THE HEP573 STUDY: A randomised, double-blind, placebo-controlled clinical trial of silymarin alone, and silymarin combined with antioxidants in chronic hepatitis C

INTERVENTION: 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. CONDITION: Chronic Hepatitis C PRIMARY OUTCOME: The primary outcome measure was the proportion of participants experiencing ALT normalisation from baseline to Week 24. ALT normalisation was defined as a single ALT reading within the normal laboratory range during the treatment period of 24 weeks using Dimension Vista Siemens(Fisher's exact test) SECONDARY OUTCOME: A secondary outcome measure was the percentage change in ALT using Dimension Vista Siemens (Linear mixed effects) A secondary outcome measure was the percentage change in HCV RNA. The method used was the Bayer Versant HCV RNA 3.0bDNA assay with a specificity of 99.5% and a cut‐off of 3200 viral copies per ml. (Linear mixed effects) A secondary outcome was the absolute change in Hepatitis Quality of Life Questionnaire Trademark which was interpreted according to the Medical Outcomes Trust guidelines and the accompanying software scoring program A secondary outcome was the absolute change in Hepatitis Quality of Life Questionnaire Trademark which was interpreted according to the Medical Outcomes Trust guidelines and the accompanying software scoring program. ; ; ; ; ; ; INCLUSION CRITERIA: INCLUSION CRITERIA: (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; ; A secondary outcome was the percentage change in F2‐isoprostanes using mass spectrometry and gas chromatography. (Linear mixed effects) A secondary outcome was the percentage change in FibroTest (Linear mixed effects) A secondary outcome was the percentage change in HCV RNA. The method used was the Bayer Versant HCV RNA 3.0bDNA assay with a specificity of 99.5% and a cut‐off of 3200 viral copies per ml. (Linear mixed effects) A secondary outcome was the percentage change in Hepascore (Linear mixed effects) ; The calculation to determine Hepascore values was as follows: Hepascore equals y divided by (1 plus y) with y equals exp(‐4.185818 minus (0.0249 multiplied by age) plus (0.7464 multiplied by 1 if male, 0 if female gender) plus (1.0039 multipled by alpha2 macroglobulin) plus (0.0302 multiplied by hyaluronate) equals (0.0691 multiplied by bilirubin) minus (0.0012 multiplied by gamma‐glutamyl transferase). ; Alpha‐2 macroglobulin was measured by nephelometry (BN II; Dade‐Behring, Marburg, Germany). Hyaluronic acid was measured by an enzyme‐linked protein binding assay, on a 96‐well microplate colorimetic reader (Corgenix Inc, Denver, Colorado, USA). ; PathWest Laboratory Medicine in‐house analytical coefficients of variation (CVs) were 2.8% at a alpha2‐macroglobulin concentration of 2.5 g/L, 3.5% at a hyaluronic acid concentration of 50 mg/L, 1.7% at a bilirubin concentration of 16 mmol/L and 2.7% at a GGT activity of 33 U/L. A secondary outcome was the percentage change in Hepascore (Linear mixed effects). ; Alpha‐2 macroglobulin was measured by nephelometry (BN II; Dade‐Behring, Marburg, Germany). Hyaluronic acid was measured by an enzyme‐linked protein binding assay, on a 96‐well microplate colorimetic reader (Corgenix Inc, Denver, Colorado, USA). ; PathWest Laboratory Medicine in‐house analytical coefficients of variation (CVs) were 2.8% at a alpha2‐macroglobulin concentration of 2.5 g/L, 3.5% at a hyaluronic acid concentration of 50 mg/L, 1.7% at a bilirubin concentration of 16 mmol/L and 2.7% at a GGT activity of 33 U/L. (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.