Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure

Study Overview
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Brief Summary
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The primary objective of this study is to compare the effects of oral Tolvaptan vs. placebo as an adjunct to fixed dose IV furosemide on dyspnea relief in patients with acute decompensated heart failure The primary hypothesis is that the addition of oral Tolvaptan to fixed dose furosemide will be more effective at relieving dyspnea than fixed dose furosemide alone

Detailed Description
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This study will be a randomized, double blind, placebo controlled, multi-center clinical trial of patients with signs and symptoms consistent with AHF within 24 hours of presentation at Emergency Department. A total of approximately 250 patients will be enrolled in the trial. Patients will be randomized in a 1:1 ratio to either of 2 treatment regimens: Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral Tolvaptan (given at 0, 24 and 48 hours) Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral placebo (given at 0, 24 and 48 hours) The study treatment regimen will be administered from randomization through 48 hours, at which point Tolvaptan/placebo will be discontinued and all diuretic treatment will be adjusted at the treating physician's discretion. The primary endpoint will be the proportion of patients with at least moderate improvement in dyspnea by Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours. Patients will be followed daily for the duration of hospitalization or for 7 days (whichever is shortest). All patients will have Day 30 follow up phone contact for assessment of vital status and interval hospitalizations.

Official Title
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The Targeting Acute Congestion With Tolvaptan In Congestive Heart Failure Study

Conditions
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Heart Failure, Dyspnea

Intervention / Treatment
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* Drug: Tolvaptan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age Daily oral dose of furosemide between ≥ 40 mg(or equivalent) Identified within 24 hours of presentation, defined for purposes of this study as the time of initial dose of intravenous loop diuretic Prior clinical HF diagnosis that was treated with oral loop diuretics for at least 1 month Admission for acute decompensated Heart Failure (HF) as determined by dyspnea at rest or with minimal exertion Brain Natriuretic Peptide (BNP) > 400 or NTproBNP > 2000 pg/mL AND at least one of the following additional signs and symptoms: Orthopnea Peripheral edema Elevated JVP (Jugular Venous Pressure) Pulmonary rales Congestion on Chest X-ray No plan for revascularization, cardiac transplant, of ventricular assist device implantation, or other cardiac surgery within 60 days of randomization Signed informed consent Exclusion Criteria: Serum Na > 140 meq/L Received IV vasoactive treatment or ultra-filtration therapy for HF since initial presentation Treatment plan during current hospitalization includes IV vasoactive treatment or ultra-filtration for HF Systolic Blood Pressure (SBP)<90mmHg Serum-Cr>3.5mg/dl or currently undergoing renal replacement therapy . Known underlying liver disease Hemodynamically significant arrhythmias ACS(Acute coronary syndrome) within 4 weeks prior to study entry Active myocarditis Hypertrophic obstructive, restrictive, constrictive cardiomyopathy Severe stenotic valvular disease Complex congenital heart disease Constrictive pericarditis Clinical evidence of digoxin toxicity Need for mechanical hemodynamic support Terminal illness (other than heart failure) with expected survival time of less than 1 year History of adverse reaction to Tolvaptan Enrollment or planned enrollment in another randomized clinical trial during this hospitalization Pregnant or breast-feeding Inability to comply with planned study procedures

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolvaptan<br>Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral Tolvaptan (given at 0, 24 and 48 hours) | Drug: Tolvaptan<br>* IV furosemide plusTolvaptan (given at 0, 24 and 48 hours)<br>* Other names: Samsca;|
| Placebo Comparator: Placebo<br>Fixed-dose IV furosemide (1 x total daily oral dose given intravenously in divided doses Q12 hours OR 40 mg IV Q12 hours, whichever is greater) + oral placebo (given at 0, 24 and 48 hours) | Drug: Placebo<br>* IV furosemide plus oral placebo (given at 0, 24 and 48 hours)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours | The number of patients with at least moderate improvement (as reported by patient) in dyspnea Likert scale at both 8 AND 24 hours AND without the need for escalation of therapy due to worsening heart failure (rescue therapy) or death within 24 hours. | 8 and 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal Function | Change in Serum creatinine from baseline to 24, 48 and 72 hours | 0, 24, 48 and 72 hours | 
| Weight Loss | Change in body weight from baseline to 24, 48, and 72 hours | 0, 24, 48, and 72 hours | 
| Fluid Loss | Change from baseline fluid balance at 24, 48, and 72 hours | 0, 24, 48, and 72 hours | 
| Dyspnea Likert | Number of patients that experience moderate or greater improvement (patient reported) in dyspnea by 7 point Likert scale at 48 and 72 hours | 48 and 72 hours | 
| Hospital Stay | Total days spent in hospital from baseline until discharge or death | 7 days | 
| Worsening or Persistent Heart Failure or Death | Number of patients with worsening heart failure or death | 72 hrs | 
| Over-diuresis | clinical evidence of volume depletion requiring intervention other than holding diuretics during the 72 hours after randomization | 72 hours | 
| Serum Sodium | Change in serum sodium from baseline to 24, 48, and 72 hours | 0, 24, 48, and 72 hours | 
| Dyspnea 11 Point NRS | Change in NRS for assessment of dyspnea from baseline to 24, 48, and 72 hours (scale ranges from 0-No difficulty breathing to 10-Difficulty as bad as you can imagine) | 0, 24, 48, and 72 hours | 
| Freedom From Congestion | Jugular Venous Pressure (JVP) < 8 cm, no orthopnea, trace peripheral edema or less, and will be assessed at 24, 48, and 72 hours | 24, 48, and 72 hours | 
| Development of Worsening Renal Function | increase in serum creatinine ≥ 0.3mg/dl from randomization at any time point during 72 hours after randomization | 72 hours | 
| Days Hospitalized or Deceased | Total days hospitalized or deceased during the 30 days after randomization | 30 days | 
| All Cause Death or Rehospitalization | All cause death or rehospitalization (to include unscheduled clinic visits or ED visits) at 30 days (Kaplan-Meier and 95% confidence interval) | 30 days |