Congestive Heart Failure
Conditions
Keywords
congestive heart failure, tolvaptan, copeptin
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.
Interventions
DRUGtolvaptan
Study will test the addition of tolvaptan to augmentation of loop diuretic as standard of care for outpatients presenting with worsening heart failure.
OTHERPlacebo
Placebo for tolvaptan
Sponsors
Otsuka America Pharmaceutical
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight at 48 Hours | Baseline, Day 3 (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 | Baseline, Day 3 (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 stratification for baseline copeptin level |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours | Day 3 (48 hours) | Number of participants with a decrease in loop diuretic diuretic dosing at 48 hours in the Tolvaptan group and the Placebo group. |
| Changes in Visual Analog Scale - Patient Dyspnea | Baseline, Day 3 (48 hours) | 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 Body Weight at Day 8 | Baseline, 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 |
| Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use | Day 3 (48 hours) | 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 Loop Diuretic Dose (Furosemide Milligram Equivalents) at 48 Hours | Day 3 (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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan Augmentation of current dose of loop diuretic + 30 mg of oral tolvaptan daily
Tolvaptan: Study will test the addition of tolvaptan to augmentation of loop diuretic as standard of care for outpatients presenting with worsening heart failure. | 19 |
| Placebo Augmentation of current dose of loop diuretic
Placebo: Placebo for tolvaptan | 21 |
| Total | 40 |
Baseline characteristics
| Characteristic | Tolvaptan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 6 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 15 Participants | 21 Participants |
| Age, Continuous | 66 years STANDARD_DEVIATION 8.9 | 60 years STANDARD_DEVIATION 14 | 63 years STANDARD_DEVIATION 12 |
| Dyspnea | 18 Participants | 21 Participants | 39 Participants |
| Edema | 17 Participants | 18 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 20 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heart Failure Reduced Ejection Fraction (≤ 40) | 13 Participants | 13 Participants | 26 Participants |
| Left Ventricular Ejection Fraction | 32 percent ejection fraction (%) STANDARD_DEVIATION 13 | 34 percent ejection fraction (%) STANDARD_DEVIATION 18 | 33 percent ejection fraction (%) STANDARD_DEVIATION 16 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 12 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 15 Participants |
| Region of Enrollment United States | 19 Participants | 21 Participants | 40 Participants |
| Serum Creatinine | 1.7 mg/dL STANDARD_DEVIATION 0.8 | 1.4 mg/dL STANDARD_DEVIATION 0.6 | 1.6 mg/dL STANDARD_DEVIATION 0.7 |
| Serum Sodium | 140 mEq/L STANDARD_DEVIATION 3.7 | 138 mEq/L STANDARD_DEVIATION 3.8 | 139 mEq/L STANDARD_DEVIATION 3.9 |
| Sex: Female, Male Female | 6 Participants | 11 Participants | 17 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 21 |
| other Total, other adverse events | 0 / 19 | 0 / 21 |
| serious Total, serious adverse events | 6 / 19 | 4 / 21 |
Outcome results
Primary
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
Time frame: Baseline, Day 3 (48 hours)
Population: One participant in the Tolvaptan group missed study Visit 2 (Day 3 (48 hours)) due to adverse weather. This participant subsequently attended study Visit 3 (Day 8) to complete the study. Thus data were available on 18 of the 19 patients in the Tolvaptan group for this endpoint at study Visit 2 (Day 3 (48 hours)).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Change in Body Weight at 48 Hours | -3.3 pounds | Standard Deviation 4.4 |
| Placebo | Change in Body Weight at 48 Hours | -0.8 pounds | Standard Deviation 3.5 |
p-value: 0.094Kruskal-Wallis
Primary
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
Time frame: Baseline, Day 3 (48 hours)
Population: One participant in the High Copeptin - Tolvaptan group missed study Visit 2 (Day 3 (48 hours)) due to adverse weather. Thus data were available on 11 of the 12 patients in the High Copeptin - Tolvaptan group for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Change in Body Weight at 48 Hours Stratified by Copeptin | -2.9 pounds | Standard Deviation 5.3 |
| Placebo | Change in Body Weight at 48 Hours Stratified by Copeptin | 0.3 pounds | Standard Deviation 3.7 |
| Low Copeptin - Tolvaptan | Change in Body Weight at 48 Hours Stratified by Copeptin | -3.8 pounds | Standard Deviation 3 |
| Low Copeptin - Placebo | Change in Body Weight at 48 Hours Stratified by Copeptin | -2.4 pounds | Standard Deviation 2.7 |
p-value: 0.166Kruskal-Wallis
p-value: 0.491Kruskal-Wallis
Secondary
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
Time frame: Baseline, 8 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Change in Body Weight at Day 8 | -1.8 pounds | Standard Deviation 3.5 |
| Placebo | Change in Body Weight at Day 8 | -2.8 pounds | Standard Deviation 4.4 |
p-value: 0.643Kruskal-Wallis
Secondary
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.
Time frame: Day 3 (48 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Change in Loop Diuretic Dose (Furosemide Milligram Equivalents) at 48 Hours | -57 furosemide milligram equivalents | Standard Deviation 94 |
| Placebo | Change in Loop Diuretic Dose (Furosemide Milligram Equivalents) at 48 Hours | -11 furosemide milligram equivalents | Standard Deviation 79 |
p-value: 0.05Kruskal-Wallis
Secondary
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.
Time frame: Day 3 (48 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use | -0.47 units on a scale | Standard Deviation 0.51 |
| Placebo | Change in Loop Diuretic Score Defined Based on Change in Loop Diuretic Use | 0 units on a scale | Standard Deviation 0.77 |
p-value: 0.034Kruskal-Wallis
Secondary
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.
Time frame: Baseline, Day 3 (48 hours)
Population: One participant in the Tolvaptan group missed study Visit 2 (Day 3 (48 hours)) due to adverse weather. This participant subsequently attended study Visit 3 (Day 8) to complete the study. Thus data were available on 18 of the 19 patients in the Tolvaptan group for this endpoint at study Visit 2 (Day 3 (48 hours)).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan | Changes in Visual Analog Scale - Patient Dyspnea | 21 score on a scale | Standard Deviation 23 |
| Placebo | Changes in Visual Analog Scale - Patient Dyspnea | 15 score on a scale | Standard Deviation 22 |
Comparison: P-value for Change in Dyspnea VAS - Baseline to Day 3 Tolvaptan versus placebo.p-value: 0.543Kruskal-Wallis
Secondary
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.
Time frame: Day 3 (48 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tolvaptan | Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours | 9 Participants |
| Placebo | Number of Participants With a Decrease in Loop Diuretic Dosing at 48 Hours | 4 Participants |
p-value: 0.092Fisher Exact