Cardiovascular Diseases, Heart Diseases, Heart Failure
Conditions
Keywords
tolvaptan, copeptin, heart failure, vasopressin antagonist
Brief summary
This pilot study will investigate the association between levels of the peptide copeptin and response to tolvaptan, a drug that blocks the action of the water retaining hormone vasopressin. The study will enroll stable outpatients with CHF with reduced LVEF (≤45) selected by targeting upper and lower quartile copeptin levels at screening (10 each). The treatment phase of the study will be a prospective, single-arm, open label protocol. All patients will receive active therapy consisting of a single oral dose of 30 mg of tolvaptan with body weight, fluid intake, and urine output monitored in a research unit for 24 hours. For analysis of study endpoints, patients in the single intervention arm will be stratified by a prospectively determined cut-point of copeptin level into two groups (≥10 versus \<10 pmol/L). The copeptin level used for the two group stratification will be the blinded copeptin value obtained at baseline from the hospital phase prior to administration of tolvaptan.
Detailed description
The study screening strategy will be designed to enroll an enriched patient population by identifying patients at the high or low end of the spectrum of copeptin levels for outpatients with stable heart failure. This will be accomplished by blinded review of copeptin levels obtained during screening. The primary endpoints for analysis will be 24 hour urine output and the change in body weight over 24 hours during the inpatient stay.
Interventions
DRUGtolvaptan
oral, 30 mg, single dose, one time administration
Sponsors
Otsuka America Pharmaceutical
University of North Carolina, Chapel Hill
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male and female patients with a history of chronic symptomatic heart failure, defined as dyspnea on exertion or edema, due to cardiac dysfunction, of at least one month's duration 2. Left ventricular ejection fraction ≤ 45% as documented by quantitative assessment by an accepted imaging technique within one year of screening 3. Meet baseline copeptin criteria for entry 4. Currently taking a diuretic (with diuretic defined as any loop or thiazide diuretic or aldosterone antagonist at any dose)
Exclusion criteria
1. Current New York Heart Association Functional Class IV heart failure 2. Patients who are felt to be volume depleted based on clinical examination or need to reduce diuretic administration 3. Presence of clinical contraindications to tolvaptan 4. Episode of acute myocardial infarction or acute coronary syndrome within the past 3 months 5. Cardiovascular surgical procedure within the past 4 weeks 6. CHF due to uncorrected thyroid disease, active myocarditis, or known amyloid cardiomyopathy. 7. History of primary significant liver disease or acute hepatic failure, as defined by the investigator. 8. Chronic uncontrolled diabetes mellitus as determined by the investigator. 9. Supine systolic arterial blood pressure \< 90 mmHg at screening 10. Serum creatinine \> 3.5 mg/dL at screening 11. Serum potassium \> 5.5 mEq/L or \< 3.5 mEq/L at screening 12. Subjects currently treated with hemofiltration or dialysis j. Subjects judged by the investigator to be unable to maintain accurate intake and output during their hospitalization related to medical or other problems
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urine Output | 24 hours | Total urine output for 24 hours following tolvaptan administration |
| Body Weight | Change over 24 hours | Change in body weight from baseline to 24 hours after tolvaptan administration |
Countries
United States
Participant flow
Recruitment details
100 patients were screened in two periods approximately six months each in duration at a dedicated Heart Failure Clinic at the University of North Carolina Chapel Hill. 43 patients met inclusion/exclusion criteria and had a blood sample sent for copeptin testing. Twenty-one patients were enrolled in the hospital phase of the study.
Pre-assignment details
Blinded copeptin results were reviewed in 43 patients for participation in the hospital phase. 11 patients were selected by targeting the upper quartile of baseline copetin and 10 patients by targeting the lower quartile of screening copeptin levels. A total of 21 patients were enrolled in hospital phase.
Participants by arm
| Arm | Count |
|---|---|
| Tolvaptan High Copeptin Tolvaptan: oral, 30 mg, single dose, one time administration
High Copeptin ≥ 10 pmol/L at baseline | 10 |
| Tolvaptan Low Copeptin Tolvaptan: oral, 30 mg, single dose, one time administration
Low Copeptin \< 10 pmol/L at baseline | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Total | Tolvaptan High Copeptin | Tolvaptan Low Copeptin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 3 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 7 Participants | 7 Participants |
| Age, Continuous | 60 years STANDARD_DEVIATION 12 | 60 years STANDARD_DEVIATION 11 | 59 years STANDARD_DEVIATION 13 |
| Baseline Copeptin | 13.1 pmol/L STANDARD_DEVIATION 9.7 | 20.5 pmol/L STANDARD_DEVIATION 8.7 | 5.7 pmol/L STANDARD_DEVIATION 1.9 |
| LVEF | 27 % STANDARD_DEVIATION 9.6 | 23 % STANDARD_DEVIATION 6 | 31 % STANDARD_DEVIATION 11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 7 Participants | 4 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 | 8 Participants | 3 Participants | 5 Participants |
| Region of Enrollment United States | 20 participants | 10 participants | 10 participants |
| Serum Creatinine | 1.10 mg/dL STANDARD_DEVIATION 0.3 | 1.18 mg/dL STANDARD_DEVIATION 0.23 | 1.03 mg/dL STANDARD_DEVIATION 0.35 |
| Serum Sodium | 141.0 mEq/L STANDARD_DEVIATION 2.86 | 141.1 mEq/L STANDARD_DEVIATION 2.28 | 140.8 mEq/L STANDARD_DEVIATION 3.46 |
| Sex: Female, Male Female | 11 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 4 Participants |
| Total Daily Dose of Loop Diuretic | 84 mg STANDARD_DEVIATION 86 | 124 mg STANDARD_DEVIATION 104 | 47 mg STANDARD_DEVIATION 46 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 0 / 11 | 0 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 |
Outcome results
Primary
Body Weight
Change in body weight from baseline to 24 hours after tolvaptan administration
Time frame: Change over 24 hours
Population: All patients in the Low Copeptin group were included in the analysis. One patient in the High Copeptin group had reduced renal function at baseline versus screening and transient hypovolemia during hospitalization indicative of volume depletion. This patient was excluded prior to review of blinded copeptin results and study data analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan High Copeptin | Body Weight | -1.3 Kg | Standard Deviation 1 |
| Tolvaptan Low Copeptin | Body Weight | -0.4 Kg | Standard Deviation 1 |
p-value: 0.035Wilcoxon Two-Sample Test
Primary
Urine Output
Total urine output for 24 hours following tolvaptan administration
Time frame: 24 hours
Population: All patients in the Low Copeptin group were included in the analysis. One patient in the High Copeptin group had reduced renal function at baseline versus screening and transient hypovolemia during hospitalization indicative of volume depletion. This patient was excluded prior to review of blinded copeptin results and study data analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan High Copeptin | Urine Output | 6498 mL | Standard Deviation 2328 |
| Tolvaptan Low Copeptin | Urine Output | 5784 mL | Standard Deviation 1835 |
p-value: 0.853Wilcoxon Two-Sample Test