Efficacy and Safety of Oltipraz in the Patients With Liver Fibrosis and Cirrhosis

Study Overview
=================
Brief Summary
-----------------
This study investigated the effectiveness and safety of oltipraz therapy in treating patients with cirrhosis induced by chronic hepatitis type B or C.

Detailed Description
-----------------
Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] has been extensively studied as a cancer chemopreventive agent. Comprehensive mechanistic and phase IIa studies supported the notion that oltipraz exerts chemopreventive effects, as supported by Phase IIa human clinical studies of oltipraz on cancer chemoprevention, conducted in Qidong, China. Hepatic stellate cells cause synthesis of large quantities of extracellular matrix. Transforming growth factor beta1 (TGF-beta1), as a key fibrogenic mediator for fibrogenesis after injuries through deposition of extracellular matrix and inhibition of collagenase activity in the liver, is associated with the regulation of cell growth and differentiation and causes synthesis of extracellular matrix proteins and cellular receptors for matrix proteins. Previously, we reported the effectiveness of oltipraz in regeneration of cirrhotic liver, which includes reduction of the intensities of liver fibrotic and cirrhotic nodules, elimination of accumulated extracellular matrix, and regeneration of cirrhotic liver in animal models. Oltipraz completely resolves fibrosis in the cirrhotic liver, thereby improving viability. TGF-beta1 signaling plays an important role in liver fibrogenesis and cirrhosis as evidenced by receptor knockout experiments. No therapeutic agent that is active in interrupting TGF-beta1 signaling is available, proposing that C/EBP serve as a molecular target for the treatment of liver cirrhosis.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Phase II Multicenter Trial of Oltipraz for the Evaluation of Efficacy and Safety in the Patients With Liver Fibrosis and Cirrhosis Induced by Chronic Hepatitis Type B or C

Conditions
-----------------
Liver Fibrosis, Liver Cirrhosis

Intervention / Treatment
-----------------
* Drug: oltipraz
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients with fibrosis and cirrhosis induced by chronic hepatitis type B or C patients with HbsAg, Anti-HCV or HCV RNA positive Exclusion Criteria: treatment with antiviral agents, immunosuppressants, glucocorticoids, within the 6 months or with biphenyl dimethyl dicarboxylate one month treatment with any investigational drug (except CJ11555PK or CJ-OPZ-201PK) within one month Child-Pugh class C, Use of a mean daily dose of 80 g alcohol with the one month, of enzyme inducers or inhibitors, or of drug abuse that might affect this study a known hypersensitivity to oltipraz or its structurally related compounds ascites, hemorrhage from varicoses, uncompensated LC with the history of hepatic encephalopathy within the 6 months hepatocellular carcinoma (a rising serum level of α-fetoprotein or a suspicious foci on hepatic ultrasonography at screening or), liver transplantation pregnancy or lactation, unwillingness of contraception during the study period other serious concurrent illness (e.g., severe hemorrhagic GI, renal, pulmonary, neurological, cardiovascular (CHF of class III or above; a history of MI within the past 6 months) diseases, or cancer, autoimmunity or psychological diseases) any patients who is inappropriate or has unwillingness of clinical study as judged by participating clinicians bilirubin content greater than 2.0 mg/dL, prothrombin time longer than 4 sec, and serum albumin below 2.5 g/dL

Ages Eligible for Study
-----------------
Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br> | Drug: placebo<br> <br> |
| Experimental: oltipraz<br> | Drug: oltipraz<br>* 60mg bid 90mg qd<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ishak fibrosis score |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Modified Knodell's HAI score |  | 24 weeks | 
| Child-Pugh score |  | 24 weeks |