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

NCT02476409 | Completed Phase 4 Results

• 1 other identifier: 15-0472
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Congestive Heart Failure

Keywords

congestive heart failure; tolvaptan; copeptin

Outcome Measures

Primary Outcomes (2)

• 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

  Baseline, Day 3 (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

  Baseline, Day 3 (48 hours)

Secondary Outcomes (5)

• Changes in Visual Analog Scale - Patient Dyspnea

  Baseline, Day 3 (48 hours)

• Change in Loop Diuretic Dose (Furosemide Milligram Equivalents) at 48 Hours

  Day 3 (48 hours)

• Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours

  Day 3 (48 hours)

• Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use

  Day 3 (48 hours)

• Change in Body Weight at Day 8

  Baseline, 8 days

Study Arms (2)

Tolvaptan

EXPERIMENTAL

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

Drug: tolvaptan

Placebo

PLACEBO COMPARATOR

Augmentation of current dose of loop diuretic

Other: Placebo

Interventions

tolvaptan DRUG

Study will test the addition of tolvaptan to augmentation of loop diuretic as standard of care for outpatients presenting with worsening heart failure.

Also known as: Samsca

Tolvaptan

Placebo OTHER

Placebo for tolvaptan

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Otsuka America Pharmaceutical: collaborator

Study Sites (1)

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (7)

• 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.

  PMID: 15113814 BACKGROUND

• 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.

  PMID: 17384438 BACKGROUND

• 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.

  PMID: 19561338 BACKGROUND

• 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.

  PMID: 17384437 BACKGROUND

• 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.

  PMID: 18291667 BACKGROUND

• 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.

  PMID: 17635944 BACKGROUND

• 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.

  PMID: 16269513 BACKGROUND

MeSH Terms

Conditions

Heart Failure; Diabetes Insipidus

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pituitary Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Amanda Lee
• Organization: University of North Carolina at Chapel Hill

akg72@med.unc.edu

919-843-9936

Study Officials

• Kirkwood F Adams, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2015
• First Posted: June 19, 2015
• Study Start: July 1, 2015
• Primary Completion: May 13, 2021
• Study Completion: May 13, 2021
• Last Updated: May 5, 2022
• Results First Posted: May 5, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)