Clinical trial NCT01644331: Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure
Official title: The Targeting Acute Congestion With Tolvaptan In Congestive Heart Failure Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Dyspnea
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2012-07-19
Enrollment: 257
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

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

Primary outcomes:
measure: Dyspnea Improvement Measured by Likert Scale at 8 and 24 Hours
timeFrame: 8 and 24 hours
Secondary outcomes:
measure: Renal Function
timeFrame: 0, 24, 48 and 72 hours
measure: Weight Loss
timeFrame: 0, 24, 48, and 72 hours
measure: Fluid Loss
timeFrame: 0, 24, 48, and 72 hours
measure: Dyspnea Likert
timeFrame: 48 and 72 hours
measure: Hospital Stay
timeFrame: 7 days
measure: Worsening or Persistent Heart Failure or Death
timeFrame: 72 hrs
measure: Over-diuresis
timeFrame: 72 hours
measure: Serum Sodium
timeFrame: 0, 24, 48, and 72 hours
measure: Dyspnea 11 Point NRS
timeFrame: 0, 24, 48, and 72 hours
measure: Freedom From Congestion
timeFrame: 24, 48, and 72 hours
measure: Development of Worsening Renal Function
timeFrame: 72 hours
measure: Days Hospitalized or Deceased
timeFrame: 30 days
measure: All Cause Death or Rehospitalization
timeFrame: 30 days
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado at Denver and Health Sciences Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Heart Center
state: Georgia
city: Macon
country: United States
facility: Mercer University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Heart and Vascular
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Lumberton
country: United States
facility: Southeastern Regional Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: The Christ Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Natrona Heights
country: United States
facility: Allegheny Valley Hospital
state: Pennsylvania
city: Sellersville
country: United States
facility: Grand View - Lehigh Valley Health Services
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical center
state: Texas
city: Falls Church
country: United States
facility: Inova Heart and Vascular Institute
state: Virginia
Study officials:
affiliation: Duke Clinical Research Institute
name: Michael Felker, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.