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Trial registered on ANZCTR


Registration number
ACTRN12614000966695
Ethics application status
Approved
Date submitted
14/08/2014
Date registered
9/09/2014
Date last updated
9/09/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
THE HEP573 STUDY: A randomised, double-blind, placebo-controlled clinical trial of silymarin alone, and silymarin combined with antioxidants in chronic hepatitis C
Scientific title
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?
Secondary ID [1] 285136 0
None
Universal Trial Number (UTN)
U1111-1160-2405
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis C 292676 0
Condition category
Condition code
Alternative and Complementary Medicine 292935 292935 0 0
Herbal remedies
Alternative and Complementary Medicine 292936 292936 0 0
Other alternative and complementary medicine
Oral and Gastrointestinal 292987 292987 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 289929 0
Treatment: Other
Comparator / control treatment
Randomised placebo-controlled clinical trial.
Six month treatment period and a six month follow up period.

ARM 3: Placebo
Each participant in Arm 3 had to take six placebo tablets orally morning and night for six months.

The ingredients used in the placebo tablets were as follows: Calcium hydrogen phosphate, cellulose microcyrstalline, sodium starch glycollate, magnesium stearate, hypromellose, coating colour. The placebo ingredients were the same for each tablet, with the exception of the coating colour which was product dependent. The tablets were coated using a coloured blackout film based on a hypromellose solution. The tablet colour was matched to the active tablet colour for each product. This blackout coat imparted a neutral taste to the tablet when swallowed.
Control group
Placebo

Outcomes
Primary outcome [1] 292845 0
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)
Timepoint [1] 292845 0
From Baseline to Week 24
Secondary outcome [1] 309791 0
A secondary outcome measure was the percentage change in ALT using Dimension Vista Siemens (Linear mixed effects)
Timepoint [1] 309791 0
From baseline at Week 24.
Secondary outcome [2] 309792 0
A secondary outcome measure was the percentage change in ALT using Dimension Vista Siemens (Linear mixed effects)
Timepoint [2] 309792 0
From Week 24 at Week 48.
Secondary outcome [3] 309793 0
A secondary outcome measure was the percentage change in ALT using Dimension Vista Siemens (Linear mixed effects)
Timepoint [3] 309793 0
From baseline at Week 48.
Secondary outcome [4] 310126 0
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)
Timepoint [4] 310126 0
From baseline at Week 24
Secondary outcome [5] 310127 0
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)
Timepoint [5] 310127 0
From Week 24 at Week 48
Secondary outcome [6] 310128 0
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)
Timepoint [6] 310128 0
From baseline at Week 48
Secondary outcome [7] 310129 0
A secondary outcome was the percentage change in F2-isoprostanes using mass spectrometry and gas chromatography. (Linear mixed effects)
Timepoint [7] 310129 0
From baseline at Week 24
Secondary outcome [8] 310130 0
A secondary outcome was the percentage change in FibroTest (Linear mixed effects)
Timepoint [8] 310130 0
From baseline at Week 24
Secondary outcome [9] 310131 0
A secondary outcome was the percentage change in FibroTest (Linear mixed effects)
Timepoint [9] 310131 0
From Week 24 at Week 48
Secondary outcome [10] 310132 0
A secondary outcome was the percentage change in FibroTest (Linear mixed effects)
Timepoint [10] 310132 0
From baseline at Week 48
Secondary outcome [11] 310133 0
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
Timepoint [11] 310133 0
From baseline at Week 24
Secondary outcome [12] 310134 0
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
Timepoint [12] 310134 0
From Week 24 at Week 48
Secondary outcome [13] 310135 0
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.

