Phase II Trial of Silymarin for Non-Cirrhotic Patients With Non-Alcoholic Steatohepatitis

Inclusion Criteria

• Age at least 18 years at screening.
• Informed consent signature.
• AST (aspartate aminotransferase) or ALT (alanine aminotransferase) greater than 40 IU/L within one year of screening and at least once during the screening period.
• The participant must agree to adhere to the alcohol consumption guidelines.
• Have a liver biopsy performed within 12 months of randomization demonstrating features consistent with NASH without cirrhosis; NAS score of at least 4. Historical biopsy must include one Trichrome and one H&E slide, otherwise the biopsy must be redone.
• No change in diabetic medications or insulin sensitizers (if applicable) between biopsy and screening or during the screening period.
• Weight loss/gain of no more than 10% between biopsy and screening, or within 30 days of screening if the biopsy is performed during the screening period.
• Negative urine pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study medication. Females of childbearing potential must be using two reliable forms of effective contraception during the study (while on study drug and during follow-up).

Exclusion Criteria

• Use of silymarin or other milk thistle preparations for a period of 90 consecutive days or longer between biopsy and initial screening, or within 30 days prior to screening if the biopsy is performed during the screening period.
• Use of other antioxidants such as vitamin E, vitamin C, glutathione, alpha-tocopherol, or non-prescribed complementary alternative medications (including dietary supplements, megadose vitamins, herbal preparations, and special teas) within 30 days prior to screening. A multivitamin at standard doses will be allowed.
• Use of silymarin or other antioxidants or non-prescribed complementary alternative medications (as above) during the screening period or patient unwilling to refrain from taking these medications through completion of the study.
• BMI > 45 kg/m2 between screening and randomization.
• Type 2 diabetes treated with oral agents other than the secretagogues or metformin; these include, thiazolidinediones, alpha-glucosidase inhibitors, exenatide, pramlintide between screening and randomization. Januvia (sitagliptin) is allowed.
• Evidence of poorly-controlled diabetes (defined as HbA1c > 8% in patients with diabetes) between screening and randomization.
• Known allergy/sensitivity to milk thistle or its preparations.
• Use of drugs associated with a clinical or histological picture consistent with fatty liver disease or NASH for more than 12 consecutive weeks in the 1 year prior to screening; these include amiodarone, tamoxifen, methotrexate, glucocorticoids, anabolic steroids, tetracyclines, estrogens at doses greater than those used for hormone replacement, valproate/valproic acid.
• For patients using antihyperlipidemic agents or accepted anti-diabetic agents, any change of agent or dose from screening through randomization.
• Use of warfarin, metronidazole, or acetaminophen (greater than 2 grams per day) from screening through randomization.
• Lactose intolerance defined as patient reported inability to tolerate milk products.
• History of other chronic liver disease, including metabolic diseases, documented by appropriate test(s).
• Previous liver biopsy that demonstrated presence of cirrhosis.
• Radiologic imaging consistent with cirrhosis or portal hypertension.
• Clinical or histological evidence of cirrhosis or, in the opinion of the investigator, the inability to safely obtain a liver biopsy due to technical reasons, such as body habitus.
• Evidence of decompensated liver disease defined as any of the following: serum albumin 1.5 mg/dl, or PT/INR (Prothrombin Time/International Normalized Ratio) > 1.3 times normal at screening, or history or presence of ascites or encephalopathy, or bleeding from esophageal varices.
• Platelet count 12 grams) per day or more than two (2) drinks on any one day ov