Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure (TACTICS-HF)

Study Description

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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

Condition or disease	Intervention/treatment	Phase
Heart Failure; Dyspnea	Drug: Tolvaptan; Drug: Placebo	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	257 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	The Targeting Acute Congestion With Tolvaptan In Congestive Heart Failure Study
Study Start Date :	October 2012
Actual Primary Completion Date :	February 2016
Actual Study Completion Date :	February 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Tolvaptan; 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; IV furosemide plusTolvaptan (given at 0, 24 and 48 hours); Other Name: Samsca
Placebo Comparator: Placebo; 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; IV furosemide plus oral placebo (given at 0, 24 and 48 hours)

Outcome Measures

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Primary Outcome Measures :

1. Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours [ Time Frame: 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.

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

United States, Colorado
University of Colorado at Denver and Health Sciences Center
Aurora, Colorado, United States, 80045
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
Northeast Georgia Heart Center
Gainesville, Georgia, United States, 30501
Mercer University School of Medicine
Macon, Georgia, United States, 31201
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Indiana
Indiana University School of Medicine
Indianapolis, Indiana, United States, 46202
United States, Minnesota
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10461
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Novant Health Heart and Vascular
Charlotte, North Carolina, United States, 28204
Duke University Medical Center
Durham, North Carolina, United States, 27713
Southeastern Regional Medical Center
Lumberton, North Carolina, United States, 28358
United States, Ohio
The Christ Hospital
Cincinnati, Ohio, United States, 45219
University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45267
United States, Pennsylvania
Allegheny Valley Hospital
Natrona Heights, Pennsylvania, United States, 15065
Grand View - Lehigh Valley Health Services
Sellersville, Pennsylvania, United States, 18960
United States, Texas
UT Southwestern Medical center
Dallas, Texas, United States, 75390
United States, Virginia
Inova Heart and Vascular Institute
Falls Church, Virginia, United States, 22042

Sponsors and Collaborators

Duke University

Investigators

Principal Investigator:	Michael Felker, MD	Duke Clinical Research Institute

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Felker GM, Mentz RJ, Cole RT, Adams KF, Egnaczyk GF, Fiuzat M, Patel CB, Echols M, Khouri MG, Tauras JM, Gupta D, Monds P, Roberts R, O'Connor CM. Efficacy and Safety of Tolvaptan in Patients Hospitalized With Acute Heart Failure. J Am Coll Cardiol. 2017 Mar 21;69(11):1399-1406. doi: 10.1016/j.jacc.2016.09.004. Epub 2016 Sep 18.

Responsible Party:	Duke University
ClinicalTrials.gov Identifier:	NCT01644331 History of Changes
Other Study ID Numbers:	Pro00037557
First Posted:	July 19, 2012
Results First Posted:	April 27, 2017
Last Update Posted:	April 27, 2017
Last Verified:	March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided
Plan Description:	Not yet decided.

Additional relevant MeSH terms:

Heart Failure; Dyspnea; Heart Diseases; Cardiovascular Diseases; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Furosemide	Tolvaptan; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Sodium Potassium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Antidiuretic Hormone Receptor Antagonists