Dose Exploring and Setting Study for Tolvaptan to Treat Hepatic Cirrhosis With Ascites

A Phase 2 Randomized, Double-blinded, Multicenter and Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of Different Doses of Tolvaptan Tablet in Patients With Cirrhotic Ascites

To observe the safety/efficacy of tolvaptan for treatment of patients with hepatic cirrhosis with ascites and exploring the dosage-effect relations of the drug.

Study Overview

• Status: Completed
• Conditions: Ascites; Hepatic Cirrhosis
• Intervention / Treatment: Drug: Tolvaptan; Drug: Tolvaptan; Drug: placebo

Detailed Description

Tolvaptan is able to exert hydragogue diuretic effects (water diuresis) via inhibition of water reabsorption by renal collecting ducts without corresponding increase in electrolyte excretion. It has been confirmed that tolvaptan is able to increase urine volume without any adverse effects on renal functions.

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200001
      • Renji Hospital, Shanghai Jiaotong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. hepatic cirrhosis patients after 7days treatment of loop diuretics and aldosterone antagonist but still with ascites
2. Hospitalized patients or those who can be hospitalized in this trial between observation period and posttherapeutic observation (Visits at clinic will be allowed after day 8);
3. During the observation period (-3 day to -1 day ), subjects whose body weight difference fall within ±1.0 kg range 2 days (day-2 and day -1) prior to initiation of trial drug treatment;
4. Ages: ≥18 and ≤75 years of age;
5. Genders: men or women;
6. Signed the Informed Consent Form.

Exclusion Criteria:

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

   • Hepatic encephalopathy (Coma scale Note 1) grade 2 or higher);
   • Malignant ascites;
   • Uncontrolled spontaneous bacterial peritonitis;
   • Patients are likely to experience alimentary tract hemorrhage during the trial;
   • Heart failure (NYHA cardiac function scale Note 2) stages 3 and 4);
   • Anuria (daily urine volume below 100mL);
   • Dysuria resulting from urethral stricture, calculus and tumors.

2. Patients with the following medical history:

   • Alimentary tract hemorrhage within 10 days prior to screening;
   • Cerebrovascular accident within 1 month prior to screening;
   • Gout attack within 1 month prior to screening;
   • Past allergy or hypersensitive reactions to benzodiazepines (e.g. benazepril hydrochloride)
3. Systolic pressure below 90mmHg at screening;

4. Patients with the following abnormalities in laboratory examinations at screening:

   Serum creatinine exceeds 2.5X upper limits of normal, serum Na+>145mmol/L (or exceeds upper limits of normal), serum K+>5.5mmol/L, uric acid>8.0mg/dL (476μmol/L), Child-pugh scale greater than 12.

5. Patients cannot take drugs orally;
6. Pregnant or breast-feeding patients or women at child-bearing ages without taking acceptable contraceptive measures;
7. Patients received albumin or other blood preparations within 4 days prior to trial drug administration;
8. Patients participated in clinical trials of other drugs within 1 month prior to screening;
9. Patients participated in tolvaptan trials and took tolvaptan previously;
10. Patients are unsuitable to participate in this trial in investigators' opinion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1. tolvaptan; 15 mg, P.O., Qd, for 7 days,	Drug: Tolvaptan; tablet, 15 mg, Qd, for 7 days; Other Names: SAMSCA; Drug: Tolvaptan; tablet, 30 mg, Qd, 7 days; Other Names: SAMSCA
Experimental: 2 tolvaptan; 30 mg, P.O., Qd, for 7 days,	Drug: Tolvaptan; tablet, 15 mg, Qd, for 7 days; Other Names: SAMSCA; Drug: Tolvaptan; tablet, 30 mg, Qd, 7 days; Other Names: SAMSCA
Experimental: 3. Placebo; 30mg,P.O.,Qd, for 7 days.	Drug: placebo; tablet, 30 mg, Qd, 7days.; Other Names: blank tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Body weight changes after 7 days of treatment (quantity of changes)	from day1 to day7

Secondary Outcome Measures

Outcome Measure	Time Frame
Body weight change after 4 days of treatment (quantity of changes)	from day1 to day4
Waist circumference after 4 and 7 days of treatment (quantity and rate of changes)	from day1 to day7

Collaborators and Investigators

• Sponsor: Otsuka Beijing Research Institute

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: March 5, 2010
• First Submitted That Met QC Criteria: May 5, 2011
• First Posted (Estimate): May 6, 2011

Study Record Updates

• Last Update Posted (Estimate): October 12, 2012
• Last Update Submitted That Met QC Criteria: October 10, 2012
• Last Verified: May 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Ascites; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: 156-08-804-01