Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000330842
Ethics application status
Approved
Date submitted
12/01/2021
Date registered
23/03/2021
Date last updated
23/03/2021
Date data sharing statement initially provided
23/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Identifying non-alcoholic fatty liver disease fibrosis risk in type 2 diabetes patients: implementing the right care, in the right place, at the right time (NAFLD-RRR study)
Scientific title
The effect of FibroScan screening on detection of non-alcoholic fatty liver disease in type 2 diabetes patients attending a Diabetes Clinic: implementing the right care, in the right place, at the right time (NAFLD-RRR study)
Secondary ID [1] 303141 0
None
Universal Trial Number (UTN)
Trial acronym
NAFLD-RRR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nonalcoholic fatty liver disease 320251 0
Type 2 Diabetes 320770 0
Condition category
Condition code
Oral and Gastrointestinal 318183 318183 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Metabolic and Endocrine 318597 318597 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective study to identify and risk-stratify nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes (T2D). Sequential participants will be recruited to the NAFLD-RRR model of care, and then followed for up to 10 years to monitor their health outcomes. The detection of patients with NAFLD ± advanced fibrosis and the surveillance for hepatocellular carcinoma (HCC) among “high-risk” patients will be compared to a historical sample of patients receiving “usual care”. The study will be conducted by a study nurse and liver fellow/student in diabetes clinics in addition to usual care (diabetes specialist review).

The starting event is a patient scheduled for consultation in a Diabetes clinic. The study nurse will review the clinic list for each Diabetes clinic and briefly review the patient referral letter or clinic notes to identify patients that meet exclusion criteria.
Scheduled patients will be invited to be screened for NAFLD when they attend a Diabetes clinic appointment, using FibroScan to assess steatosis (CAP score) and liver fibrosis (liver stiffness measurement, LSM). The invitation and assessment will be made by a specialist study nurse and/or liver fellow. The NAFLD screening assessment, including FibroScan and additional blood tests are anticipated to take 30 minutes to complete.

At the FibroScan assessment the nurse and/or liver fellow will also assess:
• Girth, alcohol consumption (using a brief AUDIT), and simple algorithms (FIB-4 and NAFLD fibrosis score) using recent routine blood test results.
• A fasting blood test (up to 30ml) may be arranged for research purposes (this could be done when the diabetes doctor asks for a fasting blood test).
• If relevant blood tests are not available within the last 6 months, the liver nurse will arrange blood tests (E/LFTs and FBC). Results will be followed up by liver fellow.
• If liver enzymes are abnormal or LSM >/=8 kPa, additional blood tests (iron studies, hepatitis C and B serology, ANA, smooth muscle Ab, antimitochondrial Ab, anti-TTG) will be arranged. Results will be followed up by liver fellow.

The study nurse will complete a template letter with the results of the FibroScan that will be sent directly to the Diabetes specialist with the patient after the procedure. A letter will also be sent to the patient’s GP and a copy of the FibroScan report will be scanned into the patient’s electronic medical record (iEMR). These templates will be designed specifically for the study.

The patient will be diagnosed with NAFLD on the basis of the FibroScan CAP score (CAP score >/=248 dB considered as likely steatosis) and stratified to low or high risk of clinically significant fibrosis on the basis of the FibroScan liver stiffness measurement (LSM).

No NAFLD: Participants with CAP score <248 dB and LSM<8 kPa will be classified as “no NAFLD”. A letter (with a copy to iEMR) will be sent to the patient’s GP and diabetes specialist advising a repeat FibroScan or liver ultrasound in 3-5 years if appropriate, to screen for development of NAFLD.

NAFLD with Low risk of clinically significant fibrosis: Participants with CAP score >/=248 dB and low FibroScan score (LSM < 8.0 kPa) will be classified as ‘Low Risk’. A letter (with a copy to iEMR) will be sent to the patient’s GP and diabetes specialist advising a repeat FibroScan in 2-3 years if appropriate, to assess for development of clinically significant fibrosis.

NAFLD with High risk of clinically significant fibrosis: Participants with CAP score >/=248 dB and elevated FibroScan score (LSM >/=8.0 kPa) will be classified as ‘High Risk’. The Liver Nurse will advise patient (and GP and diabetes specialist via letter, along with a copy to iEMR) that Hepatology referral recommended and arrange Hepatology Clinic consultation.
Participants with a low CAP score and elevated LSM will also require Hepatology referral for further evaluation of possible clinically significant fibrosis.