Timepoint [13] 310135 0
From baseline at Week 48
Secondary outcome [14] 310365 0
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.
Timepoint [14] 310365 0
From baseline at Week 24
Secondary outcome [15] 310366 0
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.
Timepoint [15] 310366 0
From Week 24 at Week 48
Secondary outcome [16] 310367 0
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.
Timepoint [16] 310367 0
From baseline at Week 48

Eligibility
Key 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;
(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.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
(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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Screening procedures of potential participants included informed consent, medical history, a physical examination performed by a gastroenterologist/hepatologist, general observations (height, weight, blood pressure and pulse rate) and laboratory investigations. Screening information obtained from participants included: history of HCV infection, source of exposure to HCV infection, country of birth, ethnicity, past medical treatment and complementary treatment for hepatitis C, symptoms, concurrent medications, caffeine intake, diet, symptoms, alcohol and other drug intake.

The Alcohol Use Disorders Identification Test for alcohol consumption (AUDIT-C) questionnaire was used as a screening tool to ensure that participants were not consuming more than 70 g alcohol per week. A full drug history including substance used, route of administration, dose and frequency, years of using and the date the substance was last used was recorded at the screening visit.

At this screening visit, the gastroenterologist/hepatologist specialists assessed the severity of the hepatitis-C-related liver disease and determined whether the potential participant should be referred for screening for pegylated interferon and ribavirin, or whether they were suitable for the herbal Study (Hep573).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants were randomised to treatment in blocks of six. In every six participants, two were allocated at random to the placebo group, two to silymarin and two to the SOX group. This randomisation method was designed by Adrienne Kirby from the National Health and Medical Research Centre (NHMRC) Clinical Trials Centre at the University of Sydney. Thirty nine participants were randomised to both the placebo and SOX group, and 40 participants to the silymarin group.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A sample size of 57 per arm was calculated to have 80% power to detect a significant increase in the ALT normalisation rate from 12% in the control group to greater than or equal to 36% in the treated group (continuity corrected chi-square test, two tailed, 5% significance level). If a drop-out rate of 20% is assumed, a total of 72 participants were required per arm. It was expected 10 subjects would be recruited each month with a total sample of 216 participants.

Response to treatment was assessed on an intention-to-treat basis.

The primary endpoint and efficacy measurement was the proportion of participants who had ALT normalisation from baseline to Week 24. Chi-squared or Fisher's exact test (as appropriate) were used to test for differences in the proportions.

Secondary outcome measures included the change over time in: ALT, HCV RNA Viral Load (VL), plasma F2-isoprostanes (ISO) and fibrosis markers (Fibrotest, Hepascore) (FM) and QOL. The statistical packages SPSS Version 17 (SPSS Inc, Chicago, IL) and S_PLUS Version 8 (Insightful Corp., Seattle, Washington) were used to analyse the data. The Medical Outcomes Trust Hepatitis Quality of Life Questionnaire (HQLQ Trademark) (QualityMetric Trademark, Version 1, 1999) were analysed at Weeks 0, 12, 24, 36 and 48 according to published guidelines and their scoring software. The change in HQLQ Trademark v1 was the difference from baseline at Weeks 24 and Weeks 48.

