Cirrhosis
Conditions
Keywords
Cirrhosis, ascites, Tolvaptan, OPC-41061
Brief summary
OPC-41061 at 7.5 mg/day or placebo will be orally administered once daily for 7 days to cirrhosis patients with ascites despite having received treatment with conventional diuretics and the change in body weight from baseline at the time of the final administration will be compared between the two groups.
Interventions
DRUGOPC-41061
Once-daily oral administration of OPC-41061 at 7.5 mg after breakfast for 7 days
DRUGPlacebo
Once-daily oral administration of placebo after breakfast for 7 days
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients judged as having cirrhosis based on previous imaging diagnosis * Definition of cirrhosis includes patients with collateral circulation due to chronic hepatic impairment * Patients with ascites in whom the dose of existing diuretics cannot be increased due to risk of adverse drug reactions such as electrolyte abnormalities, or in whom sufficient therapeutic effect cannot be obtained with existing diuretics * Patients who have been receiving oral combination therapy with a loop diuretic and an anti-aldosterone agent from at least 7 days prior to receipt of informed consent, with a dose combination of either loop diuretic equivalent to furosemide 40 mg/day or higher plus spironolactone 25 mg/day or higher, or loop diuretic equivalent to furosemide 20 mg/day or higher plus spironolactone 50 mg/day or higher * Patients who are hospitalized or who can be hospitalized for the trial * Patients capable of giving informed consent * Patients who, together with their partner, agree to use an appropriate method of contraception until 4 weeks after the final trial drug administration
Exclusion criteria
* Patients with any of the following complications or symptoms: * Hepatic encephalopathy (hepatic coma of grade 2 or higher) * Hepatocellular carcinoma with imaging-diagnosed vascular infiltration into trunk or primary branch of portal vein, inferior vena cava, or trunk of hepatic vein * Endoscopic findings from screening examination or from within 30 days prior to screening examination indicating the need for new therapy for esophageal or gastric varices during the trial period * Repeated hemorrhoidal bleeding due to rectal varicose veins within 30 days prior to informed consent * Heart failure (New York Heart Association Class III or IV) * Anuria * Impaired urination due to urinary tract stricture, urinary calculus, tumor in urinary tract, or other cause * Patients with a history of any of the following disorders: * Cerebrovascular disorder within 30 days prior to informed consent * Hypersensitivity or idiosyncratic reaction to benzazepine derivatives (such as mozavaptan hydrochloride or benazepril hydrochloride) * Morbidly obese patients with a body mass index (BMI: body weight (kg)/height (m)2) exceeding 35 * Patients with sitting systolic blood pressure lower than 90 mmHg * Patients with any of following abnormal clinical laboratory values at time of the screening examination: Hemoglobin lower than 8.0 g/dL, total bilirubin higher than 4.0 mg/dL, serum creatinine higher than 2.0 mg/dL, serum sodium higher than 147 mEq/L, or serum potassium higher than 5.5 mEq/L * Patients who are unable to take oral medication * Female patients who are pregnant, possibly pregnant, or breast-feeding, or who are planning to become pregnant * Patients who have used albumin preparations (therapeutic agents for hypoalbuminemia) or blood products containing albumin from within 7 days prior to informed consent * Patients who received any investigational drug other than OPC-41061 within 30 days prior to informed consent * Patients who have previously received OPC-41061 * Any patient who, in the opinion of the principle investigator or subinvestigator, is inappropriate for participation in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Body ｗeight | Baseline, Day 7 or at the discontinued of treatment | Change in body weight from baseline after 7-day repeated oral administration of OPC |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ascites Volume | Baseline, Day 7 or at the discontinued of treatment | Change in ascites volume from baseline as measured by CT at end of treatment |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OPC-41061 OPC-41061: Once-daily oral administration of OPC-41061 at 7.5 mg after breakfast for 7 days | 82 |
| Placebo Placebo: Once-daily oral administration of placebo after breakfast for 7 days | 80 |
| Total | 162 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Lack of Efficacy | 1 | 4 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | OPC-41061 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 50 Participants | 51 Participants | 101 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 29 Participants | 61 Participants |
| Age, Continuous | 66.3 years STANDARD_DEVIATION 9.4 | 66.4 years STANDARD_DEVIATION 8.7 | 66.4 years STANDARD_DEVIATION 9.1 |
| Region of Enrollment Japan | 82 participants | 80 participants | 162 participants |
| Sex: Female, Male Female | 30 Participants | 31 Participants | 61 Participants |
| Sex: Female, Male Male | 52 Participants | 49 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 82 | 26 / 80 |
| serious Total, serious adverse events | 7 / 82 | 10 / 80 |
Outcome results
Primary
Body ｗeight
Change in body weight from baseline after 7-day repeated oral administration of OPC
Time frame: Baseline, Day 7 or at the discontinued of treatment
Population: Full Analysis Set; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-41061 | Body ｗeight | -1.95 Kg | Standard Deviation 1.77 |
| Placebo | Body ｗeight | -0.44 Kg | Standard Deviation 1.93 |
p-value: <0.000195% CI: [-2.08, -0.93]t-test, 2 sided
Secondary
Ascites Volume
Change in ascites volume from baseline as measured by CT at end of treatment
Time frame: Baseline, Day 7 or at the discontinued of treatment
Population: Full Analysis Set; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-41061 | Ascites Volume | -492.4 mL | Standard Deviation 760.3 |
| Placebo | Ascites Volume | -191.8 mL | Standard Deviation 690.8 |
p-value: 0.009395% CI: [-526.2, -75.1]t-test, 2 sided