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

NCT00680407 | Completed Phase 2 Results DMC

• 2 other identifiers: U01AT003566-02IND 105,461 (orig. IND 74,887)
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 6

Brief 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.

Conditions

Non-alcoholic Steatohepatitis

Keywords

NASH; non-alcoholic steatohepatitis

Outcome Measures

Primary Outcomes (1)

• Efficacy - Improvement by at Least 2 Points in Histology (NAS)

  Histological Scoring System for Nonalcoholic Fatty Liver Disease ranges from 0-8 with the increase in number representing a worse outcome. Therefore the efficacy improvement was to be at least 2 points in lowering the score.

  48-50 week treatment period

Secondary Outcomes (1)

• Safety - Occurrence of a Dose-limiting Toxicity

  48-50 week treatment period

Study Arms (3)

silymarin 420 mg

EXPERIMENTAL

420 mg Legalon (silymarin) three times daily

Drug: Silymarin 420 mg

silymarin 700 mg

EXPERIMENTAL

700 mg of Legalon (silymarin) three times daily

Drug: Silymarin 700 mg

Placebo

PLACEBO COMPARATOR

Placebo (lactose pill)

Other: Placebo

Interventions

Placebo OTHER

Placebo (5 pills, three times daily) for 48-50 week treatment period

Also known as: lactose pill

Placebo

Silymarin 700 mg DRUG

700 mg dose (5 pills, three times daily) for 48-50 week treatment period

Also known as: Legalon, milk thistle

silymarin 700 mg

Silymarin 420 mg DRUG

420 mg dose (5 pills, three times daily) for 48-50 week treatment period

Also known as: Legalon, milk thistle

silymarin 420 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Madaus Inc: lead
• University of Pennsylvania: collaborator
• University of North Carolina: collaborator
• Thomas Jefferson University: collaborator
• Beth Israel Deaconess Medical Center: collaborator
• Brooke Army Medical Center: collaborator
• University of Pittsburgh: collaborator

Study Sites (6)

Beth Isreal Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Brooke Army Medical Center

San Antonio, Texas, 78234, United States

Location

Related Publications (1)

• Navarro VJ, Belle SH, D'Amato M, Adfhal N, Brunt EM, Fried MW, Reddy KR, Wahed AS, Harrison S; Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial. PLoS One. 2019 Sep 19;14(9):e0221683. doi: 10.1371/journal.pone.0221683. eCollection 2019.

  PMID: 31536511 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Lactose; Silymarin; milk-thistle extract

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars; Flavonolignans; Flavonoids; Chromones; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Associate Director, Clinical Research and Operations
• Organization: Meda Pharmaceuticals, Inc.

michael.purzycki@meda.us

Study Officials

• Michael Fried, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

• Victor Navarro, MD

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

• Nezam Afdhal, MD

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

• K. Rajender Reddy, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• Steven H. Belle, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

• Stephen A. Harrison, MD

  Brooke Army Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2008
• First Posted: May 20, 2008
• Study Start: April 1, 2008
• Primary Completion: November 1, 2012
• Study Completion: November 1, 2012
• Last Updated: July 17, 2019
• Results First Posted: January 29, 2016

Record last verified: 2019-07

Locations

US (6)