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

This study has been completed.
Sponsor:
Collaborators:
University of Pennsylvania
University of North Carolina, Chapel Hill
Thomas Jefferson University
Beth Israel Deaconess Medical Center
University of Pittsburgh
Information provided by (Responsible Party):
National Center for Complementary and Alternative Medicine (NCCAM)
ClinicalTrials.gov Identifier:
NCT00680342
First received: May 15, 2008
Last updated: March 11, 2013
Last verified: March 2013
  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 10 visits so recruitment will be limited to a geographically restricted area around participating clinical centers.


Condition Intervention Phase
Chronic Hepatitis C
Drug: Silymarin
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Patients With Chronic Hepatitis C Who Failed Conventional Antiviral Therapy

Resource links provided by NLM:


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 ]

Enrollment: 154
Study Start Date: April 2008
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 1
Placebo (lactose pill)
Other: Placebo
Placebo (5 pills, three times daily) for 24-week treatment period
Other Name: lactose pill
Experimental: 2
700mg of Legalon (silymarin) three times daily
Drug: Silymarin
700mg dose (5 pills, three times daily) for 24-week treatment period
Other Names:
  • Legalon
  • milk thistle
Experimental: 3
420mg Legalon (silymarin) three times daily
Drug: Silymarin
420mg dose (5 pills, three times daily) for 24-week treatment period
Other Names:
  • Legalon
  • milk thistle

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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00680342

Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 00215
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pennsylvania
University of North Carolina, Chapel Hill
Thomas Jefferson University
Beth Israel Deaconess Medical Center
University of Pittsburgh
Investigators
Principal Investigator: 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 Belle, PhD University of Pittsburgh
  More Information

Publications:
Responsible Party: National Center for Complementary and Alternative Medicine (NCCAM)
ClinicalTrials.gov Identifier: NCT00680342     History of Changes
Other Study ID Numbers: U01 AT003566, IND 74,887
Study First Received: May 15, 2008
Last Updated: March 11, 2013
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

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis C
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Antiviral Agents
Silymarin
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 29, 2014