A Dose-defining Study of OPC-41061 in Treatment of Hepatic Edema
A Dose-defining Study of OPC-41061 in Treatment of Hepatic Edema
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.
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