A Randomized, Double-blinded, Multicenter, Placebo Controlled, Parallel Designed Study, to Evaluate the Efficacy and Safety of Tolvaptan Tablet in Treatment of Patients With Cirrhosis Ascites, Using Diuretics as Initial Treatment

Phase III Study of Tolvaptan Tablet to Treat Cirrhosis Ascites

Sponsors

Lead sponsor: Otsuka Beijing Research Institute

Source Otsuka Beijing Research Institute
Brief Summary

To evaluate the efficacy and safety of Tolvaptan 7.5mg and 15mg in treatment of patients with cirrhosis ascites who fail to response adequately to treatment with common diuretics.

Detailed Description

For symptoms of fluid retention due to liver diseases (ascites and/or lower extremity edema, i.e. hepatic edema), treatment generally starts with bed rest and a low-salt diet. Aldosterone antagonists and loop diuretics are commonly used diuretics in the treatment of fluid retention due to liver diseases. In aldosterone antagonists' therapy, nevertheless, hyperkalemia is frequently reported, slow onset of action and dose escalation needed also impair its effect. If aldosterone antagonists' therapy is ineffective, loop diuretics as strong diuretics are usually added up. However, Dose escalation of loop diuretics also boost the occurrence of hyponatremia and hypokalemia, and combination of the two drugs provided fastest onset of effectiveness with less adverse events. While, because both diuretics can cause sodium lose which is difficult to prevent and treat, hyponatremia is easy to occur. The combination of aldosterone antagonists and K-sparing diuretics reduces the occurrence of hypokalemia but have little effect on the prevention and treatment of hyponatremia. In addition, there are still some patients who are resistent to loop diuretics or intolerant of an effective diuretic dosage due to adverse events.

Tolvaptan increases the excretion of electrolyte-free water (aquaretic) without changing electrolytes excretion by inhibiting the water reabsorption of collecting duct in kidney. It is demonstrated that Tolvaptan increased urine volume without impairing renal function.

Overall Status Completed
Start Date October 2010
Completion Date July 2012
Primary Completion Date May 2012
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Change from baseline in body weight after 7 days randomized treatment (Day 8). 7 days
Secondary Outcome
Measure Time Frame
Change from baseline in body weight after 4 days randomized treatment (Day 5); 4days
The rate of change from baseline in body weight after 4, 7 days randomized treatment (Day 5, Day 8); 4 and 7 days
Enrollment 535
Condition
Intervention

Intervention type: Drug

Intervention name: Tolvaptan

Description: tablet, 15 mg, Qd, for 7 days

Arm group label: Tolvaptan 15mg

Other name: SAMSCA

Intervention type: Drug

Intervention name: Tolvaptan

Description: tablet, 7.5 mg, Qd, for 7 days

Arm group label: Tolvaptan 7.5mg

Other name: SAMSCA

Intervention type: Drug

Intervention name: placebo

Description: tablet, 7.5/15mg , Qd, 7days.

Arm group label: Placebo

Other name: Blank tablet

Eligibility

Criteria:

Inclusion criteria:

1. Patients diagnosed with liver cirrhosis clinically or pathologically;

2. Patients with ascites confirmed by Type-B ultrasound scan after receiving combination therapies of oral loop diuretics and aldosterone antagonists for at least 4 days with the fixed usage and dosage

3. Inpatients or patients who can be hospitalized for this study from Day -3 (Screening) to Day 8 (the day for efficacy evaluation);

4. Patients with body weight change within ±1.0 kg in the 2 days prior to initiation of treatment (Day -2 and Day -1)

5. Age: 18 to 75 years, inclusive(at the time informed consent is obtained);

6. Genders: men or women;

7. Patients who have signed informed consent form.

Exclusion criteria:

1. Patients with any of the following diseases, complications or symptoms:

- Hepatic encephalopathy (hepatic coma of grade II or higher1));

- Malignant ascites (patients have tumor cells detected in ascites if malignant ascites be highly suspected);

- Uncontrolled spontaneous bacterial peritonitis;

- Patients who are likely to experience alimentary tract hemorrhage during the study;

- Heart failure (NYHA2) grade III or IV);

- Anuresis (daily urine volume is less than 100mL);

- Dysuria due to urinary tract stricture, urinary calculus, tumor in the urinary tract or other cause.

2. Patients with history of :

- Alimentary tract hemorrhage within 10 days prior to screening;

- Cerebral accident suffered within 30 days prior to screening;

- Past history of hypersensitivity or idiosyncratic reaction to benzazepine derivatives (Benazepril).

3. Patients with systolic pressure below 90mmHg at screening;

4. Patients with any of the following abnormal laboratory parameters at screening:

- Serum creatinine >1.5x upper limit of normal range;

- Serum Na+>145mmol/L (or higher than upper limit of normal range);

- Serum K+>5.5mmol/L;

5. Patients with Child-pugh score3)>12;

6. Patients who are unable to take medicine orally;

7. Female patients who are pregnant, lactating, or who are at child-bearing age without using acceptable contraceptive means;

8. Patients who received blood products including albumin within 4 days prior to the initiation of treatment

9. Patients who participated in any clinical trial other than tolvaptan within one month prior to screening;

10. Patients who participated in Tolvaptan trials and took Tolvaptan previously;

11. Patients otherwise judged by the investigator, to be inappropriate for inclusion in the study.

Gender: All

Minimum age: 18 Years

Maximum age: 75 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Minde Zeng Principal Investigator RenJi Hospital
Location
facility
Renji Hospital, Shanghai Jiaotong University School of Medicine
Location Countries

China

Verification Date

October 2012

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Arm group label: Tolvaptan 15mg

Arm group type: Experimental

Description: Tablet;15mg/tab

Arm group label: Tolvaptan 7.5mg

Arm group type: Experimental

Description: Tablet;7.5mg/tab

Arm group label: Placebo

Arm group type: Placebo Comparator

Description: Tolvaptan 0mg/tab

Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov