Brief Summary
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
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
Brief Title
Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure
Detailed Description
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Heart Failure
Dyspnea
Eligibility Criteria
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
* ≥ 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
Inclusion Criteria
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
* ≥ 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
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01644331
Org Class
Other
Org Full Name
Duke University
Org Study Id
Pro00037557
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
The Targeting Acute Congestion With Tolvaptan In Congestive Heart Failure Study
Primary Outcomes
Outcome Description
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.
Outcome Measure
Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours
Outcome Time Frame
8 and 24 hours
Secondary Outcomes
Outcome Description
Change in Serum creatinine from baseline to 24, 48 and 72 hours
Outcome Time Frame
0, 24, 48 and 72 hours
Outcome Measure
Renal Function
Outcome Description
Change in body weight from baseline to 24, 48, and 72 hours
Outcome Time Frame
0, 24, 48, and 72 hours
Outcome Measure
Weight Loss
Outcome Description
Change from baseline fluid balance at 24, 48, and 72 hours
Outcome Time Frame
0, 24, 48, and 72 hours
Outcome Measure
Fluid Loss
Outcome Description
Number of patients that experience moderate or greater improvement (patient reported) in dyspnea by 7 point Likert scale at 48 and 72 hours
Outcome Time Frame
48 and 72 hours
Outcome Measure
Dyspnea Likert
Outcome Description
Total days spent in hospital from baseline until discharge or death
Outcome Time Frame
7 days
Outcome Measure
Hospital Stay
Outcome Description
Number of patients with worsening heart failure or death
Outcome Time Frame
72 hrs
Outcome Measure
Worsening or Persistent Heart Failure or Death
Outcome Description
clinical evidence of volume depletion requiring intervention other than holding diuretics during the 72 hours after randomization
Outcome Time Frame
72 hours
Outcome Measure
Over-diuresis
Outcome Description
Change in serum sodium from baseline to 24, 48, and 72 hours
Outcome Time Frame
0, 24, 48, and 72 hours
Outcome Measure
Serum Sodium
Outcome Description
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)
Outcome Time Frame
0, 24, 48, and 72 hours
Outcome Measure
Dyspnea 11 Point NRS
Outcome Description
Jugular Venous Pressure (JVP) \< 8 cm, no orthopnea, trace peripheral edema or less, and will be assessed at 24, 48, and 72 hours
Outcome Time Frame
24, 48, and 72 hours
Outcome Measure
Freedom From Congestion
Outcome Description
increase in serum creatinine ≥ 0.3mg/dl from randomization at any time point during 72 hours after randomization
Outcome Time Frame
72 hours
Outcome Measure
Development of Worsening Renal Function
Outcome Description
Total days hospitalized or deceased during the 30 days after randomization
Outcome Time Frame
30 days
Outcome Measure
Days Hospitalized or Deceased
Outcome Description
All cause death or rehospitalization (to include unscheduled clinic visits or ED visits) at 30 days (Kaplan-Meier and 95% confidence interval)
Outcome Time Frame
30 days
Outcome Measure
All Cause Death or Rehospitalization
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
James Tauras
Investigator Email
jtauras@montefiore.org
Investigator Phone