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Trial registered on ANZCTR


Registration number
ACTRN12622000185763
Ethics application status
Approved
Date submitted
13/12/2021
Date registered
3/02/2022
Date last updated
29/10/2024
Date data sharing statement initially provided
3/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
THE IC3 TRIAL: Identifying Cirrhosis and liver Cancer in primary Care
Scientific title
The IC3 Trial: A Multi-Centre Parallel Randomised Controlled Trial of a Cirrhosis Detection Pathway and Hepatocellular Carcinoma Screening Program in Australian Primary Care
Secondary ID [1] 305706 0
Nil
Universal Trial Number (UTN)
Trial acronym
IC3
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatocellular Carcinoma 324194 0
Liver Cirrhosis 324195 0
Condition category
Condition code
Cancer 321677 321677 0 0
Liver
Oral and Gastrointestinal 321678 321678 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Public Health 321679 321679 0 0
Health service research
Public Health 321680 321680 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following consent, both groups will have a brief discussion about lifestyle factors to reduce risk of cirrhosis and liver cancer (approx. 3-5 mins). During this discussion participants will be provided with an information leaflet about liver health (developed from recommendations in 1-3’). This informational brochure is designed as a credible ‘attention control’ while not altering ‘usual care’ since it is unlikely to prompt discussions about cirrhosis/HCC risk or screening with their GP. It also increases engagement in the trial for control participants to minimise attrition.
Following randomisation, patients assigned to the intervention arm will enter a two-stage cirrhosis detection pathway co-ordinated by study staff. If diagnosed with a liver stiffness measure of equal to or greater than 8.0 kPa the participant will be referred by their GP to a hepatologist. At review, the participant may be entered into Hepatocellular Carcinoma (HCC) surveillance by the specialist. This surveillance pathway will become part of normal specialist care' conducted under the guidance of the local Hepatologist and supported by the trials team. This model of care reflects the efficacy design of our clinical trial and could be readily implemented in the future into a GP practice team with a practice or community nurse case worker.
Two-stage Cirrhosis Detection Pathway: Participants will initially undergo a non-fasting blood test at a Sonic pathology laboratory. FIB4 will be calculated from standard of care blood tests performed locally with serum then forwarded to Pathwest for Hepascore analysis. Results will be available within two weeks. We anticipate 25% of the intervention arm will have high readings of either serum biomarker (FIB-4 >1.30 or Hepascore greater than or equal to 0.60). All intervention participants will be contacted with their results, with those who have an elevated screening test to undergo a Fibroscan (liver stiffness measure). This will be performed at the GP practice by trained research staff. Fibroscan (Echosens, France) will be performed on portable calibrated machines using a standardized protocol and validated quality control criteria as per the manufacturer recommendations. Those with an elevated reading (greater than or equal to 8 kPa), changed in October 2022 to bring in line with current guidelines, will be referred by their GP to a hepatologist. The specialist will determine, whether they will be entered into HCC surveillance (defined as two liver diagnostic imaging with or without serum AFP levels in a 12 month period. Patients with an unreliable Fibroscan (anticipated <5%) will be referred for specialist review. All referred patients will be followed to see if they are enrolled into HCC surveillance or discharged back to GP care.
HCC Surveillance Program: Participants will receive written appointment times and text message reminders for surveillance imaging and serum testing, which will be performed at local radiology and pathology providers respectively, ideally, twice within a 12 (+/-2) month period. Missed appointments or testing will be followed-up by phone by study staff with a re-appointment and discussion about the importance of surveillance provided. This approach has been demonstrated to be effective in capturing 79% of early HCC in community-based surveillance. There is no set 'total period' for HCC surveillance - the period will be determined by clinical relevance and will be managed by a hepatologist or GP or both.

1. Gofton, C., & George, J. (2021). Updates in fatty liver disease: Pathophysiology, diagnosis and management. Australian Journal of General Practice, 50(10), 702-707.
2. Nobili, V., Carter-Kent, C., & Feldstein, A. E. (2011). The role of lifestyle changes in the management of chronic liver disease. BMC medicine, 9(1), 1-7.
3. Beg, S., Curtis, S., & Shariff, M. (2016). Patient education and its effect on self-management in cirrhosis: a pilot study. European journal of gastroenterology & hepatology, 28(5), 582-587.
Intervention code [1] 322114 0
Early detection / Screening
Comparator / control treatment
Participants assigned to the control arm will receive usual care by their GP over their 12 months in the trial. Participants assigned to usual care will have the option at the end of the trial (after 12 month follow-up questionnaire) to undergo blood test for FIB-4 by their GP.
Both groups will have a brief and generic discussion about lifestyle factors to reduce risk of liver disease (approx. 5 mins). During this, they will be provided an information leaflet about liver health (developed from recommendations in 1-3’). This is designed as a credible ‘attention control’ while not altering ‘usual care’ since it is unlikely to prompt discussions about cirrhosis/HCC risk or screening with their GP. It also increases engagement in the trial for control participants to minimise attrition.
Control group
Active

