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

A Multicenter, Randomized, Placebo Controlled Study to Assess the Safety and Efficacy of Orally Administered Silymarin Preparation (Legalon®) for the Treatment of Non-Cirrhotic Patients With Non-Alcoholic Steatohepatitis

Silymarin, also known as milk thistle, is an alternative medicine commonly found in health food and vitamin stores. People with liver disease sometimes use silymarin because it is thought to have liver protecting effects; however, this benefit has not been proven. The purpose of this research study is to determine the effectiveness of silymarin and assess the safety of different silymarin doses in patients with varying severity of liver disease compared to a placebo (lactose pill).

Following a screening visit, patients with histologically confirmed NASH will be randomized to either placebo or one of two active treatment groups of silymarin (Legalon®). One active treatment group will receive 420 mg, each dose given three times daily, the other active treatment group will receive 700 mg, each dose given three times daily. Patients will be treated for 48-50 weeks. Participation in this research study requires the patient to travel to the clinic for at least 11 visits so recruitment will be limited to a geographically restricted area around participating clinical centers. Liver biopsy must be performed up to 12 months prior to, and immediately after, the treatment phase.

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.