Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000143729
Ethics application status
Approved
Date submitted
1/01/2022
Date registered
27/01/2022
Date last updated
15/01/2024
Date data sharing statement initially provided
27/01/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Venesection in iron overload and concurrent non-alcoholic fatty liver disease
Scientific title
Assessing the efficacy and safety of venesection in patients with dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease
Secondary ID [1] 306127 0
Nil known
Universal Trial Number (UTN)
U1111-1272-8572
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-alcoholic fatty liver disease 324799 0
Dysmetabolic iron overload syndrome 324800 0
Condition category
Condition code
Metabolic and Endocrine 322252 322252 0 0
Other metabolic disorders
Oral and Gastrointestinal 322253 322253 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
Patients will undergo 4-weekly venesection of 1 unit (400-500mL) of blood in the outpatient pathology centre, with experienced nursing staff performing venipuncture. Each venesection takes between 15-30 minutes. Up to a maximum of 10 venesections will be performed, with patients not undergoing their next scheduled venesection if they develop anaemia (Hb <120 g/L for women, Hb <130 g/L for men) or de-iron to a serum ferritin <200 micrograms/L. Patients who achieve a serum ferritin <200 micrograms/L prior to 10 venesections will remain in the study and continue to have 4-weekly blood tests, recommencing venesection if ferritin rises above 200 micrograms/L within 8 weeks of last venesection and if within 10 months of first venesection. The maximum total duration of the intervention is 12 months. Adherence to venesection will be monitored through view of planned blood tests on the same day as scheduled venesection.

All patients will be provided with identical dietary advice and exercise advice for non-alcoholic fatty liver disease as per standard of care (this will be recommendations to reduce simple carbohydrates and saturated fats, with advice to follow the Mediterranean diet; and recommendation to undergo 30 minutes of exercise of at least moderate intensity 4-5 days per week). This advice will be provided verbally.
Intervention code [1] 322533 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330016 0
Change in histological liver iron concentration assessed by liver biopsy
Timepoint [1] 330016 0
This will be assessed at enrolment and within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [1] 404612 0
Change in NAFLD Activity Score (NAS) assessed through liver biopsy
Timepoint [1] 404612 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [2] 404613 0
Change in lobular inflammation component of NAFLD Activity Score (NAS) assessed through liver biopsy
Timepoint [2] 404613 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [3] 404614 0
Change in steatosis component of NAFLD Activity Score (NAS) assessed through liver biopsy
Timepoint [3] 404614 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [4] 404615 0
Change in hepatocyte ballooning component of NAFLD Activity Score (NAS) assessed through liver biopsy
Timepoint [4] 404615 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [5] 404616 0
Change in alanine transaminase (ALT) serum concentration (units per litre) assessed through blood test
Timepoint [5] 404616 0
This will be assessed at enrolment and 4-weekly up until 8-weeks following the final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [6] 404617 0
Change in aspartate transaminase (AST) serum concentration (units per litre) assessed through blood test
Timepoint [6] 404617 0
This will be assessed at enrolment and 4-weekly up until 8-weeks following the final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [7] 404618 0
Change in gamma glutamyl transferase (GGT) serum concentration (units per litre) assessed through blood test
Timepoint [7] 404618 0
This will be assessed at enrolment and 4-weekly up until 8-weeks following the final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [8] 404619 0
Change in alkaline phosphatase (ALP) serum concentration (units per litre) assessed through blood test
Timepoint [8] 404619 0
This will be assessed at enrolment and 4-weekly up until 8-weeks following the final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [9] 404620 0
Change in serum bilirubin concentration (micromole per litre) assessed through blood test
Timepoint [9] 404620 0
This will be assessed at enrolment and 4-weekly up until 8-weeks following the final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [10] 404621 0
Change in controlled attenuation parameter measured through vibration-controlled transient elastography
Timepoint [10] 404621 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [11] 404622 0
Change in liver stiffness measured through vibration-controlled transient elastography
Timepoint [11] 404622 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [12] 404623 0
Change in attenuation imaging parameter measured on ultrasonography
Timepoint [12] 404623 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [13] 404624 0
Change in haemoglobin concentration measured through blood test
Timepoint [13] 404624 0
This will be assessed at enrolment and 4-weekly up until 8-weeks following the final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [14] 404625 0
Change in serum ferritin measured through blood test
Timepoint [14] 404625 0
This will be assessed at enrolment and 4-weekly up until 8-weeks following the final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [15] 404626 0
Change in patient-reported quality of life measured through Short-Form 36 (SF36) questionnaire
Timepoint [15] 404626 0
This will be assessed at enrolment and within 8 weeks of final venesection. The secondary timepoint is within 8 weeks of final venesection, only occurring after the final venesection
Secondary outcome [16] 405242 0
Safety of venesection
Timepoint [16] 405242 0
This will be assessed with clinical history after each venesection (assessing for adverse symptoms related to venesection), along with assessment of haemoglobin and iron studies at each venesection (to assess for occult anaemia and iron deficiency, respectively). Safety will be assessed one day after each venesection.

