Edema, Heart Failure, Congestive
Conditions
Keywords
OPC-41061, Tolvaptan, Heart Failure, Edema, Extracellular volume expansion
Brief summary
This drug is being developed to treat cardiac edema. The primary purpose of this study is to investigate the dose response for body weight in seven-day repeated oral administration of OPC-41061 at 15, 30, and 45 mg or placebo in patients with extracellular volume expansion secondary to CHF despite taking furosemide at 40 mg/d or more. This study is being conducted in Japan.
Interventions
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with CHF who exhibit edema, jugular venous distention, hepatomegaly, pulmonary congestion, or 3rd sound due to extracellular volume expansion 2. Hospitalized patients or patients who can be hospitalized for the study from the commencement of the observation period to the end-of-study examination 3. Men and women between the ages of 20 and 80 (non-inclusive) at the time of giving consent 4. Patients who have taken furosemide at 40 mg/d or more (oral dosing) without alteration of dosage for the 3 days of the observation period 5. Patients whose body weight has been stable (±1.0 kg) for 2 days prior to commencement of study drug administration
Exclusion criteria
1. Patients with unstable heart failure (acute heart failure, acute exacerbation of chronic heart failure, etc) 2. Patients with an implanted ventricular assist device 3. Patients who have undergone or are scheduled to undergo any of the following procedures * Heart surgery involving thoracotomy within 60 days prior to the screening examination * Pacemaker implant surgery involving bilateral pacing within 60 days prior to the screening examination * Angioplasty, electrophysiologic device implantation, ventricular assist device implantation, heart transplant, or other cardiac surgery scheduled within 30 days after the screening examination 4. Patients with any of the following diseases, complications, or symptoms * Suspected hypovolemia * Onset of acute myocardial infarction within 30 days prior to the screening examination * Hypertrophic cardiomyopathy (excluding diastolic phase) * Definitively diagnosed active myocarditis or amyloid cardiomyopathy * Valvular heart disease with significant stenosis * Untreated thyroid disease * Progressive neurological disease (Alzheimer's disease, Parkinson's disease, multiple sclerosis, etc) or severe episodic neurological disease (epilepsy, Guillain-Barre syndrome, etc) * Diabetes with poor glycemic control * Anuria * Hepatic coma * Hyponatremia of moderate or greater severity (serum Na \< 120 mEq/L) 5. Patients with a history of the following conditions * Occurrence of sustained ventricular tachycardia or ventricular fibrillation within 30 days prior to the screening examination (except for patients using an implantable cardioverter-defibrillator) * Evident cerebral infarction * Multiple stroke * Occurrence of a cerebrovascular accident within 30 days prior to the screening examination * Hypersensitivity or idiosyncratic reaction to benzazepine derivatives, such as benazapril 6. Patients with a history of drug abuse or alcoholism in the past year 7. Patients in a state of morbid obesity with a body mass index (weight\[kg\] ÷ height \[m\]2) over 35 8. Patients with a supine systolic arterial blood pressure of less than 90 mmHg 9. Patients with any of the following abnormal laboratory values: Hemoglobin \<9 g/dL, total bilirubin \>3.0 mg/dL, serum creatine \>3.0 mg/dL, serum Na \>147 mEq/L, or serum K \>5.5 mEq/L 10. Patients not capable of taking oral medication 11. Patients who are nursing, pregnant, capable of pregnancy, or intending to become pregnant during or shortly after the study period 12. Patients who have taken a study drug other than OPC-41061 within 30 days prior to screening 13. Patients who have previously taken OPC-41061 in this study or another study of OPC-41061 14. Patients otherwise judged by the principal investigator or attending investigator to be inappropriate for inclusion in the study (eg, patients with hepatic cirrhosis, renal disease, etc.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Body Weight | Baseline, at the time of final trial drug administration | The body weight change from baseline following final trial drug administration |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo OPC-41061 0 mg/day | 29 |
| 15 mg of OPC-41061 OPC-41061 15 mg/day | 28 |
| 30 mg of OPC-41061 OPC-41061 30 mg/day | 33 |
| 45 mg of OPC-41061 OPC-41061 45 mg/day | 28 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 | 3 | 5 |
| Overall Study | Physician Decision | 0 | 1 | 2 | 2 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 15 mg of OPC-41061 | 30 mg of OPC-41061 | Placebo | 45 mg of OPC-41061 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 22 Participants | 18 Participants | 14 Participants | 72 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 11 Participants | 11 Participants | 14 Participants | 46 Participants |
| Age Continuous | 66.9 years STANDARD_DEVIATION 9.6 | 66.4 years STANDARD_DEVIATION 12.5 | 67.9 years STANDARD_DEVIATION 9.4 | 62.6 years STANDARD_DEVIATION 12.5 | 66.0 years STANDARD_DEVIATION 11.2 |
| Region of Enrollment Japan | 28 participants | 33 participants | 29 participants | 28 participants | 118 participants |
| Sex: Female, Male Female | 13 Participants | 8 Participants | 11 Participants | 4 Participants | 36 Participants |
| Sex: Female, Male Male | 15 Participants | 25 Participants | 18 Participants | 24 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 29 | 21 / 28 | 25 / 33 | 21 / 28 |
| serious Total, serious adverse events | 4 / 29 | 0 / 28 | 1 / 33 | 2 / 28 |
Outcome results
Primary
Body Weight
The body weight change from baseline following final trial drug administration
Time frame: Baseline, at the time of final trial drug administration
Population: 1 Subject of Placebo arm who experienced a serious adverse event was excluded from efficacy analysis set because the emergency code was broken.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Body Weight | -0.53 Kg | Standard Deviation 0.96 |
| 15 mg of OPC-41061 | Body Weight | -1.62 Kg | Standard Deviation 1.55 |
| 30 mg of OPC-41061 | Body Weight | -1.35 Kg | Standard Deviation 1.54 |
| 45 mg of OPC-41061 | Body Weight | -1.85 Kg | Standard Deviation 1.1 |
p-value: 0.0074t-test, 2 sided
p-value: 0.0459t-test, 2 sided
p-value: 0.001t-test, 2 sided