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Trial registered on ANZCTR


Registration number
ACTRN12610000868088
Ethics application status
Approved
Date submitted
4/10/2010
Date registered
18/10/2010
Date last updated
2/01/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effect of venesection on insulin resistance and oxidative stress in people with non-alcoholic fatty liver disease.
Scientific title
Impact of therapeutic venesection on Insulin Resistance and oxidative stress in non-alcoholic fatty liver disease.
Secondary ID [1] 252548 0
Not applicable
Universal Trial Number (UTN)
Trial acronym
IIRON study TWO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-alcoholic fatty liver disease (NAFLD) 258029 0
Hepatic steatosis 258352 0
Iron overload 258353 0
Insulin resistance 258354 0
Condition category
Condition code
Metabolic and Endocrine 258195 258195 0 0
Other metabolic disorders
Oral and Gastrointestinal 258535 258535 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
Therapeutic venesection in NAFLD patients with hepatic steatosis and hyperferritinaemia.
a) Participants will be randomised into either the intervention group and non-intervention group.
b) For the intervention group, fortnightly venesection will be performed by the haematologist until serum ferritin level has reached 50 ug/L. Haemoglobin and iron studies will be checked in between venesection sessions and all adverse events either related or not related to the venesection will be captured.
c) Removal of iron by venesection in patients with NAFLD has a number of parallel effects on iron metabolism, oxidative stress, insulin resistance and subsequent liver damage. Specifically, venesection reduces circulating and intracellular iron. This reduces serum free fatty acid (FFA) levels and oxidative stress thereby improving insulin sensitivity independent of changes in adiponectin or body fat mass. This results in an improvement in hepatic steatosis, inflammation and fibrosis.
Hepcidin and hepatocyte and adipocyte intracellular iron content modulates insulin sensitivity.
d) Duration of the study is 6 months. Frequency of venesection will depend on the participant's haemoglobin and ferritin levels. It is likely that partcipants will need fortnightly venesection initially and taper towards longer intervals between sessions gradually.
Intervention code [1] 257070 0
Treatment: Other
Intervention code [2] 288520 0
Other interventions
Comparator / control treatment
Controls will not undergo venesection but receive the same standard dietary and lifestyle counselling as the intervention group.
Control group
Active

Outcomes
Primary outcome [1] 259054 0
Improvement in hepatic Steatosis and a reduction of quantitative liver iron load by using Magnetic Resonance Imaging-Ferriscan (MRI-Ferriscan ), in participants with non-alcoholic fatty liver disease.
Timepoint [1] 259054 0
End of treatment (6 months)
Secondary outcome [1] 265319 0
Improvement in insulin resistance by Homeostasis Model Assessment (HOMA).
Timepoint [1] 265319 0
End of treatmnent (6 months)

Measured with fasting blood test.
Secondary outcome [2] 265900 0
Biomarkers of oxidative stress
Timepoint [2] 265900 0
End of treatment (6 months)

Measured with Fasting blood test
Secondary outcome [3] 265901 0
Serum hepcidin level
Timepoint [3] 265901 0
End of treatment (6 months)

Measured with Fasting blood test
Secondary outcome [4] 265902 0
Serum adipocytokine level
Timepoint [4] 265902 0
End of treatment (6 months)

Measured with Fasting blood test

Eligibility
Key inclusion criteria
Abdominal ultrasound demonstrated hepatic steatosis within three months of study entry.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unable to provide informed consent, Ischaemic heart disease. Anaemia, pregnancy or lactation. Ferritin <50ug/L. Venesection in the last 12 months prior to study entry. Other causes of liver disease: positive hepatitis B serology, positive hepatitis C serology, auto-antibodies, alpha-one anti-trypsin level and ceruloplasmin. Acute or chronic inflammatory conditions. Hereditary haemochromatosis (C282Y/C282Y or C282Y/H63D, HFE gene mutation). Alcohol consumption >20 grams/day for males or >10 grams/day for females. Secondary causes of NAFLD (corticostearoids, gastro-intestinal bypass). Use of anti-oxidants (vitamin E or C) or anti-Tumor Necrosis Factor (TNF) agents (pentocifylline). Poor glycaemic control diabetics-glycated haemoglobin >8% (HbA1c>8%). Decompensated cirrhosis International Normalised Ratio (INR>1.3, albumin >35mg/dl or bilirubin >20 mmol/L or ascites or hepatic encephalopathy. Malignancy (excluding basal cell or squamous cell skin cnacers)

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)
Visit 1: Screening. Obtain informed consent, inclusion/exclusion criteria, record medical history including alcohol and smoking habits. Physical examination including blood pressure, height, weight, and waist circumference. Completion of Alcohol Quantification and Physical activity Questionaires. Fasting blood test and urine sample for storage. Appointment for Ferriscan. Ferriscan wil be performed in a major teaching hospital.