Karen Byth (PhD, DIC, C Stat RSS, Biomedical Statistician at Westmead Millennium Institute, NHMRC Clinical Trials Centre, University of Sydney) conducted all statistical analyses of the outcome measures in the Hep573 Study in consultation with the Study Coordinator.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 2812 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [2] 2813 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [3] 2814 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 8516 0
2310 - Hunter Region
Recruitment postcode(s) [2] 8517 0
2050 - Camperdown
Recruitment postcode(s) [3] 8518 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 289725 0
Charities/Societies/Foundations
Name [1] 289725 0
John Hunter Hospital Charitable Trust
Address [1] 289725 0
John Hunter Hospital
Locked Bag 1, Hunter Region Mail Centre, NSW 2310
Country [1] 289725 0
Australia
Funding source category [2] 289726 0
Other
Name [2] 289726 0
Vicki Kotsirilos Integrative Medicine Grant
Address [2] 289726 0
The Royal Australian College of General Practitioners (RACGP)
RACGP House, 100 Wellington Parade, East Melbourne,
Victoria 3002
Country [2] 289726 0
Australia
Primary sponsor type
Hospital
Name
John Hunter Hospital
Address
Locked Bag 1, Hunter Region Mail Centre, NSW 2310
Country
Australia
Secondary sponsor category [1] 288420 0
University
Name [1] 288420 0
University of Newcastle
Address [1] 288420 0
University Drive
Callaghan NSW 2308
Country [1] 288420 0
Australia
Secondary sponsor category [2] 288421 0
Hospital
Name [2] 288421 0
Royal Prince Alfred Hospital
Address [2] 288421 0
Missenden Rd, Camperdown NSW 2050
Country [2] 288421 0
Australia
Secondary sponsor category [3] 288423 0
Hospital
Name [3] 288423 0
Westmead Hospital
Address [3] 288423 0
PO Box 533, Wentworthville NSW 2145
Country [3] 288423 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291459 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 291459 0
(Formerly Hunter New England Area Research Ethics Committee) Hunter New England Research Ethics and Governance Unit
HNE Local Health District, Locked Bag 1, New Lambton NSW 2305
Ethics committee country [1] 291459 0
Australia
Date submitted for ethics approval [1] 291459 0
28/02/2001
Approval date [1] 291459 0
03/06/2002
Ethics approval number [1] 291459 0
01/02/14/3.07
Ethics committee name [2] 291460 0
University of Newcastle Human Research Ethics Committee
Ethics committee address [2] 291460 0
The Chancellery, University of Newcastle, Ring Road, Callaghan NSW 2308
Ethics committee country [2] 291460 0
Australia
Date submitted for ethics approval [2] 291460 0
28/02/2001
Approval date [2] 291460 0
03/06/2002
Ethics approval number [2] 291460 0
H-342-0602
Ethics committee name [3] 291461 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [3] 291461 0
(Formerly Central Sydney Area Health Service Ethics Review Committee (RPAH Zone))
Research Development Office, Suite 210A, RPAH Medical Centre, 100 Carillon Avenue, Newtown, NSW 2042
Ethics committee country [3] 291461 0
Australia
Date submitted for ethics approval [3] 291461 0
11/03/2002
Approval date [3] 291461 0
27/06/2002
Ethics approval number [3] 291461 0
RPAH zone: X02-0071
Ethics committee name [4] 291462 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [4] 291462 0
(Formerly Sydney West Area Health Service Human Research Ethics Committee)
Research Office, Westmead Hospital, Room 2020, Clinical Sciences Building, Darcy Road, Westmead NSW 2145
Ethics committee country [4] 291462 0
Australia
Date submitted for ethics approval [4] 291462 0
30/04/2003
Approval date [4] 291462 0
23/06/2003
Ethics approval number [4] 291462 0
2003/2/4.4 (1583)

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 50346 0
Prof Robert Batey AM MD BSC(MED) MB FRACP FRCP (UK) FACHAM
Address 50346 0
Professorial Fellow, Flinders University at Alice Springs Hospital
Department of Medicine
Alice Springs Hospital
Gap Road
Alice Springs NT 0870
Country 50346 0
Australia
Phone 50346 0
+61419481546
Fax 50346 0
+61249488424
Email 50346 0
Robert.batey@uni.sydney.edu.au
Contact person for public queries
Name 50347 0
Dr Ses Salmond
Address 50347 0
Leichhardt Women’s Community Health Centre,
PO Box 240, Leichhardt NSW 2040
Country 50347 0
Australia
Phone 50347 0
+61 414 453 243
Fax 50347 0
+61 2 9560 2887
Email 50347 0
ses@lwchc.org.au/sessalmond@optusnet.com.au
Contact person for scientific queries
Name 50348 0
Dr Ses Salmond
Address 50348 0
Leichhardt Women’s Community Health Centre, PO Box 240, Leichhardt NSW 2040
Country 50348 0
Australia
Phone 50348 0
+61 414 453 243
Fax 50348 0
+61 2 9560 2887
Email 50348 0
ses@lwchc.org.au/sessalmond@optusnet.com.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary