heart failure.

Patients who qualify for the study will be enrolled within 24 hours of identification.
Patients will be randomized in a 1:1 fashion to one of two treatment arms:

- Augmentation of current daily dose of oral loop diuretic + 30 mg of oral Tolvaptan daily

- Augmentation of current daily dose of oral loop diuretic + placebo of oral Tolvaptan
daily

Patients will initiate study medication in a hospital setting and will be observed for a
period of time that will depend upon their baseline serum sodium and response to study drug.
In most cases patients will be observed for 8 hours. Following this observational period,
patients will leave the hospital setting and the remainder of the study will consist of
follow-up by outpatient visits or by telephone. All patients will have Day 30 follow up phone
contact for assessment of vital status, adverse events and morbidity during this period.

The primary objectives of this study will be to compare the effects of oral tolvaptan plus
augmented loop diuretic versus augmented loop diuretic on 1) short term changes in body
weight with and without stratification for baseline copeptin and 2) an index targeted to
signs and symptoms of congestion in patients presenting with worsening congestive heart
failure in the outpatient setting with and without prespecified post hoc stratification based
on baseline copeptin level.

Inclusion Criteria:

- ≥ 18 years of age

- Presenting to clinic with worsening heart failure due congestion (fluid overload)
Patient reported worsening fluid overload based on perception of edema and/or weight
gain With at least one of the following symptoms

- Worsening dyspnea on exertion or fatigue

- Worsening orthopnea or paroxysmal nocturnal dyspnea (PND)

- Perception of abdominal and/or lower extremity edema

- Early satiety and/or decreased appetite And at least one of the following signs

- Lower extremity edema

- Ascites

- Elevated jugular venous distension (JVD)

- Pulmonary rales

- Daily oral dose of loop diuretic

- Prior history of heart failure with this diagnosis for at least 1 month with preserved
or reduced left ventricular ejection fraction

- Signed informed consent

Exclusion Criteria:

- Patients with symptomatic hyponatremia will be excluded from the study.

- Patients with severe hyponatremia, defined as serum sodium < 125 milliequivalents per
Liter (mEq/L) at the time of screening, will be excluded regardless of whether they
are symptomatic or not.

- Patients with the following predisposing factors for osmotic demyelinating syndrome
(ODS), assessed by the study investigator judgment, will be excluded: chronic
alcoholism at the time of study, severe liver disease, marked malnutrition, and risk
for chronic hypoxia.

- Patients currently undergoing renal replacement therapy

- Planned hospitalization for acute heart failure

- History of primary significant liver disease or acute hepatic failure, as defined by
the investigator

- Hemodynamically significant arrhythmias

- Acute coronary syndrome (ACS) or acute myocardial infarction within 4 weeks prior to
study entry

- Active myocarditis

- Hypertrophic obstructive, restrictive, or constrictive cardiomyopathy

- Severe stenotic valvular disease amendable to surgical treatment

- Complex congenital heart disease

- Constrictive pericarditis

- Clinical evidence of digoxin toxicity

- History of adverse reaction or clinical contraindication to tolvaptan

- Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors

- Inability of patient to sense and/or respond to thirst

- History of hypersensitivity to tolvaptan

- Patient is anuric

- Enrollment or planned enrollment in another randomized clinical trial during the study
period

- Pregnant or breast-feeding

- Inability to comply with planned study procedures