The Efficacy and Safety of Pioglitazone in Patients With Nonalcoholic Steatohepatitis
The Efficacy and Safety of Pioglitazone in Patients With Nonalcoholic Steatohepatitis
Recent studies have demonstrated that PPARγ as well as diet control could improve glycemic
 control, decrease serum ALT level, decrease hepatic fat distribution, and increase
 intrahepatic insulin sensitivity. The purposes of this study are:

 1. Primary aims:

 1. Comparison between Pioglitazone and placebo groups in terms of steatosis and liver
 function tests.

 2. Evaluation of clinical safety of Pioglitazone

 2. Secondary aims:

 1. Comparison between Pioglitazone and placebo groups in terms of liver necroinflammation
 and fibrosis.

 2. The impact of Pioglitazone on the related metabolic index, including insulin
 resistance(HOMA-IR), newly-onset diabetes, metabolic syndrome, lipid profiles (T-Chol,
 HDL-C, LDL-C, TG).

 3. Comparison between Pioglitazone and placebo groups in terms of high-sensitive C-reactive
 protein changes.

 3. Interventional aim: Assessment the association between magnetic resonance imaging study
 and intrahepatic fat distribution before and after Pioglitazone treatment.
Pioglitazone belongs to thiazolidinediones and anti-diabetes drug which decreases the insulin
 resistance. It increases the use of glucose of peripheral tissues and decrease the production
 of glucose from liver and dose not influence the production of insulin. It is agonist of
 peroxisome proliferator-activated receptor-gamma (PPARγ) and by binding to the receptors of
 PPARγ in various tissues it has effects on transcription of the insulin-dependent gene. In
 animal model, pioglitazone has shown to influence the metabolism by the insulin-dependent
 mechanism.

 Recent studies have demonstrated that PPARγ as well as diet control could improve glycemic
 control, decrease serum ALT level, decrease hepatic fat distribution, and increase
 intrahepatic insulin sensitivity. Meanwhile, PPARγ could also prevent the development of
 alcohol-induced steatohepatitis, improve hepatic necroinflammatory activity, and decrease
 lipid deposition. It is not yet clearly known how the effect of P-PARγ agonist among Asian
 peoples.
Main inclusion criteria:

 1. Male and female patients with 18-70 years of age

 2. Liver biopsy findings consistent with the diagnosis of NASH with or without
 compensated cirrhosis within one year before baseline

 3. Compensated liver disease

 4. Negative urine or blood pregnancy test (for women of childbearing potential)
 documented within the 24-hour period prior to the first dose of study drug

 5. All fertile males and females must be using two forms of effective contraception
 during treatment during the 3 months after treatment.

 6. ALT level between 1.3-5 x ULN for 2 occasions during 6 months before screening.

 7. HbA1C ≦ 8.0 during screening

 Main exclusion criteria:

 1. Therapy with any systemic anti-neoplastic or immunomodulatory treatment (including
 supraphysiologic doses of steroids and radiation) *6 months before baseline.

 2. History or other evidence of a medical condition associated with chronic liver disease
 other than NASH (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease,
 > 20 g/day for female or > 40 g/day for male, toxin exposures)

 3. hepatocellular carcinoma

 4. History or other evidence of bleeding from esophageal varices or other conditions
 consistent with decompensated liver disease

 5. Serum creatinine level >1.5 times the upper limit of normal at screening and
 calculated creatinine clearance as calculated by Cockcroft and Gault < 60mL/min during
 screening

 6. History of ischemic heart disease during screening

 7. New York Heart Association (NYHA) Functional Class 1-4 cardiac status during screening

 8. Albumin <3.2g/dL during screening

 9. Total bilirubin >1.2 x ULN during screening. Patients with history of asymptomatic
 indirect hyperbilirubinemia whose total bilirubin < 2 x ULN and direct bilirubin < 20%
 of total bilirubin could be included.

 10. History of prothrombin time > 15 seconds or International normalized ratio (INR) > 1.3

 11. Organ, stem cell, or bone marrow transplant

 12. History of serious concurrent medical illness that in the investigator's opinion might
 interfere with therapy this includes significant systemic illnesses (other than liver
 disease) such as chronic pancreatitis

 13. Active systemic autoimmune disorder

 14. Pregnancy (or lactation) or, in subjects capable of bearing children, inability /
 unwillingness to practice adequate contraception

 15. Females of child-bearing potential (post-puberty) unwilling or unable to have
 pregnancy testing at any study visit

 16. Therapy with a systemic antiviral agent (with the exception of prophylaxis or
 treatment of influenza or chronic HSV) within the past 30 days prior to screening.

 17. Concurrent participation in another clinical trial in which the subject is or will be
 exposed to another investigational or a non-investigational drug or device within 6
 weeks of the screening visit

 18. Current therapy with insulin within 1 week prior to screening.

 19. Experienced use with PPARg agonist (e.g., rosiglitazone, pioglitazone) within 6 months
 prior to screening.

 20. Known hypersensitivity to any component of PPARg agonists

 21. A history of hepatotoxicity to TZDs and/or a history of severe edema or a medically
 serious fluid-related event associated with the use of TZDs

 22. History of metformin use within 3 months prior to screening.

 23. Type Ⅰ diabetes

 24. Seropositive of HBsAg, anti-HCV or anti-HIV during screening or 3 month prior to
 screening.