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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Congestive Heart Failure

Intervention / Treatment
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* Drug: tolvaptan
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 3 (48 hours) | 
| 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. | Day 3 (48 hours) | 
| 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. | Day 3 (48 hours) | 
| 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. | Day 3 (48 hours) | 
| 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 | Baseline, 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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congestive heart failure, tolvaptan, copeptin