A Dose-defining Study of OPC-41061 in Treatment of Hepatic Edema
Condition: Cirrhosis
MeSH terms: Fibrosis
Intervention: OPC-41061 7.5mg; OPC-41061 placebo; OPC-41061 15mg; OPC-41601 30mg
Intervention description: 7.5mg, 1 tablet a day; placebo, 1 tablet a day; 15mg, 1 tablet a day; 30mg, 1 tablet a day
Intervention MeSH terms: Tolvaptan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 104.0
Sex: All
Minimum age: 20 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: OPC-41061; Tolvaptan; ascites; Cirrhosis

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.
    

Eligibility criteria:

        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