ANZCTR - Registration

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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]

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

Dysmetabolic iron overload syndrome

Condition category

Condition code

Metabolic and Endocrine

Other metabolic disorders

Oral and Gastrointestinal

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]

Treatment: Other

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Change in histological liver iron concentration assessed by liver biopsy

Timepoint [1]

This will be assessed at enrolment and within 8 weeks of final venesection, only occurring after the final venesection

Secondary outcome [1]

Change in NAFLD Activity Score (NAS) assessed through liver biopsy

Timepoint [1]

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]

Change in lobular inflammation component of NAFLD Activity Score (NAS) assessed through liver biopsy

Timepoint [2]

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]

Change in steatosis component of NAFLD Activity Score (NAS) assessed through liver biopsy

Timepoint [3]

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]

Change in hepatocyte ballooning component of NAFLD Activity Score (NAS) assessed through liver biopsy

Timepoint [4]

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]

Change in alanine transaminase (ALT) serum concentration (units per litre) assessed through blood test

Timepoint [5]

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]

Change in aspartate transaminase (AST) serum concentration (units per litre) assessed through blood test

Timepoint [6]

Secondary outcome [7]

Change in gamma glutamyl transferase (GGT) serum concentration (units per litre) assessed through blood test

Timepoint [7]

Secondary outcome [8]

Change in alkaline phosphatase (ALP) serum concentration (units per litre) assessed through blood test

Timepoint [8]

Secondary outcome [9]

Change in serum bilirubin concentration (micromole per litre) assessed through blood test

Timepoint [9]

Secondary outcome [10]

Change in controlled attenuation parameter measured through vibration-controlled transient elastography

Timepoint [10]

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]

Change in liver stiffness measured through vibration-controlled transient elastography

Timepoint [11]

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]

Change in attenuation imaging parameter measured on ultrasonography

Timepoint [12]

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]

Change in haemoglobin concentration measured through blood test

Timepoint [13]

Secondary outcome [14]

Change in serum ferritin measured through blood test

Timepoint [14]

Secondary outcome [15]

Change in patient-reported quality of life measured through Short-Form 36 (SF36) questionnaire

Timepoint [15]

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]

Safety of venesection

Timepoint [16]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Austin Medical Research Foundation

Address [1]

Austin Hospital
145-163 Studley Road
Heidelberg, Vic 3084

Country [1]

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]

Individual

Name [1]

Andrew Grigg

Address [1]

Level 4 Olivia Newton John Centre
Austin Hospital
145-163 Studley Road
Heidelberg, Vic 3084

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

Office for Research, Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

30/08/2021

Ethics approval number [1]

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

Dr Marie Sinclair

Address

Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084

Country

Australia

Phone

+61 03 9496 5353

Fax

[email protected]

Contact person for public queries

Name

Marie Sinclair

Address

Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084

Country

Australia

Phone

+61 03 9496 5353

Fax

[email protected]

Contact person for scientific queries

Name

Marie Sinclair

Address

Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
Austin Health
145-163 Studley Road
Heidelberg, Vic 3084

Country

Australia

Phone

+61 03 9496 5353

Fax

[email protected]

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 ([email protected])

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
14582	Study protocol			[email protected]
14585	Ethical approval			[email protected]		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.

Trial Review

Documents added manually

Documents added automatically