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

Study Overview
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Brief Summary
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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.

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

Conditions
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Cirrhosis

Intervention / Treatment
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* Drug: OPC-41061 7.5mg
* Drug: OPC-41061 placebo
* Drug: OPC-41061 15mg
* Drug: OPC-41601 30mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) 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. Subjects capable of giving informed consent to participate in the study of their own free will. Exclusion Criteria: 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 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. Subjects who are obese (body mass index [BMI, body weight (kg)/height (m)2] exceeding 35) Patients with supine systolic blood pressure exceeding 90 mmHg 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 Patients who are unable to take oral medication Female subjects who are pregnant, possibly pregnant, or lactating, or who plan to become pregnant Subjects who received blood products, including albumins, within 7 days prior to the screening examination Subjects who received any investigational drug other than OPC-41061 within 30 days prior to the screening examination Subjects who previously participated in this or any other study of OPC-41061 and received OPC-41061 Subjects otherwise judged by the investigator or subinvestigator to be inappropriate for inclusion in the study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br> | Drug: OPC-41061 placebo<br>* placebo, 1 tablet a day<br>|
| Experimental: 2<br> | Drug: OPC-41061 7.5mg<br>* 7.5mg, 1 tablet a day<br>|
| Experimental: 3<br> | Drug: OPC-41061 15mg<br>* 15mg, 1 tablet a day<br>|
| Experimental: 4<br> | Drug: OPC-41601 30mg<br>* 30mg, 1 tablet a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 7 or at the discontied of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abdominal Circumference | Change in abdominal circumference from baseline (LOCF) | Baseline, Day 7 or at the discontied of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OPC-41061, Tolvaptan, ascites, Cirrhosis