Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the short term efficacy and safety of tolvaptan in subjects hospitalized for worsening heart failure who have volume overload and one of the following: renal insufficiency, or hyponatremia or inadequate response to diuretic therapy. The primary variable for assessing efficacy will be self-assessed 7-point dyspnea score at 8 and 16 hours.

Official Title
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A Phase 3 Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Tolvaptan or Samsca
* Drug: placebo or sugar pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects hospitalized for worsening heart failure and randomized within 36 hours of initial presentation. Males and females 18 years of age or older. NYHA Class III or IV on admission to the hospital. Able to understand content of and willing to provide written informed consent Dyspnea, measured by the 5-point current dyspnea scale (moderately short of breath or worse), within 2 hours of randomization and dosing. The following must be met within 12 hours of randomization. The subject must have signs of extracellular volume expansion, defined as two or more of the following five: Signs of RHF ( jugular venous distention, pitting edema (≥1+), ascites) and/or Signs of LHF (pulmonary congestion on chest x-ray, pulmonary rales) Have at least one of the following: eGFR < 60ml/min/1.73m2, OR serum sodium ≤ 134 mEq/L, OR urine output ≤ 125 ml/hr over anytime frame of at least 2 hours, following administration of IV furosemide of at least 40mg. See table below. Time Period (hr) Cumulative UO (mL) 2 <250 3 <375 4 <500 5 <625 6 <750 7 <875 8 <1000 Exclusion Criteria: Positive urine pregnancy test for women of child bearing potential. Inability to provide written informed consent. Cardiac surgery within 60 days prior to study randomization. Acute Coronary Syndrome (ACS) or percutaneous coronary intervention within 30 days prior to study randomization. Planned revascularization procedures, cardiac mechanical support implantation, cardiac transplantation, or other cardiac surgery within 30 days following study randomization. Planned electrophysiologic (EP) device implantation within 7 days following study randomization. Subjects who are on cardiac mechanical support. Co-morbid condition with an expected survival less than six months. History of a cerebrovascular accident within the last 30 days. Hemodynamically significant uncorrected primary cardiac valvular disease. Hypertrophic cardiomyopathy (obstructive or non-obstructive). Uncorrected thyroid disease, active myocarditis or known amyloid cardiomyopathy. History of primary significant liver disease or acute hepatic failure, as defined by the investigator. Chronic uncontrolled diabetes mellitus as determined by the investigator. Supine systolic arterial blood pressure < 90 mmHg. Serum creatinine > 3.5 mg/dL or undergoing dialysis. Hemoglobin < 9 g/dL History of hypersensitivity and/or idiosyncratic reaction to benzazepine derivatives (such as benazepril). Inability to take oral medications. Participation in another clinical drug or device trial where the last dose of drug was within the past 30 days or an investigational medical device is currently implanted. Previous exposure to tolvaptan within 7 days prior to randomization. Subjects with refractory, end-stage, heart failure defined as subjects who are appropriate candidates for specialized treatment strategies, such as ventricular assist devices, continuous positive IV inotropic therapy, or hospice care. Ultrafiltration within 7 days prior to randomization or planned. Active gout Serum sodium >144 mEq/L

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tolvaptan, Samsca<br>Tolvaptan, Samsca, uncoated tablet, 30 mg, once per day, up to 7 days. | Drug: Tolvaptan or Samsca<br>* uncoated tablet, 30mg, once per day, for up to 7 days.<br>|
| Placebo Comparator: sugar pill<br>placebo, sugar pill | Drug: placebo or sugar pill<br>* sugar pill<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the short term efficacy and safety of tolvaptan in subjects hospitalized for worsening heart failure who have volume overload and one of the following: renal insufficiency, or hyponatremia or inadequate response to diuretic therapy. | The primary variable for assessing efficacy will be self-assessed 7-point dyspnea score at 8 and 16 hours. | 8 and 16 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in body weight measured daily while hospitalized up to 7 days. | Change from baseline in body weight measured daily while hospitalized up to 7 days. | up to 7 days | 
| Diuretic dose measured daily while hospitalized up to 7 days. | Diuretic dose measured daily while hospitalized up to 7 days. | up to 7 days. | 
| Change from baseline in estimated glomerular filtration rate (eGFR) at discharge or day 7, whichever comes first. | Change from baseline in estimated glomerular filtration rate (eGFR) at discharge or day 7, whichever comes first. | at discharge or day 7, whichever comes first. | 
| Days alive and out of the hospital over 30 days | Days alive and out of the hospital over 30 days | 30 days. | 
| Change from baseline in cognitive function at 48 hours or discharge, whichever comes first | Change from baseline in cognitive function at 48 hours or discharge, whichever comes first | at 48 hours or dischage, whichever comes first | 
| Re-hospitalization for worsening heart failure or death at 30 days | Re-hospitalization for worsening heart failure or death at 30 days | 30 days. |