THE HEP573 STUDY: A randomised, double-blind, placebo-controlled clinical trial of silymarin alone, and silymarin combined with antioxidants in chronic hepatitis C
In compensated chronic hepatitis C patients, what is the effect of silymarin alone or silymarin combined with antioxidants compared to placebo on the proportion of hepatitis C patients with ALT normalisation at week 24 compared to baseline?
John Hunter Hospital
216 participants
Jul 1, 2003
Interventional
Conditions
Summary
Oxidative stress (OS) is a key mechanism by which liver injury occurs in chronic hepatitis C (CHC) virus infection. For this Study, it was hypothesised the use of antioxidant compounds would reduce OS, hepatic necroinflammation and hepatic fibrosis in CHC patients. To test this hypothesis, a randomised, double-blind, placebo-controlled clinical trial (termed the Hep573 Study) was conducted in three Australian teaching hospitals in New South Wales. One hundred and eighteen participants were recruited through the liver outpatient clinics at the hospitals from July, 2003 to March, 2006. They were randomised to treatment in blocks of six to one of three groups: placebo; silymarin (720 mg silybin/day); and silymarin with antioxidants (720 mg silybin plus 12 other ingredients). Study duration was 48 weeks: 24 weeks on active treatment or placebo, and 24 weeks follow-up post treatment. The primary outcome measure was the proportion of patients with alanine aminotransferase (ALT) normalisation at Week 24 (Fisher's exact test). Secondary outcome measures were the percentage change from baseline to Week 24 in F2-isoprostanes, and to Week 24 and Week 48 in ALT, HCV viral load (HCV RNA), FibroTest and Hepascore (Linear Mixed Effects). Results were analysed on an intention-to-treat basis. In patients with compensated CHC, the use of silymarin and antioxidant compounds achieved a higher rate of ALT normalisation than placebo (P=0.02) or silymarin (P=0.003) at Week 24. This result could not be attributed to alcohol, diet or caffeine, as intake across the groups did not change throughout the Study. In addition, there was a significant improvement in the overall mental-health score (Mental Component Summary), QualityMetric Hepatitis Quality of Life Questionnaire Trademark (HQLQ) in the silymarin and antioxidant (SOX) group (P=0.002). This novel randomised, double-blind, placebo-controlled trial of oral silymarin and oral antioxidants has shown a reduction in hepatic necroinflammation and an improvement in overall mental-health status in a specific CHC population.
Eligibility
Inclusion Criteria8
- (1) able to give informed consent;
- (2) aged between 18 and 75 years;
- (3) hepatitis C antibody and HCV RNA positive;
- (4) abnormal liver tests on at least three occasions in the past two years;
- (5) prepared to stop Western and Chinese herbs, vitamins and nutritional supplements used in the Study for the study duration and for a wash out period of 12 weeks prior to trial entry;
- (6) prepared to visit the hospital site monthly for blood tests and to complete questionnaires;
- (7) stable on their methadone dose and less than 100 mg daily dose; and
- (8) women were prepared to practice two methods of contraception during the Study period.
Exclusion Criteria17
- (1) Alcohol-related liver disease;
- (2) alpha 1-antitrypsin deficiency;
- (3) autoimmune hepatitis;
- (4) drug-induced liver disease;
- (5) haemochromatosis;
- (6) hepatitis B and D;
- (7) decompensated cirrhosis (Child-Pugh Score greater than 7);
- (8) human immunodeficiency virus (HIV);
- (9) non-alcoholic steatohepatitis;
- (10) antiviral therapy (pegylated interferon and ribavirin) in the past six months;
- (11) platelet count less than or equal to 50 x 10 to the power of 9/L;
- (12) alcohol intake greater than 70 grams per week;
- (13) methadone greater than 100 mg/day or unstable on methadone dose;
- (14) non prescription or recreational drugs greater than 3-4 times per week;
- (15) pregnant or lactating females;
- (16) potential drug-herb interactions, i.e., cyclosporin, warfarin, digoxin, selective serotonin reuptake inhibitor (SSRI), theophylline; and
- (17) normal alanine aminotransferase (ALT) levels.
Interventions
Participants were randomised to the three treatment arms. ARM 1: Silymarin and antioxidant. This intervention contained the following three combinations: Hepavir - Silybum marianum (milk thistle) 70:1 seed extract (standardised) 14,000 mg, Andrographis paniculata (andrographis) 19:1 herb extract (standardised to 34.8mg andrographolide) 750 mg; Phyllanthus amarus (phyllanthus) 5:1 herb extract 750 mg; and Hypericum perforatum (Saint John's wort) 6:1 herb extract (standardised 0.8mg hypericin) 375 mg. Immuhep: Astragalus membranaceus (astragalus) 5:1 extract 750 mg; Eleutherococcus senticosus (Siberian ginseng) 10:1 root extract (standardised 1.2mg syringaresinol diglucosides) 750 mg; Vitamin C as calcium ascorbate 100 mg; Zinc amino acid chelate 20% 62.5 mg equivalent to elemental zinc 12.5 mg; and Alpha lipoic acid 50 mg. Antioxidant Compound: Vitis vinifera (grape) 120:1 seed extract (standardised 80mg procyanidins) 3000 mg; Silybum marianum (milk thistle) seed 70:1 extract (standardised) 1000 mg; Camellia sinensis (green tea) 5.5:1 leaf extract 1000 mg; Curcuma longa (turmeric) 25:1 rhizome extract (standardised 280mg curcuminoids) 2000 mg; Lycopene 5% 100 mg equivalent to 20 mg (tablet grade); and Selenomethionine 10 mg equivalent to elemental selenium 50 mcg. Each participant in Arm 1 had to take two of each tablet morning and night orally for six months. ARM 2: Silymarin The silymarin was equivalent to 60 grams of Silybum marianum, standardised to contain 720 mg silybin per day. Each participant in Arm 2 had to take two silymarin tablets and four placebo tablets orally morning and night for six months. Dose compliance (number of tablets remaining) was measured by tablet count of the returns at each visit by the hepatitis C nurse consultants or the Study Coordinator at each of the hospital sites as well as by audits of hospital pharmacy records. The hospital pharmacy record was seen as the primary source document for the calculation of dose/tablet compliance. Where there were missing data, the information on dose compliance in the case-report form-folders, or the hospital medical record was used. Compliance to the Study protocol was monitored at each monthly visit by documenting alcohol intake, concurrent medications and CAM use. In the event of a Study protocol violation, the participant was discontinued.
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ACTRN12614000966695