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

NCT00680342 | Completed Phase 2 DMC

• 2 other identifiers: U01AT003566IND 74,887
• Study Type: interventional
• Target: 154
• Locations: 1 country
• Sites: 5

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.

Conditions

Chronic Hepatitis C

Keywords

hepatitis C

Outcome Measures

Primary Outcomes (2)

• 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)

  24-week treatment period

• Safety - occurence of a dose-limiting toxicity

  24-week treatment period

Secondary Outcomes (2)

• Adherence - summary of missed dose information obtained from patient diaries and dose counts

  24 week treatment period

• 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

  24 week treatment period

Study Arms (3)

1

PLACEBO COMPARATOR

Placebo (lactose pill)

Other: Placebo

2

EXPERIMENTAL

700mg of Legalon (silymarin) three times daily

Drug: Silymarin

3

EXPERIMENTAL

420mg Legalon (silymarin) three times daily

Drug: Silymarin

Interventions

Silymarin DRUG

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

Also known as: Legalon, milk thistle

2

Placebo OTHER

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

Also known as: lactose pill

1

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.
• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Center for Complementary and Integrative Health (NCCIH): lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• University of Pennsylvania: collaborator
• University of North Carolina, Chapel Hill: collaborator
• Thomas Jefferson University: collaborator
• Beth Israel Deaconess Medical Center: collaborator
• University of Pittsburgh: collaborator

Study Sites (5)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 00215, United States

Location

University of North Carolina

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

Related Publications (2)

• 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.

  PMID: 22058086 BACKGROUND

• 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.

  PMID: 22797645 RESULT

MeSH Terms

Conditions

Hepatitis C, Chronic; Hepatitis C

Interventions

Silymarin; milk-thistle extract; Lactose

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

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 Belle, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

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: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2008
• First Posted: May 20, 2008
• Study Start: April 1, 2008
• Primary Completion: January 1, 2011
• Study Completion: January 1, 2011
• Last Updated: March 18, 2013

Record last verified: 2013-03

Locations

US (5)