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Phase III Study of Tolvaptan Tablet to Treat Cirrhosis Ascites

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Otsuka Beijing Research Institute
ClinicalTrials.gov Identifier:
NCT01349348
First received: May 4, 2011
Last updated: October 10, 2012
Last verified: October 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Ascites
Hepatic Cirrhosis
 Drug: Tolvaptan
Drug: placebo
 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

MedlinePlus related topics: Cirrhosis
Drug Information available for: Tolvaptan
U.S. FDA Resources

Further study details as provided by Otsuka Beijing Research Institute:

Primary Outcome Measures:
  • Change from baseline in body weight after 7 days randomized treatment (Day 8). [ Time Frame: 7 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change from baseline in body weight after 4 days randomized treatment (Day 5); [ Time Frame: 4days ] [ Designated as safety issue: No ]
  • The rate of change from baseline in body weight after 4, 7 days randomized treatment (Day 5, Day 8); [ Time Frame: 4 and 7 days ] [ Designated as safety issue: No ]

Enrollment: 535
Study Start Date: October 2010
Study Completion Date: July 2012
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tolvaptan 15mg
Tablet;15mg/tab
 Drug: Tolvaptan
tablet, 15 mg, Qd, for 7 days
Other Name: SAMSCA
Experimental: Tolvaptan 7.5mg
Tablet;7.5mg/tab
 Drug: Tolvaptan
tablet, 7.5 mg, Qd, for 7 days
Other Name: SAMSCA
Placebo Comparator: Placebo
Tolvaptan 0mg/tab
 Drug: placebo
tablet, 7.5/15mg , Qd, 7days.
Other Name: Blank tablet

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01349348

Locations
China, Shanghai
Renji Hospital, Shanghai Jiaotong University School of Medicine
Shanghai, Shanghai, China, 200001
Sponsors and Collaborators
Otsuka Beijing Research Institute
Investigators
Principal Investigator: Minde Zeng Renji hospital, Shanghai Jiaotong University School of Medicine
  More Information

No publications provided

Responsible Party: Otsuka Beijing Research Institute
ClinicalTrials.gov Identifier: NCT01349348     History of Changes
Other Study ID Numbers: 156-08-805-01
Study First Received: May 4, 2011
Last Updated: October 10, 2012
Health Authority: China: Food and Drug Administration

Keywords provided by Otsuka Beijing Research Institute:
Tolvaptan treatment to ascites and hepatic cirrhosis

Additional relevant MeSH terms:
Ascites
Liver Cirrhosis
Fibrosis
 Pathologic Processes
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on May 21, 2013