Outcomes
Primary outcome [1] 329448 0
The proportion of newly diagnosed cirrhosis patients in HCC surveillance defined as two diagnostic imaging tests at least 6 month apart, with or without serum AFP levels in a 12-month period following randomisation.
Timepoint [1] 329448 0
12 months post-randomisation
Secondary outcome [1] 402650 0
Incident early stage (Barcelona Clinic Liver Cancer Stage 0 or A) and any stage incident HCC.
This is a composite secondary outcome. It will be assessed via data linkage to medical records (MBS records, state database linkage and GP records)


Timepoint [1] 402650 0
At 12 months post-randomisation.
Secondary outcome [2] 402651 0
Incidence cirrhosis, advanced fibrosis, and hepatic decompensation (new-onset ascites, hepatic encephalopathy, variceal bleeding). This is a composite secondary outcome. It will be assessed via data linkage to medical records (MBS records, state database linkage and GP records)
Timepoint [2] 402651 0
At 12 months after randomisation
Secondary outcome [3] 405777 0
To compare cost-effectiveness associated with a cirrhosis detection pathway and HCC surveillance compared to usual care.
Timepoint [3] 405777 0
Cost effective analysis will calculate resource use, GP, hospital or other medical related visits/treatment and costs identified from linked state-based administrative datasets and MBS/PBS data over the 12 month period, between groups.
The 'event driven time point surveys are now being conducted at 'varied time points'. For those in the control arm of the trial, they receive the questionnaire one week after receiving their 'attention control' brochure. For participants in the intervention arm, they receive their questionnaire one week after receiving receipt of their blood test results. Participants who subsequently receive a fibroscan also receive an event driven questionnaire to complete post fibroscan results given.
Secondary outcome [4] 405778 0
To compare patient reported outcomes (PRO) associated with a cirrhosis detection pathway and HCC surveillance compared to usual care.
Timepoint [4] 405778 0
Measured at baseline, and at 'event driven' time points, participants will complete surveys specific to 'trial related activities'. All participants will complete the baseline and 12 months survey. Those in the control arm will complete one 'event driven' questionnaire (which measures patient reported outcomes specific to anxiety and quality of life measures; AQoL-8D and STAI-6 (Copyright © 1968, 1977 by Charles D. Spielberger. All rights reserved.), a week after they receive the 'attention control brochure'
Participants allocated to the intervention arm have 'event driven time point surveys post results being given for blood tests and results being given post fibroscan. Patient reported outcomes are measured at Baseline, and within 1-2 week of 'trial related activities' being completed, and 12 months post-randomisation using a study specific questionnaires (including AQoL-8D and STAI-6 (Copyright © 1968, 1977 by Charles D. Spielberger. All rights reserved.)

Eligibility
Key inclusion criteria
Each participant must meet the following criteria to be enrolled in this trial:
Aged 45-75 years at time of enrolment;
AND Has greater than or equal to 1 risk factor for chronic liver disease, namely;
- Type 2 diabetes; OR
- BMI greater than or equal to 30kg/m2 or terms for ‘obesity’ in addition to a metabolic risk factor (hypertension: BP greater than or equal to 130/85 or active prescription of antihypertensive or; dyslipidaemia: triglycerides greater than or equal to 150mg/dL (greater than or equal to 1.70mmol/L) or HDL-cholesterol less than 40mg/dL (<1.0mmol/L) for men and less than 50mg/dL (<1.3mmol/L) for women; OR
- Elevated liver enzymes in previous 12 months defined as any of these: (ALT: >30 in men >19 in women IU/l, AST > 45 IU/l, GGT > 60 IU/l); OR
- Chronic viral hepatitis defined as any of these: (Chronic hepatitis including chronic Hep B or, chronic Hep C (Positive HBsAg, HCV positive Ab)); OR
- Fatty liver including, steatohepatitis and non-alcoholic steatohepatitis (NASH) and non-alcoholic liver disease (NAFLD); OR
- Alcohol abuse and excess alcohol as determined from GP records;
AND self-report this practice as their main GP practice
Minimum age
45 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients meeting any of the following criteria will be excluded from the trial:
• Existing diagnosis of cirrhosis, HCC, metastatic liver cancer, ascites or oesophageal varices;
• Unwillingness to participate or inability to provide informed consent;
• Co-morbidities precluding benefit from HCC surveillance (eg frailty with ECOG score >2, advanced cardiac, respiratory, renal disease or other serious co-morbid conditions);
• or;
• Currently under the care of or being referred to a gastroenterologist/hepatologist for liver health