Eligibility
Key inclusion criteria
- Non-alcoholic fatty liver disease evident radiologically (hepatic steatosis on ultrasonography, computed tomography or magnetic resonance of the liver, or controlled attenuation parameter >248 dB/m on transient elastography) and/or histological evidence of steatosis on liver biopsy
- Serum ferritin >600 micrograms/L
- Histological evidence of hepatic iron overload identified by Perl's stain for iron on liver biopsy
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Anaemia (Hb less than 120 g/L for women, less than 130 g/L for men)
• Hereditary haemochromatosis defined by C282Y homozygosity or C282Y/H63D compound heterozygosity
• Alcohol consumption greater than 140 grams per week for men, or greater than 100 grams per week for women
• Weight loss greater than 5% body weight 6 months prior to study inclusion
• Chronic kidney disease stage 3 or greater, defined by eGFR less than 30 mL/min
• Heart failure with left ventricular ejection fraction less than 40%, or ischaemic heart disease
• Decompensated cirrhosis, defined by Child Pugh class B or C
• Alternate cause of liver disease other than NAFLD
• Concurrent use of steatogenic medications (eg. tamoxifen, methotrexate, amiodarone, prednisolone)
• Inadequate venous access to facilitate regular venesection as assessed by apharesis unit
• HbA1c greater than 10%
• Coagulopathy such that risk of liver biopsy unacceptable
• Pregnancy
• Change in diabetic medication within 3 months
• Those who do not speak English as a first language

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Given this is a pilot study, only small numbers (15 patients) are planned for enrolment to investigate whether venesection in this population reduces histological iron staining. As this is a pilot study aimed at obtaining preliminary data that can be utilized to plan for a larger study, no power calculation has been conducted. Statistical analysis of paired results (at enrolment, at completion of study intervention) for each patient will be undertaken.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
29/09/2021
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/10/2025
Actual
Sample size
Target
15
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 21427 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 36328 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 310475 0
Charities/Societies/Foundations
Name [1] 310475 0
Austin Medical Research Foundation
Country [1] 310475 0
Australia
Primary sponsor type
Individual
Name
Marie Sinclair
Address
Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084
Country
Australia
Secondary sponsor category [1] 311627 0
Individual
Name [1] 311627 0
Andrew Grigg
Address [1] 311627 0
Level 4 Olivia Newton John Centre
Austin Hospital
145-163 Studley Road
Heidelberg, Vic 3084
Country [1] 311627 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310105 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 310105 0
Office for Research, Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084
Ethics committee country [1] 310105 0
Australia
Date submitted for ethics approval [1] 310105 0
Approval date [1] 310105 0
30/08/2021
Ethics approval number [1] 310105 0
HREC/73720/Austin-2021

Summary
Brief summary
This study is assessing the utility of regular venesection (blood removal) for treatment of patients with non-alcoholic fatty liver disease and concurrent iron-overload on liver biopsy. Patients involved in this study will undergo 4-weekly venesection for up to 10-months, with a liver biopsy prior to and after the venesection schedule to assess the impact on non-alcoholic fatty liver disease and liver iron overload. We hypothesise that regular venesection will be a tolerable therapy that improves iron overload on liver biopsy and reduces severity of non-alcoholic fatty liver disease on liver biopsy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116490 0
Dr Marie Sinclair
Address 116490 0
Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084
Country 116490 0
Australia
Phone 116490 0
+61 03 9496 5353
Fax 116490 0
Email 116490 0
marie.sinclair@austin.org.au
Contact person for public queries
Name 116491 0
Dr Marie Sinclair
Address 116491 0
Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084
Country 116491 0
Australia
Phone 116491 0
+61 03 9496 5353
Fax 116491 0
Email 116491 0
marie.sinclair@austin.org.au
Contact person for scientific queries
Name 116492 0
Dr Marie Sinclair
Address 116492 0
Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084
Country 116492 0
Australia
Phone 116492 0
+61 03 9496 5353
Fax 116492 0
Email 116492 0
marie.sinclair@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All de-identified patient data collected during the trial
When will data be available (start and end dates)?
Following publication, no end date
Available to whom?
Case-by-case at the discretion of the Principal Investigator
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Subject to approval by Principal Investigator (marie.sinclair@austin.org.au)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14582Study protocol  marie.sinclair@austin.org.au
14585Ethical approval  marie.sinclair@austin.org.au 383358-(Uploaded-01-01-2022-09-32-04)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.