Cirrhosis
Conditions
Keywords
OPC-41061, Tolvaptan, ascites, Cirrhosis
Brief summary
To investigate the dose response for changes from baseline in body weight as a primary endpoint and to investigate improvement in ascites, abdominal circumference, lower-limb edema, and pleural effusion as secondary endpoints in seven-day repeated oral administration of OPC-41061 at 7.5, 15, and 30 mg/day or placebo in cirrhosis patients with ascites despite taking conventional diuretics.
Interventions
DRUGOPC-41061 7.5mg
7.5mg, 1 tablet a day
DRUGOPC-41061 placebo
placebo, 1 tablet a day
DRUGOPC-41061 15mg
15mg, 1 tablet a day
DRUGOPC-41601 30mg
30mg, 1 tablet a day
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
1. Subjects with ascites despite taking either of the following combinations of loop diuretics and an anti-aldosterone agent (spironolactone) for at least 7 days prior to start of the study drug administration. Combination 1: Loop diuretics at indicated below in combination with an anti-aldosterone agent at a daily dose of 25 mg or more * Furosemide: 40 mg/day or more * Other loop diuretic: a daily dosage equivalent to 40 mg or more of furosemide Bumetanide: 1 mg/day or more, Piretanide: 6 mg/day or more, Azosemide: 60 mg/day or more, Torasemide: 8 mg/day or more Combination 2: Anti-aldosterone agent at a daily dose of 50 mg or more in combination with furosemide at a daily dose of 20 mg or more (or one of the other loop diuretics specified in Combination 1 at a daily dosage equivalent to 20 mg or more of furosemide) 2. Patients who have been hospitalized or are able to stay at the study site from the start of the run-in observation period until completion of postdosing observation 2. 3. Subjects capable of giving informed consent to participate in the study of their own free will.
Exclusion criteria
1. Subjects with any of the following complications or symptoms: (1) Hepatic encephalopathy (Hepatic coma grade: II or more), (2) Poorly-controlled hepatocellular carcinoma (i.e., hepatocellular carcinoma with vessel infiltration confirmed by imaging in the main trunk or main branch of the portal vein, inferior vena cava, or the main trunk of the hepatic vein), (3)Endoscopic findings within 30 days prior to screening examination requiring new therapy for esophageal and gastric varicose vein during the study period, (4)Repeated haemorrhoidal bleeding due to rectal varicose vein within 30 days prior to screening examination, (5)Diabetes mellitus with poorly controlled blood glucose, (6)Heart failure (NYHA class III or IV), (7)Anuria, (8)Impairment of urination due to urinary tract stricture, urinary calculus, tumor in the urinary tract, or other cause 2. Subjects with a history of any of the following diseases: (1) Cerebrovascular disorder within 30 days prior to the screening examination, (2)Episode of gout within 90 days prior to the screening examination, (3)Hypersensitivity or idiosyncratic reaction to benzazepine derivatives such as mozavaptan hydrochloride or benazepril hydrochloride. 3. Subjects who are obese (body mass index \[BMI, body weight (kg)/height (m)2\] exceeding 35) 4. Patients with supine systolic blood pressure exceeding 90 mmHg 5. Subjects with any of following abnormal laboratory values: hemoglobin exceeding 8.0 g/dL, total bilirubin exceeding 3.0 mg/dL, serum creatinine exceeding 3.0 mg/dL, serum sodium exceeding 147 mEq/L, serum potassium exceeding 5.5 mEq/L, or uric acid exceeding 8.0 mg/dL 6. Patients who are unable to take oral medication 7. Female subjects who are pregnant, possibly pregnant, or lactating, or who plan to become pregnant 8. Subjects who received blood products, including albumins, within 7 days prior to the screening examination 9. Subjects who received any investigational drug other than OPC-41061 within 30 days prior to the screening examination 10. Subjects who previously participated in this or any other study of OPC-41061 and received OPC-41061 11. Subjects otherwise judged by the investigator or subinvestigator to be inappropriate for inclusion in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Body Weight (Amount of Change) | Baseline, Day 7 or at the discontied of treatment | Changes in body wight from baseline at the final timepoint (LOCF). A linear regression model using changes in body weight from baseline at the final timepoint as the criterion variable and dose as the explanatory variable was fitted to the dataset. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Abdominal Circumference | Baseline, Day 7 or at the discontied of treatment | Change in abdominal circumference from baseline (LOCF) |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo, 1 tablet a day | 26 |
| OPC-41061 7.5 mg 7.5 mg, 1 tablet a day | 25 |
| OPC-41061 15 mg 15 mg, 1 tablet a day | 25 |
| OPC-41061 30 mg 30 mg, 1 tablet a day | 25 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 3 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 2 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Resolution of all hepatic edema findings | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | OPC-41061 7.5 mg | OPC-41061 15 mg | OPC-41061 30 mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 14 Participants | 14 Participants | 12 Participants | 53 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 11 Participants | 11 Participants | 13 Participants | 48 Participants |
| Age, Continuous | 63.5 years STANDARD_DEVIATION 10.1 | 64.5 years STANDARD_DEVIATION 9.4 | 64.8 years STANDARD_DEVIATION 9.7 | 62.8 years STANDARD_DEVIATION 10.4 | 63.9 years STANDARD_DEVIATION 9.8 |
| Region of Enrollment Japan | 26 participants | 25 participants | 25 participants | 25 participants | 101 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 4 Participants | 10 Participants | 30 Participants |
| Sex: Female, Male Male | 17 Participants | 18 Participants | 21 Participants | 15 Participants | 71 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 | 18 / 26 | 20 / 25 | 19 / 25 | 24 / 25 |
| serious Total, serious adverse events | 5 / 26 | 0 / 25 | 1 / 25 | 3 / 25 |
Outcome results
Primary
Body Weight (Amount of Change)
Changes in body wight from baseline at the final timepoint (LOCF). A linear regression model using changes in body weight from baseline at the final timepoint as the criterion variable and dose as the explanatory variable was fitted to the dataset.
Time frame: Baseline, Day 7 or at the discontied of treatment
Population: Full Analysis Set; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Body Weight (Amount of Change) | -0.68 Kg | Standard Deviation 2.5 |
| OPC-41061 7.5 mg | Body Weight (Amount of Change) | -2.31 Kg | Standard Deviation 2.35 |
| OPC-41061 15 mg | Body Weight (Amount of Change) | -1.88 Kg | Standard Deviation 2.45 |
| OPC-41061 30 mg | Body Weight (Amount of Change) | -1.67 Kg | Standard Deviation 1.46 |
Comparison: A linear regression model using change in body weight from baseline at the final timepoint as the criterion variable and dose as the explanatory variable was fitted to the dataset. The null hypothesis of whether the regression coefficient is zero (analysis using t-statistics) was tested at a two-tailed significance level of 0.05, and estimated values for the slope and 95% confidence interval were calculated.p-value: 0.316795% CI: [-0.061, 0.02]Regression, Linear
Secondary
Abdominal Circumference
Change in abdominal circumference from baseline (LOCF)
Time frame: Baseline, Day 7 or at the discontied of treatment
Population: Full Analysis Set; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Abdominal Circumference | -1.39 cm | Standard Deviation 3.16 |
| OPC-41061 7.5 mg | Abdominal Circumference | -2.98 cm | Standard Deviation 3.22 |
| OPC-41061 15 mg | Abdominal Circumference | -2.42 cm | Standard Deviation 3.96 |
| OPC-41061 30 mg | Abdominal Circumference | -2.62 cm | Standard Deviation 2.83 |