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

Primary Purpose

Congestive Heart Failure

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
tolvaptan
Placebo
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Congestive Heart Failure focused on measuring congestive heart failure, tolvaptan, copeptin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of North Carolina at Chapel Hill

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tolvaptan

Placebo

Arm Description

Augmentation of current dose of loop diuretic + 30 mg of oral tolvaptan daily

Augmentation of current dose of loop diuretic

Outcomes

Primary Outcome Measures

Change in Body Weight at 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
Change in Body Weight at 48 Hours Stratified by Copeptin
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

Secondary Outcome Measures

Changes in Visual Analog Scale - Patient Dyspnea
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.
Change in Loop Diuretic Dose (Furosemide Milligram Equivalents) at 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.
Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours
Number of participants with a decrease in loop diuretic diuretic dosing at 48 hours in the Tolvaptan group and the Placebo group.
Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use
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.
Change in Body Weight at Day 8
Change in body weight at 8 days will be analyzed in a similar fashion to the change in body weight at 48 hours

Full Information

First Posted
June 12, 2015
Last Updated
May 3, 2022
Sponsor
University of North Carolina, Chapel Hill
Collaborators
Otsuka America Pharmaceutical
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1. Study Identification

Unique Protocol Identification Number
NCT02476409
Brief Title
Tolvaptan For Worsening Outpatient Heart Failure: Role of Copeptin In Identifying Responders
Acronym
TROUPER
Official Title
Tolvaptan Treatment to Reverse Worsening Outpatient Heart Failure: Possible Role of Copeptin In Identifying Responders (TROUPER)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Completed
Study Start Date
July 2015 (undefined)
Primary Completion Date
May 13, 2021 (Actual)
Study Completion Date
May 13, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
Otsuka America Pharmaceutical

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Congestive Heart Failure
Keywords
congestive heart failure, tolvaptan, copeptin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tolvaptan
Arm Type
Experimental
Arm Description
Augmentation of current dose of loop diuretic + 30 mg of oral tolvaptan daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Augmentation of current dose of loop diuretic
Intervention Type
Drug
Intervention Name(s)
tolvaptan
Other Intervention Name(s)
Samsca
Intervention Description
Study will test the addition of tolvaptan to augmentation of loop diuretic as standard of care for outpatients presenting with worsening heart failure.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo for tolvaptan
Primary Outcome Measure Information:
Title
Change in Body Weight at 48 Hours
Description
The primary endpoint for the study will be change in body weight between patients randomized to tolvaptan versus placebo from baseline to 48 hours
Time Frame
Baseline, Day 3 (48 hours)
Title
Change in Body Weight at 48 Hours Stratified by Copeptin
Description
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
Time Frame
Baseline, Day 3 (48 hours)
Secondary Outcome Measure Information:
Title
Changes in Visual Analog Scale - Patient Dyspnea
Description
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.
Time Frame
Baseline, Day 3 (48 hours)
Title
Change in Loop Diuretic Dose (Furosemide Milligram Equivalents) at 48 Hours
Description
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.
Time Frame
Day 3 (48 hours)
Title
Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours
Description
Number of participants with a decrease in loop diuretic diuretic dosing at 48 hours in the Tolvaptan group and the Placebo group.
Time Frame
Day 3 (48 hours)
Title
Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use
Description
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.
Time Frame
Day 3 (48 hours)
Title
Change in Body Weight at Day 8
Description
Change in body weight at 8 days will be analyzed in a similar fashion to the change in body weight at 48 hours
Time Frame
Baseline, 8 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kirkwood F Adams, MD
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of North Carolina at Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
15113814
Citation
Gheorghiade M, Gattis WA, O'Connor CM, Adams KF Jr, Elkayam U, Barbagelata A, Ghali JK, Benza RL, McGrew FA, Klapholz M, Ouyang J, Orlandi C; Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) Investigators. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004 Apr 28;291(16):1963-71. doi: 10.1001/jama.291.16.1963.
Results Reference
background
PubMed Identifier
17384438
Citation
Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007 Mar 28;297(12):1332-43. doi: 10.1001/jama.297.12.1332. Epub 2007 Mar 25.
Results Reference
background
PubMed Identifier
19561338
Citation
Pang PS, Konstam MA, Krasa HB, Swedberg K, Zannad F, Blair JE, Zimmer C, Teerlink JR, Maggioni AP, Burnett JC Jr, Grinfeld L, Ouyang J, Udelson JE, Gheorghiade M; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) Investigators. Effects of tolvaptan on dyspnoea relief from the EVEREST trials. Eur Heart J. 2009 Sep;30(18):2233-40. doi: 10.1093/eurheartj/ehp253. Epub 2009 Jun 27.
Results Reference
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PubMed Identifier
17384437
Citation
Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-31. doi: 10.1001/jama.297.12.1319. Epub 2007 Mar 25.
Results Reference
background
PubMed Identifier
18291667
Citation
Morgenthaler NG, Struck J, Jochberger S, Dunser MW. Copeptin: clinical use of a new biomarker. Trends Endocrinol Metab. 2008 Mar;19(2):43-9. doi: 10.1016/j.tem.2007.11.001.
Results Reference
background
PubMed Identifier
17635944
Citation
Szinnai G, Morgenthaler NG, Berneis K, Struck J, Muller B, Keller U, Christ-Crain M. Changes in plasma copeptin, the c-terminal portion of arginine vasopressin during water deprivation and excess in healthy subjects. J Clin Endocrinol Metab. 2007 Oct;92(10):3973-8. doi: 10.1210/jc.2007-0232. Epub 2007 Jul 17.
Results Reference
background
PubMed Identifier
16269513
Citation
Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem. 2006 Jan;52(1):112-9. doi: 10.1373/clinchem.2005.060038. Epub 2005 Nov 3.
Results Reference
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Tolvaptan For Worsening Outpatient Heart Failure: Role of Copeptin In Identifying Responders

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