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

This is a multicenter, randomized, double masked, placebo controlled Phase II trial to
evaluate the safety and explore the efficacy of silymarin (Legalon®) compared with placebo
on hepatic histology in patients with NASH (nonalcoholic steatohepatitis) after 48-50 weeks
of therapy. This study was originally sponsored through a cooperative agreement (U01) award
from the NCCAM and the NIDDK (RFA-AT-05-006: "Phase I/II Trials of Silymarin for Chronic
Liver Diseases"), and now will continue with Madaus Inc. (Rottapharm Group) providing
financial and regulatory support to the investigators. The broad aim of this study is to
evaluate the safety and explore the efficacy of silymarin (Legalon®) in NASH patients and to
form the basis for future studies which will establish its efficacy for treating patients
with NASH. The specific objectives of this study are to determine the effect of silymarin
(Legalon®) on the histologic NASH Activity Score (NAS), the liver enzymes, and HOMAr. The
primary endpoint of the study is an improvement in the NAS by at least 2 points. Various
secondary endpoints will be assessed, including the change in liver enzymes and HOMAr.

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 <3.2 g/dl, total bilirubin > 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 < 130,000/mm3 at screening.

- Serum creatinine of 2.0 mg/dL or greater or CrCl ≤ 60cc/min, or on dialysis, at
screening. The creatinine clearance (CrCl) will be calculated according to
Cockcroft-Gault.

- Average alcohol consumption of more than one drink or equivalent (>12 grams) per day
or more than two (2) drinks on any one day over the 30 days prior to screening.
Patients who met either criterion more than 30 days prior to screening must have
consumed a monthly average of 12 grams or less per day of alcohol for at least six
months prior to screening.

- Evidence of drug abuse in the year prior to screening or prior to randomization.

- History of immunologically mediated disease (e.g., inflammatory bowel disease,
idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic
anemia, severe psoriasis, rheumatoid arthritis) that could affect the assessment of
biomarkers of inflammation.

- History of solid organ or bone marrow transplantation.

- History of thyroid disease poorly controlled on prescribed medications.

- Use of oral steroids for more than 14 days within 30 days of screening or prior to
randomization.

- Primary hepatic malignancy.

- Secondary hepatic malignancy (metastatic disease) or extrahepatic malignancy.

- Women with ongoing pregnancy or breast feeding, or contemplating pregnancy.

- History of bariatric surgery, or undergoing evaluation for bariatric surgery.

- Participation in a research drug trial, exclusive of the SyNCH Phase I trial, within
30 days of screening.

- History or other evidence of severe illness or any other conditions that would make
the patient, in the opinion of the investigator, unsuitable for the study (such as
poorly controlled psychiatric disease, coronary artery disease, or active
gastrointestinal conditions that might interfere with drug absorption).

- Inability or unwillingness to give informed consent or abide by the study protocol.