Phase II Trial of Silymarin for Non-Cirrhotic Patients With Non-Alcoholic Steatohepatitis
Condition: Non-alcoholic Steatohepatitis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Placebo; Silymarin 700 mg; Silymarin 420 mg
Intervention description: Placebo (5 pills, three times daily) for 48-50 week treatment period; 700 mg dose (5 pills, three times daily) for 48-50 week treatment period; 420 mg dose (5 pills, three times daily) for 48-50 week treatment period
Intervention MeSH terms: Silymarin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NASH; non-alcoholic steatohepatitis

Summary:

      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.
    

Eligibility criteria:

        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.