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Phase II Trial of Silymarin for Non-Cirrhotic Patients With Chronic Hepatitis C Who Have Failed Conventional Antiviral Treatment (SyNCH)
This study is currently recruiting participants.
Verified by National Center for Complementary and Alternative Medicine (NCCAM), July 2008
Sponsors and Collaborators: National Center for Complementary and Alternative Medicine (NCCAM)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pennsylvania
University of North Carolina
Thomas Jefferson University
Beth Israel Deaconess Medical Center
University of Pittsburgh
Information provided by: National Center for Complementary and Alternative Medicine (NCCAM)
ClinicalTrials.gov Identifier: NCT00680342
  Purpose

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 11 visits so recruitment will be limited to a geographically restricted area around participating clinical centers.


Condition Intervention Phase
Non Cirrhotic Chronic Hepatitis C
Drug: Silymarin
Other: Placebo
Phase II

MedlinePlus related topics: Hepatitis Hepatitis C Liver Diseases
Drug Information available for: Lactose Silymarin
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title: A Multicenter, Randomized, Double-Masked, Placebo-Controlled Phase II Study to Assess the Safety and Efficacy of a Standardized Orally Administered Silymarin Preparation (Legalon) for the Treatment of Non-Cirrhotic Patients With Chronic Hepatitis C Who Failed Conventional Antiviral Therapy

Further study details as provided by National Center for Complementary and Alternative Medicine (NCCAM):

Primary Outcome Measures:
  • Efficacy - whether or not serum ALT (mg/dl) is less than or equal to 45 IU/L (approximate normal range) or achieves at least 50% decline to less than 65 IU/L (approximately 1.5 times the upper limit of normal) [ Time Frame: 24-week treatment period ] [ Designated as safety issue: No ]
  • Safety - occurence of a dose-limiting toxicity [ Time Frame: 24-week treatment period ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Adherence - summary of missed dose information obtained from patient diaries and dose counts [ Time Frame: 24 week treatment period ] [ Designated as safety issue: No ]
  • Biomarkers - the following relationships will be explored: dose and change in biomarkers, changes in biomarkers and rate of treatment success, change in biomarkers and rate of toxicity [ Time Frame: 24 week treatment period ] [ Designated as safety issue: No ]

Estimated Enrollment: 153
Study Start Date: April 2008
Estimated Study Completion Date: January 2010
Estimated Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Placebo Comparator
Placebo (lactose pill)
Other: Placebo
Placebo (5 pills, three times daily) for 24-week treatment period
2: Experimental
700mg of Legalon (silymarin) three times daily
Drug: Silymarin
700mg dose (5 pills, three times daily) for 24-week treatment period
3: Experimental
420mg Legalon (silymarin) three times daily
Drug: Silymarin
420mg dose (5 pills, three times daily) for 24-week treatment period

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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age at least 18 years at screening
  • Serum HCV RNA above quantifiable level of detection by any assay, within 1 year of screening and 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 (Hba1c > 8%)
  • 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 cirrhosis
  • Radiologic imaging consistent with cirrhosis or portal hypertension
  • Previous liver biopsy that demonstrated presence of moderate to severe steatosis or evidence of steatohepatitis
  • Positive test for anti-HIV or HBsAg within 3 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
  • Platelet count <130,000 cells/mm3 at screening
  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00680342

Contacts
Contact: Michael Fried, MD 919-966-2516 mfried@med.unc.edu

Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 00215
Principal Investigator: Nezam Afdhal, MD            
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Principal Investigator: Michael Fried, MD            
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Principal Investigator: K. Rajender Reddy, MD            
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Principal Investigator: Victor Navarro, MD            
University of Pittsburgh Active, not recruiting
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pennsylvania
University of North Carolina
Thomas Jefferson University
Beth Israel Deaconess Medical Center
University of Pittsburgh
Investigators
Principal Investigator: Michael Fried, MD The University of North Carolina, Chapel Hill
Principal Investigator: Victor Navarro, MD Thomas Jefferson University
Principal Investigator: Nezam Afdhal, MD Beth Isreal Deaconess Medical Center
Principal Investigator: K. Rajender Reddy, MD University of Pennsylvania
Principal Investigator: Steven Belle, PhD University of Pittsburgh
  More Information

Responsible Party: NCCAM/NIDDK/UNC/UPenn/TJU/BIDMC/UPitt ( SyNCH Steering Committee )
Study ID Numbers: U01 AT003566, IND 74,887
Study First Received: May 15, 2008
Last Updated: July 31, 2008
ClinicalTrials.gov Identifier: NCT00680342  
Health Authority: United States: Food and Drug Administration;   United States: Federal Government;   United States: Institutional Review Board

Keywords provided by National Center for Complementary and Alternative Medicine (NCCAM):
hepatitis C

Study placed in the following topic categories:
Virus Diseases
Hepatitis
Liver Diseases
Digestive System Diseases
Hepatitis, Chronic
Silymarin
Hepatitis, Viral, Human
Hepatitis C
Hepatitis C, Chronic

Additional relevant MeSH terms:
RNA Virus Infections
Antioxidants
Molecular Mechanisms of Pharmacological Action
Flaviviridae Infections
Physiological Effects of Drugs
Protective Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 14, 2009