Tolvaptan For Worsening Outpatient Heart Failure: Role of Copeptin In Identifying Responders (TROUPER)

May 3, 2022 updated by: University of North Carolina, Chapel Hill

Tolvaptan Treatment to Reverse Worsening Outpatient Heart Failure: Possible Role of Copeptin In Identifying Responders (TROUPER)

Patients who present to clinic or in the outpatient setting with worsening heart failure represent a unique opportunity for novel approaches to decongestion (removing fluid) that may more rapidly improve fluid status and symptoms as well as reduce the risk of hospitalization.

In these patients with less severe congestion (fluid overload), combining the vasopressin antagonist tolvaptan with loop diuretics (or fluid pills like furosemide/bumetanide/torsemide) may represent a more effective strategy for decongestion. In addition, looking at patients' copeptin levels may help identify those who are more likely to respond to tolvaptan.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This study will be a randomized, double blind, positive control, multi-center clinical trial enrolling patients who present in the outpatient setting with signs and symptoms consistent with worsening congestive heart failure. The sample size for the study is 40 patients. Candidates for the study will be identified by screening outpatients presenting with worsening heart failure.

Patients who qualify for the study will be enrolled within 24 hours of identification. Patients will be randomized in a 1:1 fashion to one of two treatment arms:

  • Augmentation of current daily dose of oral loop diuretic + 30 mg of oral Tolvaptan daily
  • Augmentation of current daily dose of oral loop diuretic + placebo of oral Tolvaptan daily

Patients will initiate study medication in a hospital setting and will be observed for a period of time that will depend upon their baseline serum sodium and response to study drug. In most cases patients will be observed for 8 hours. Following this observational period, patients will leave the hospital setting and the remainder of the study will consist of follow-up by outpatient visits or by telephone. All patients will have Day 30 follow up phone contact for assessment of vital status, adverse events and morbidity during this period.

The primary objective of this study will be to compare the effects of oral tolvaptan plus augmented loop diuretic versus augmented loop diuretic on short term changes in body weight with and without stratification for baseline copeptin.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina at Chapel Hill

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

  • Presenting to clinic with worsening heart failure due congestion (fluid overload) Patient reported worsening fluid overload based on perception of edema and/or weight gain With at least one of the following symptoms

    • Worsening dyspnea on exertion or fatigue
    • Worsening orthopnea or paroxysmal nocturnal dyspnea (PND)
    • Perception of abdominal and/or lower extremity edema
    • Early satiety and/or decreased appetite And at least one of the following signs
    • Lower extremity edema
    • Ascites
    • Elevated jugular venous distension (JVD)
    • Pulmonary rales
  • Daily oral dose of loop diuretic
  • Prior history of heart failure with this diagnosis for at least 1 month with preserved or reduced left ventricular ejection fraction
  • Signed informed consent

Exclusion Criteria:

  • Patients with symptomatic hyponatremia will be excluded from the study.
  • Patients with severe hyponatremia, defined as serum sodium < 125 milliequivalents per Liter (mEq/L) at the time of screening, will be excluded regardless of whether they are symptomatic or not.
  • Patients with the following predisposing factors for osmotic demyelinating syndrome (ODS), assessed by the study investigator judgment, will be excluded: chronic alcoholism at the time of study, severe liver disease, marked malnutrition, and risk for chronic hypoxia.
  • Patients currently undergoing renal replacement therapy
  • Planned hospitalization for acute heart failure
  • History of primary significant liver disease or acute hepatic failure, as defined by the investigator
  • Hemodynamically significant arrhythmias
  • Acute coronary syndrome (ACS) or acute myocardial infarction within 4 weeks prior to study entry
  • Active myocarditis
  • Hypertrophic obstructive, restrictive, or constrictive cardiomyopathy
  • Severe stenotic valvular disease amendable to surgical treatment
  • Complex congenital heart disease
  • Constrictive pericarditis
  • Clinical evidence of digoxin toxicity