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealed using a randomisation module embedded in the online database. Within the online database, each record (participant) will have 2 check boxes for the researcher to confirm both stratum were entered/calculated correctly in baseline (clinic and AUDIT-C score) prior to the researcher clicking a button labelled ‘randomise’. No record can proceed without randomisation via this method. After the record has been randomised, it will be included in analysis as intention to treat. No record can be randomised more than once. Next steps for the participant will be outlined on the screen after the randomise button is clicked (i.e. usual care will instruct researcher to thank participant for their time and remind them of the follow-up questionnaires. The intervention arm will instruct researcher to complete a pathology slip for providing a blood sample for serum testing.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Using restricted randomisation within the stratum ensures that the number of individuals is balanced between study groups within each stratum and the stratification factors will be balanced in each study group.
A statistician not directly involved in the analysis of the trial results will prepare the randomisation schedule using block randomisation and stratification factors (listed above) to maintain balance between treatment arms. The schedule will be held by Patty Chondros.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
For 90% power and 5% significance level (two-sided), 2804 eligible participants are required to detect a between-arm difference of 1.12% in the primary endpoint (1.3% for intervention arm and 0.18% for control arm). We conservatively assumed 2.5% prevalence of cirrhosis in the general population with risk factors for chronic liver disease, of which 80% in the intervention arm and 30% in usual care will be detected. Of those detected, 65% and 24% will uptake HCC surveillance in the intervention and usual care arms, respectively.
Analyses will use an intention-to-treat approach. Primary endpoint will be compared between the two arms using penalised maximum likelihood logistic regression adjusted for stratification factors. Similar regression analyses appropriate to the data type will be performed for secondary endpoints. In secondary analyses, pre-specified baseline variables strongly associated with the outcome will also be considered for adjustment in the regression analysis. A detailed statistical analysis plan will be developed and published prior to conducting the statistical analysis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2022
Actual
19/07/2022
Date of last participant enrolment
Anticipated
30/05/2025
Actual
Date of last data collection
Anticipated
30/11/2026
Actual
Sample size
Target
2804
Accrual to date
2192
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC

Funding & Sponsors
Funding source category [1] 310065 0
Government body
Name [1] 310065 0
Australian Government, Department of Health (Medical Research Future Fund)
Country [1] 310065 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
The University of Western Australia
35 Stirling Highway
Perth WA 6009
Australia
Country
Australia
Secondary sponsor category [1] 311773 0
None
Name [1] 311773 0
Address [1] 311773 0
None
Country [1] 311773 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309758 0
University of Melbourne, Human Research Ethics Committee
Ethics committee address [1] 309758 0
Ethics committee country [1] 309758 0
Australia
Date submitted for ethics approval [1] 309758 0
10/01/2022
Approval date [1] 309758 0
25/02/2022
Ethics approval number [1] 309758 0
2022-23168-25744-3

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

Contacts
Principal investigator
Name 115286 0
Prof Leon Adams
Address 115286 0
The University of Western Australia (M503), 35 Stirling Highway,
6009 Perth, WA
Australia
Country 115286 0
Australia
Phone 115286 0
+61 8 6151 0835
Fax 115286 0
Email 115286 0
leon.adams@uwa.edu.au
Contact person for public queries
Name 115287 0
Deborah de Guingand
Address 115287 0
University of Melbourne, Victorian Comprehensive Cancer Centre Level 13, 305 Grattan St, 3010 Parkville, VIC Australia
Country 115287 0
Australia
Phone 115287 0
+61 3 85597129
Fax 115287 0
Email 115287 0
deborahd@unimelb.edu.au
Contact person for scientific queries
Name 115288 0
Leon Adams
Address 115288 0
The University of Western Australia (M503),
35 Stirling Highway,
6009 Perth, WA
Australia
Country 115288 0
Australia
Phone 115288 0
+61 8 6151 0835
Fax 115288 0
Email 115288 0
leon.adams@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13949Study protocol    We will supply the approved protocol by HREC when ... [More Details]
13950Statistical analysis plan    We will supply the latest approved Statistical ana... [More Details]
13951Informed consent form    TBC 383057-(Uploaded-11-07-2023-09-27-25)-Study-related document.pdf
13952Ethical approval    I cannot remove the TBC 383057-(Uploaded-23-08-2022-11-21-00)-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.