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

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ClinicalTrials.gov Identifier: NCT02476409
Recruitment Status : Active, not recruiting
First Posted : June 19, 2015
Last Update Posted : November 5, 2019
Sponsor:
Collaborator:
Otsuka America Pharmaceutical
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

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.


Condition or disease Intervention/treatment Phase
Congestive Heart Failure Drug: tolvaptan Other: Placebo Phase 4

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 objectives of this study will be to compare the effects of oral tolvaptan plus augmented loop diuretic versus augmented loop diuretic on 1) short term changes in body weight with and without stratification for baseline copeptin and 2) an index targeted to signs and symptoms of congestion in patients presenting with worsening congestive heart failure in the outpatient setting with and without prespecified post hoc stratification based on baseline copeptin level.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Tolvaptan Treatment to Reverse Worsening Outpatient Heart Failure: Possible Role of Copeptin In Identifying Responders (TROUPER)
Study Start Date : July 2015
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tolvaptan

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 Name: Samsca

Placebo Comparator: Placebo
Augmentation of current dose of loop diuretic
Other: Placebo
Placebo for tolvaptan




Primary Outcome Measures :
  1. Change in body weight at 48 hours [ Time Frame: 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 and without stratification for baseline copeptin level


Secondary Outcome Measures :
  1. Changes in congestion (patient reported and investigator assessed) [ Time Frame: 48 hours and day 8 ]

    Changes in the patient reported and investigator assessed congestion index based on the Likert scale from baseline to 48 hours. Changes in the patient reported and investigator assessed index of congestion at 8 days based on the Likert scale.

    Changes in the patient reported and investigator assessed index of congestion from baseline to 48 hours and 8 days based on the visual analog scale .


  2. Change in body weight at day 8 [ Time Frame: 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

  3. Clinical composite of morbidity [ Time Frame: 30 days ]
    This composite will include days of hospitalization, Emergency Department (ED) visits, clinic visits not required by the protocol during the 30 days after randomization into the study


Other Outcome Measures:
  1. Exploratory endpoint longitudinal changes in renal function [ Time Frame: 48 hours and day 8 ]
    Longitudinal changes in renal function

  2. Exploratory endpoint longitudinal changes in serum sodium [ Time Frame: 48 hours and day 8 ]
    Longitudinal changes in serum sodium

  3. Exploratory endpoint longitudinal changes in copeptin [ Time Frame: 48 hours and day 8 ]
    Longitudinal changes in copeptin



Information from the National Library of Medicine

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02476409


Locations
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United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Otsuka America Pharmaceutical
Investigators
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Principal Investigator: Kirkwood F Adams, MD University of North Carolina, Chapel Hill

Publications:

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02476409     History of Changes
Other Study ID Numbers: 15-0472
First Posted: June 19, 2015    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: November 2019
Keywords provided by University of North Carolina, Chapel Hill:
congestive heart failure
tolvaptan
copeptin
Additional relevant MeSH terms:
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Diabetes Insipidus
Heart Failure
Heart Diseases
Cardiovascular Diseases
Kidney Diseases
Urologic Diseases
Pituitary Diseases
Endocrine System Diseases
Tolvaptan
Arginine Vasopressin
Diuretics
Sodium Potassium Chloride Symporter Inhibitors
Natriuretic Agents
Physiological Effects of Drugs
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Hemostatics
Coagulants
Vasoconstrictor Agents
Antidiuretic Agents
Membrane Transport Modulators