Clinical trial NCT02476409: Tolvaptan For Worsening Outpatient Heart Failure: Role of Copeptin In Identifying Responders
Official title: Tolvaptan Treatment to Reverse Worsening Outpatient Heart Failure: Possible Role of Copeptin In Identifying Responders (TROUPER)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Congestive Heart Failure
Keywords: congestive heart failure
tolvaptan
copeptin
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Otsuka America Pharmaceutical
First posted: 2015-06-19
Enrollment: 40
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: 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.

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

Primary outcomes:
measure: Change in Body Weight at 48 Hours
timeFrame: Baseline, Day 3 (48 hours)
measure: Change in Body Weight at 48 Hours Stratified by Copeptin
timeFrame: Baseline, Day 3 (48 hours)
Secondary outcomes:
measure: Changes in Visual Analog Scale - Patient Dyspnea
timeFrame: Baseline, Day 3 (48 hours)
measure: Change in Loop Diuretic Dose (Furosemide Milligram Equivalents) at 48 Hours
timeFrame: Day 3 (48 hours)
measure: Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours
timeFrame: Day 3 (48 hours)
measure: Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use
timeFrame: Day 3 (48 hours)
measure: Change in Body Weight at Day 8
timeFrame: Baseline, 8 days
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Kirkwood F Adams, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.