A Study of OPC-41061 in Subjects With Cardiac-induced Edema (Congestive Heart Failure)

Phase 3 Open-label, Study of OPC-41061 in Subjects With Cardiac-induced Edema (Congestive Heart Failure) - an Investigation of the Safety of Treatment Beyond 7 Days and the Effect of Dose Escalation to 30 mg

To investigate the plasma drug level, efficacy, and safety of 7-day repeated oral administration of OPC-41061 at 15 mg/day (treatment period 1) and subsequent 7-day repeated administration of OPC-41061 at 15 mg/day or 30 mg/day if diuretic effect is insufficient (treatment period 2) in congestive heart failure (CHF) patients with extracellular volume expansion despite conventional diuretic therapy.

Inclusion Criteria:

1. Subjects with cardiac edema receiving diuretic treatment since 7 days prior to the commencement of study drug administration.

2. Subjects receiving one of the following diuretic treatments since 3 days prior to the commencement of study drug administration without changing the dose or dosing regimen (including subjects scheduled to start treatment during the run-in observation period).

   • 1. A loop diuretic at a daily dosage equivalent to 40 mg or more of furosemide
   • 2. Concomitant administration of a loop diuretic and a thiazide diuretic (at any doses)
   • 3. Concomitant administration of a loop diuretic and an anti-aldosterone drug (at any doses)

3. CHF patients with lower limb edema, jugular venous distention, or pulmonary congestion due to extracellular volume expansion.

4. Male or female subjects between the ages of 20 and 85, inclusive (at time of informed consent)

5. Subjects able to stay at the study site from the day before the start of the run-in observation period until completion of post-treatment observation 2 (7 to 10 days after final study drug administration)

6. Subjects capable of giving informed consent to participate in the study of their own free will

Exclusion Criteria:

1. Heart failure patients with markedly fluctuating symptoms

2. Patients with an assisted circulation device

3. Patients with any of the following complications or symptoms:

   • 1. Suspected decrease in circulatory blood flow ，
   • 2. Hypertrophic cardiomyopathy (other than dilated phase)，
   • 3. Cardiac valve disease with significant heart valve stenosis，
   • 4. Hepatic coma

4. Patients who develop acute myocardial infarction within 30 days prior to the screening examination

5. Patients with a definite diagnosis of active myocarditis or amyloid cardiomyopathy

6. Subjects with any of the following complications or symptoms:

   • 1. Poorly controlled diabetes melllitus，
   • 2. Anuria，
   • 3. Urination impaired due to urinary tract stricture, urinary calculus, tumor in urinary tract, or other cause

7. Subjects with any of the following disease histories:

   • 1. Sustained ventricular tachycardia or ventricular fibrillation within 30 days prior to the screening examination in subjects without an implanted defibrillator，
   • 2. Cerebrovascular disorder within 6 months prior to the screening examination (other than asymptomatic cerebral infarction)，
   • 3. A history of hypersensitivity or idiosyncratic reaction to benzazepine derivatives such as mozavaptan hydrochloride or benazepril hydrochloride.

8. Subjects who are severely obese [body mass index (BMI, body weight (kg)/height (m)2] exceeding 35]

9. Subjects with systolic blood pressure in the decubitus position exceeding 90 mmHg

10. Subjects with any of the following abnormal laboratory values:

    • 1. Total bilirubin > 3.0 mg/dL,
    • 2. serum creatinine > 3.0 mg/dL,
    • 3. serum sodium > 147 mEq/L,
    • 4. serum potassium > 5.5 mEq/L

11. Patients who are unable to take oral medication

12. Female subjects who are pregnant, possibly pregnant, or lactating, or who plan to become pregnant during the study period

13. Subjects who received any investigational drug other than OPC-41061 within 30 days prior to the screening examination

14. Subjects otherwise judged by the investigator or subinvestigator to be inappropriate for inclusion in the study