Phase II Trial of Silymarin for Patients With Chronic Hepatitis C Who Have Failed Conventional Antiviral Treatment

NCT ID: NCT00680342

Last Updated: 2013-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 154 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2011-01-31

Brief Summary

Silymarin (Legalon), 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).

Eligible subjects will be randomized to treatment with placebo or one of two dosages of Legalon® 420 mg or 700 mg administered orally thrice daily. Investigators and subjects will be masked to treatment assignment. The study design includes a screening period during which patients will undergo full medical evaluation to verify protocol eligibility and a treatment period of 24 weeks during which time clinic visits and laboratory studies will be performed every 2-4 weeks to monitor for safety and efficacy of therapy. Subjects will continue to be followed for an additional 12 weeks after the completion of study medication to monitor for adverse events and investigate post-treatment outcomes. Participation in this research study requires the subject to travel to the clinic for at least 10 visits so recruitment will be limited to a geographically restricted area around participating clinical centers.

Detailed Description

This proposal is a phase II study that will evaluate the safety and efficacy of silymarin for the treatment of subjects with chronic hepatitis C who did not respond to conventional antiviral therapy. The primary objectives of this study are to assess the safety and adverse event profile of silymarin over a range of doses compared to placebo and to assess efficacy of silymarin in normalizing serum aminotransferase activity in patients with chronic hepatitis C. Secondary objectives are to characterize the effect of silymarin on serum levels of HCV RNA and to explore relationships between silymarin therapy and serum biomarkers of HCV hepatic disease activity (oxidative stress, apoptosis, and fibrogenesis).

Conditions

Chronic Hepatitis C

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

Placebo (lactose pill)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo (5 pills, three times daily) for 24-week treatment period

2

700mg of Legalon (silymarin) three times daily

Group Type: EXPERIMENTAL

Silymarin

Intervention Type: DRUG

700mg dose (5 pills, three times daily) for 24-week treatment period

3

420mg Legalon (silymarin) three times daily

Group Type: EXPERIMENTAL

Silymarin

Intervention Type: DRUG

420mg dose (5 pills, three times daily) for 24-week treatment period

Interventions

Silymarin

700mg dose (5 pills, three times daily) for 24-week treatment period

Intervention Type: DRUG

Silymarin

420mg dose (5 pills, three times daily) for 24-week treatment period

Intervention Type: DRUG

Placebo

Placebo (5 pills, three times daily) for 24-week treatment period

Intervention Type: OTHER

Other Intervention Names

Legalon; milk thistle; Legalon; milk thistle; lactose pill

Eligibility Criteria

Inclusion Criteria

• Age at least 18 years at screening.
• Serum HCV RNA above quantifiable level of detection by any assay after the end of previous therapy.
• ALT > 65 IU/L (i.e., approximately 1.5 X upper limit of normal) obtained during the screening period.
• Previous treatment with any interferon-based therapy without sustained virological response.
• Negative urine pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of silymarin. Females of childbearing potential must be using two reliable forms of effective contraception during the study (while on drug and during follow-up).

Exclusion Criteria

• Use of silymarin or other milk thistle preparations within 30 days prior to screening.
• 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.
• Any antiviral therapy within 6 months prior to screening visit.
• Known allergy/sensitivity to milk thistle or its preparations.
• Evidence of poorly-controlled diabetes (defined as HbA1c > 8% in patients with diabetes).
• Use of warfarin, metronidazole or acetaminophen (greater than two grams per day) within 30 days of screening.
• Lactose intolerance defined as patient reported inability to tolerate milk products.
• Previous liver biopsy that demonstrated presence of moderate to severe steatosis or evidence of steatohepatitis.
• Positive test for anti-HIV or HBsAg within 5 years of screening.
• 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 ago must have consumed a monthly average of 12 grams or less per day of alcohol for at least six months prior to screening.
• History of other chronic liver disease, including metabolic diseases, documented by appropriate test(s).
• Women with ongoing pregnancy or breast-feeding, or contemplating pregnancy.
• Serum creatinine level 2.0 mg/dL or greater at screening or CrCl ≤ 60cc/min, or currently on dialysis. The creatinine clearance (CrCl) will be calculated according to Cockcroft-Gault.
• Evidence of drug abuse within 6 months prior to screening or during the screening period.
• 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 > 1.3 times normal at screening, or history or presence of ascites or encephalopathy, or bleeding from esophageal varices.
• 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).
• History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hepatitis, autoimmune hemolytic anemia, severe psoriasis, rheumatoid arthritis) that could affect inflammatory biomarkers.
• 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 prior to screening.
• Participation in a research drug trial, exclusive of the SyNCH Phase I trial, within 6 months of enrollment.
• Inability or unwillingness to provide informed consent or abide by the study protocol.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: collaborator

Thomas Jefferson University

OTHER

Sponsor Role: collaborator

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: collaborator

University of Pittsburgh

OTHER

Sponsor Role: collaborator

National Center for Complementary and Integrative Health (NCCIH)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michael Fried, MD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Victor Navarro, MD

Role: PRINCIPAL_INVESTIGATOR

Thomas Jefferson University

Nezam Afdhal, MD

Role: PRINCIPAL_INVESTIGATOR

Beth Israel Deaconess Medical Center

K. Rajender Reddy, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Steven Belle, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

University of North Carolina

Chapel Hill, North Carolina, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Thomas Jefferson University

Philadelphia, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

References

Reddy KR, Belle SH, Fried MW, Afdhal N, Navarro VJ, Hawke RL, Wahed AS, Doo E, Meyers CM; SyNCH Study Group. Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C. Clin Trials. 2012 Feb;9(1):102-12. doi: 10.1177/1740774511427064. Epub 2011 Nov 4.

Reference Type: BACKGROUND

PMID: 22058086 (View on PubMed)

Fried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, Doo E, Meyers CM, Reddy KR; Silymarin in NASH and C Hepatitis (SyNCH) Study Group. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA. 2012 Jul 18;308(3):274-82. doi: 10.1001/jama.2012.8265.

Reference Type: RESULT

PMID: 22797645 (View on PubMed)

Other Identifiers

IND 74,887

Identifier Type: -

Identifier Source: secondary_id

U01AT003566

Identifier Type: NIH

Identifier Source: org_study_id

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