  • History of adverse reaction or clinical contraindication to tolvaptan

    • Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors
    • Inability of patient to sense and/or respond to thirst
    • History of hypersensitivity to tolvaptan
    • Patient is anuric
  • Enrollment or planned enrollment in another randomized clinical trial during the study period
  • Pregnant or breast-feeding
  • Inability to comply with planned study procedures

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tolvaptan
Augmentation of current dose of loop diuretic + 30 mg of oral tolvaptan daily
Drug: tolvaptan
Study will test the addition of tolvaptan to augmentation of loop diuretic as standard of care for outpatients presenting with worsening heart failure.
Other Names:
  • Samsca
Placebo Comparator: Placebo
Augmentation of current dose of loop diuretic
Other: Placebo
Placebo for tolvaptan

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Body Weight at 48 Hours
Time Frame: Baseline, Day 3 (48 hours)
The primary endpoint for the study will be change in body weight between patients randomized to tolvaptan versus placebo from baseline to 48 hours
Baseline, Day 3 (48 hours)
Change in Body Weight at 48 Hours Stratified by Copeptin
Time Frame: Baseline, Day 3 (48 hours)
The primary endpoint for the study will be change in body weight between patients randomized to tolvaptan versus placebo from baseline to 48 hours with stratification for baseline copeptin level
Baseline, Day 3 (48 hours)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Visual Analog Scale - Patient Dyspnea
Time Frame: Baseline, Day 3 (48 hours)

Changes in patient reported dyspnea scale from baseline to 48 hours based on the visual analog scale.

Visual Analog Scale (VAS) - Patient Dyspnea has a minimum value of 0 and a maximum value of 100. Higher scores mean a better outcome.
Baseline, Day 3 (48 hours)
Change in Loop Diuretic Dose (Furosemide Milligram Equivalents) at 48 Hours
Time Frame: Day 3 (48 hours)
Change in loop diuretic dose at 48 hours where doses of loop diuretic are expressed as furosemide milligram equivalents based on standard conversions of bumetanide and torsemide doses to milligram equivalents of furosemide. The formula for the conversion of doses of loop diuretics were standardized to milligram equivalents of furosemide based on 40 milligrams of furosemide for each 1 milligram of bumetanide and 2 milligrams of furosemide for each 1 milligram of torsemide.
Day 3 (48 hours)
Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours
Time Frame: Day 3 (48 hours)
Number of participants with a decrease in loop diuretic diuretic dosing at 48 hours in the Tolvaptan group and the Placebo group.
Day 3 (48 hours)
Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use
Time Frame: Day 3 (48 hours)
Change in loop diuretic score defined by change in loop diuretic use at Visit 2. The change in loop diuretic score endpoint was calculated as follows: patients having an increase in loop diuretic use at Visit 2 were given a score of 2, patients with no change a score of 0, and patients with a decrease in loop use at Visit 2 were given a score of -1. Increases in loop diuretic use were given a higher weighting to account for their reflection of treatment failure.
Day 3 (48 hours)
Change in Body Weight at Day 8
Time Frame: Baseline, 8 days
Change in body weight at 8 days will be analyzed in a similar fashion to the change in body weight at 48 hours
Baseline, 8 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of North Carolina, Chapel Hill

Collaborators

Otsuka America Pharmaceutical

Investigators

  • Principal Investigator: Kirkwood F Adams, MD, University of North Carolina, Chapel Hill

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2015

Primary Completion (Actual)

May 13, 2021

Study Completion (Actual)

May 13, 2021

Study Registration Dates

First Submitted

June 12, 2015

First Submitted That Met QC Criteria

June 16, 2015

First Posted (Estimate)

June 19, 2015

Study Record Updates

Last Update Posted (Actual)

May 5, 2022

Last Update Submitted That Met QC Criteria

May 3, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 15-0472

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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