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

The Targeting Acute Congestion With Tolvaptan In Congestive Heart Failure Study

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

Study Overview

• Status: Completed
• Conditions: Heart Failure; Dyspnea
• Intervention / Treatment: Drug: Tolvaptan; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 257
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: Michael Felker, MD, Duke Clinical Research Institute

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: July 17, 2012
• First Submitted That Met QC Criteria: July 17, 2012
• First Posted (Estimate): July 19, 2012

Study Record Updates

• Last Update Posted (Actual): April 27, 2017
• Last Update Submitted That Met QC Criteria: March 17, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Heart Failure; Dyspnea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: Pro00037557

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Not yet decided.