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Phase III Study of Tolvaptan Tablet to Treat Cirrhosis Ascites

Primary Purpose

Ascites, Hepatic Cirrhosis

Status
Completed
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
Tolvaptan
Tolvaptan
placebo
Sponsored by
Otsuka Beijing Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ascites focused on measuring Tolvaptan treatment to ascites and hepatic cirrhosis

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Renji Hospital, Shanghai Jiaotong University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Tolvaptan 15mg

Tolvaptan 7.5mg

Placebo

Arm Description

Tablet;15mg/tab

Tablet;7.5mg/tab

Tolvaptan 0mg/tab

Outcomes

Primary Outcome Measures

Change from baseline in body weight after 7 days randomized treatment (Day 8).

Secondary Outcome Measures

Change from baseline in body weight after 4 days randomized treatment (Day 5);
The rate of change from baseline in body weight after 4, 7 days randomized treatment (Day 5, Day 8);

Full Information

First Posted
May 4, 2011
Last Updated
October 10, 2012
Sponsor
Otsuka Beijing Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT01349348
Brief Title
Phase III Study of Tolvaptan Tablet to Treat Cirrhosis Ascites
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2012
Overall Recruitment Status
Completed
Study Start Date
October 2010 (undefined)
Primary Completion Date
May 2012 (Actual)
Study Completion Date
July 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Beijing Research Institute

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ascites, Hepatic Cirrhosis
Keywords
Tolvaptan treatment to ascites and hepatic cirrhosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
535 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tolvaptan 15mg
Arm Type
Experimental
Arm Description
Tablet;15mg/tab
Arm Title
Tolvaptan 7.5mg
Arm Type
Experimental
Arm Description
Tablet;7.5mg/tab
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Tolvaptan 0mg/tab
Intervention Type
Drug
Intervention Name(s)
Tolvaptan
Other Intervention Name(s)
SAMSCA
Intervention Description
tablet, 15 mg, Qd, for 7 days
Intervention Type
Drug
Intervention Name(s)
Tolvaptan
Other Intervention Name(s)
SAMSCA
Intervention Description
tablet, 7.5 mg, Qd, for 7 days
Intervention Type
Drug
Intervention Name(s)
placebo
Other Intervention Name(s)
Blank tablet
Intervention Description
tablet, 7.5/15mg , Qd, 7days.
Primary Outcome Measure Information:
Title
Change from baseline in body weight after 7 days randomized treatment (Day 8).
Time Frame
7 days
Secondary Outcome Measure Information:
Title
Change from baseline in body weight after 4 days randomized treatment (Day 5);
Time Frame
4days
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Patients diagnosed with liver cirrhosis clinically or pathologically; 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 Inpatients or patients who can be hospitalized for this study from Day -3 (Screening) to Day 8 (the day for efficacy evaluation); Patients with body weight change within ±1.0 kg in the 2 days prior to initiation of treatment (Day -2 and Day -1) Age: 18 to 75 years, inclusive(at the time informed consent is obtained); Genders: men or women; Patients who have signed informed consent form. Exclusion criteria: 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. 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). Patients with systolic pressure below 90mmHg at screening; 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; Patients with Child-pugh score3）>12; Patients who are unable to take medicine orally; Female patients who are pregnant, lactating, or who are at child-bearing age without using acceptable contraceptive means; Patients who received blood products including albumin within 4 days prior to the initiation of treatment Patients who participated in any clinical trial other than tolvaptan within one month prior to screening; Patients who participated in Tolvaptan trials and took Tolvaptan previously; Patients otherwise judged by the investigator, to be inappropriate for inclusion in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Minde Zeng
Organizational Affiliation
RenJi Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Renji Hospital, Shanghai Jiaotong University School of Medicine
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200001
Country
China

12. IPD Sharing Statement

Citations:
PubMed Identifier
33213378
Citation
Tang J, Wang Y, Han T, Mao Q, Cheng J, Ding H, Shang J, Zhang Q, Niu J, Ji F, Chen C, Jia J, Jiang X, Lv N, Gao Y, Wang Z, Wei Z, Chen Y, Zeng M, Mao Y. Tolvaptan therapy of Chinese cirrhotic patients with ascites after insufficient diuretic routine medication responses: a phase III clinical trial. BMC Gastroenterol. 2020 Nov 19;20(1):391. doi: 10.1186/s12876-020-01536-0.
Results Reference
derived
PubMed Identifier
30180806
Citation
Wang S, Zhang X, Han T, Xie W, Li Y, Ma H, Liebe R, Weng H, Ding HG. Tolvaptan treatment improves survival of cirrhotic patients with ascites and hyponatremia. BMC Gastroenterol. 2018 Sep 4;18(1):137. doi: 10.1186/s12876-018-0857-0.
Results Reference
derived

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Phase III Study of Tolvaptan Tablet to Treat Cirrhosis Ascites

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