Visit 2: Randomisation (within 2 weeks of screening). Inclusion/exclusion criteria, referral to see a dietician, dietary and lifestyle counselling, ECG for venesection group, appointment with haematologist for venesection.

For the venesection (intervention group):- Fortnightly venesection until serum ferritin level is<50 ug/L-skip one session of venesection if anaemia (Hb<115g/L (female) <135g/L (male), Further maintenance on a three monthly basis or as frequently as required to keep ferritin level <50g/L. Iron studies will be performed prior to each venesection-vital signs and any adverse events will be recorded at each visit.

Visit 3: Month 3 (for both groups). Check for any adverse events since last visit. Record any change in medications, alcohol and smoking habits. Brief physical examination including blood pressure, weight, and waist circumference. Completion of Physical activity questionaire. Fasting blood test and urine sample for storage.

Visit 4: Month 6 (End of study for both groups) Check for any adverse events since last visit. Record any change in medications, alcohol and smoking habits. Brief physical examination including blood pressure, weight, and waist circumference. Completion of Physical activity questionaire. Fasting blood test and collection of urine sample for storage. Appointment for Ferriscan.
Allocation codes will be sealed in thick brown envelopes and kept by the study coordinator.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation: Eighty participants will be recruited across two major teaching hospitals and be randomised into: 40 in venesection (group 3) and 40 in non-venesection (group 4). Numbers were divided equally between the 2 sites with study numbers from 01-80. Hospital 1: Numbers 01-40 (20 for group 3 and 20 for group 4). Hospital 2: Numbers 41-80 (20 for group 3 and 20 for group 4). Participants were then randomised to study numbers allocated for each site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis

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)
Recruitment hospital [1] 1889 0
Greenslopes Private Hospital - Greenslopes
Recruitment postcode(s) [1] 7665 0
4120 - Greenslopes

Funding & Sponsors
Funding source category [1] 257622 0
Charities/Societies/Foundations
Name [1] 257622 0
Raine Medical Research Foundation.
Address [1] 257622 0
Hollywood Specialist Centre
95 Monash Avenue
Nedlands WA 6009
Country [1] 257622 0
Australia
Funding source category [2] 257819 0
Government body
Name [2] 257819 0
Western Australia (WA) Department of Health
Address [2] 257819 0
189, Royal Street
East Perth
Western Australia 6004
Country [2] 257819 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Raine Medical Research Foundation
Address
Hollywood Specialist Centre
95 Monash Avenue
Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 256843 0
Government body
Name [1] 256843 0
WA Department of Health
Address [1] 256843 0
189 Royal Street
East Peth
WA 6004
Country [1] 256843 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259638 0
Sir Charles Gairdner Group Human Research Ethics Committee
Ethics committee address [1] 259638 0
A Block, 2nd Floor
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands WA 6009
Ethics committee country [1] 259638 0
Australia
Date submitted for ethics approval [1] 259638 0
18/01/2010
Approval date [1] 259638 0
23/03/2010
Ethics approval number [1] 259638 0
2008-008 (#2)

Summary
Brief summary
This trial aims to examine the effect of removing iron in people with nonalcoholic fatty liver disease (fatty liver). We hypothesize that removing iron will improve insulin resistance (how the body produces insulin in response to glucose), reduce oxidative stress in the body and reduce the amount of fat in the liver.
Trial website
na
Trial related presentations / publications
Poster presented at AASLD, 01Nov 2013-05 Nov 2013 Washington DC.
Public notes

Contacts
Principal investigator
Name 31559 0
A/Prof Leon Adams
Address 31559 0
Liver Transplant Unit G Blsok, 6th Floor Sir Charles Gairdner Hospital Hospital Avenue Nedlands WA 6009
Australia
Country 31559 0
Australia
Phone 31559 0
+61 8 93463228
Fax 31559 0
Email 31559 0
leon.adams@uwa.edu.au
Contact person for public queries
Name 14806 0
A/Prof Leon Adams
Address 14806 0
Liver Transplant Unit
G Blsok, 6th Floor
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands WA 6009
Country 14806 0
Australia
Phone 14806 0
+61 8 93463983
Fax 14806 0
+61 8 93463098
Email 14806 0
helena.ching@health.wa.gov.au
Contact person for scientific queries
Name 5734 0
A/Prof Associate Professor Leon Adams
Address 5734 0
Liver Transplant Unit
G Block, 6th Floor
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands WA 6009
Country 5734 0
Australia
Phone 5734 0
+61 8 93463228
Fax 5734 0
+61 8 93463098
Email 5734 0
leon.adams@uwa.edu.au

No information has been provided regarding IPD availability
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