The recommendations will be provided in the summary letter to the GP and diabetes specialist which will be designed specifically for this study. The letter will contain for each patient the results of their FibroScan with a CAP score and LSM. It will also contain a summary of the recommendations and will have a standard format for each category of: no NAFLD, NAFLD with Low risk of clinically significant fibrosis, NAFLD with High risk of clinically significant fibrosis. If advanced fibrosis is confirmed in the secondary care hepatology clinic, the patient may be offered ongoing hepatology follow-up that may involve HCC and variceal surveillance programs.
For all patients with NAFLD, the letter to the GP and diabetes specialist will provide recommendations regarding management of NAFLD with ongoing assessment and management of cardiometabolic risk factors and lifestyle intervention with consideration of referral to a dietician, exercise physiologist and psychologist for assistance with weight management and increased physical activity.
Intervention code [1] 319440 0
Diagnosis / Prognosis
Intervention code [2] 319755 0
Early detection / Screening
Comparator / control treatment
The outcomes from the study will be compared with data collected previously from patients receiving “usual care”, which does not involve standardised procedures for assessing and managing NAFLD in primary care. The medical records of patients attending Diabetes clinics over the preceding 12 months will be audited to determine the number of patients with a recorded diagnosis of NAFLD and whether an assessment of liver disease severity was performed.
Control group
Historical

Outcomes
Primary outcome [1] 326167 0
Number of participants diagnosed with NAFLD following FibroScan, using a CAP score of greater than or equal to 248dB.
Timepoint [1] 326167 0
3 years post-intervention commencement.
Secondary outcome [1] 390345 0
Number of participants with ‘high-risk’ NAFLD diagnosed using FibroScan, defined as liver stiffness measure (LSM) greater than or equal to 8.0 kPa on FibroScan, that were referred to secondary care (Hepatology) based on the study intervention.
Timepoint [1] 390345 0
3 years post-intervention commencement.
Secondary outcome [2] 390347 0
Number of unnecessary referrals to secondary care. Unnecessary referrals are defined as patients with ‘low risk’ NAFLD with a TE less than or equal to 8.0 kPa. This will be assessed using patient medical records.
Timepoint [2] 390347 0
3 years post-intervention commencement.
Secondary outcome [3] 390348 0
Assess the rate of surveillance for HCC among ‘high-risk’ patients with NAFLD. This will be calculated based on the number of participants diagnosed with advanced fibrosis/cirrhosis following clinical assessment by a Hepatologist, who receive liver imaging, usually ultrasound, every 6 months. This will be assessed using data-linkage to patient medical records.
Timepoint [3] 390348 0
3 years post-intervention commencement.
Secondary outcome [4] 390349 0
Cost analysis of the NAFLD detection/risk stratification pathway in patients with type 2 diabetes. Will be assessed by calculating the difference in resource use and costs before and 3 years post-intervention commencement, from hospital medical records, patient out-of-pocket costs and MediCare Statistics.
Timepoint [4] 390349 0
Economic benefits will be determined 3 years post-intervention commencement.
Secondary outcome [5] 390353 0
Assessment of patients’ supportive care needs:
The type and level of perceived supportive needs of people living with advanced liver disease (assessed with FibroScan with TE greater than or equal to 8.0 kPa) secondary to NAFLD, will be assessed using the Supportive Needs Assessment tool for Chronic liver disease (SNAC).
Timepoint [5] 390353 0
Baseline, and every year post intervention-commencement for the 3 year duration of the study.

Eligibility
Key inclusion criteria
• Referred to a Diabetes Clinic for management of type 2 diabetes
• Aged >/=18 years
• Understand the consent procedures and give their full consent .
• Consent to access their Queensland Health, primary care and Medicare Benefits
Schedule (MBS)/Pharmaceutical Benefits Schedule (PBS) data.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Are pregnant.
Have advanced cardiac disease or another terminal illness.
NESB and interpreter not available

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
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
Statistical methods / analysis
Data analysis will be largely descriptive; that is, we will report means, proportions, and measures of variance. Differences in the proportion of patients (i) diagnosed with NAFLD (ii) identified to have clinically significant fibrosis (iii) referred to Hepatology with “high-risk” vs. “low-risk” disease, and enrolled in a surveillance program for HCC before and after implementation of the intervention will be assessed using statistical tests for categorical data (e.g. Pearson’s chi-squared test, McNemar test). Where appropriate we will use regression models to identify associations between variables. For example, we may assess the association between treatment group (intervention vs. usual care) and clinical and sociodemographic factors.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2021
Actual
Date of last participant enrolment
Anticipated
29/03/2024
Actual
Date of last data collection
Anticipated
29/03/2034
Actual
Sample size
Target
400
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 18385 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 32472 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 307545 0
Charities/Societies/Foundations
Name [1] 307545 0
PA Hospital Foundation
Country [1] 307545 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
PA Hospital Foundation
Address
Princess Alexandra Hospital
Ipswich Rd, Woolloongabba
Brisbane QLD 4102
Country
Australia
Secondary sponsor category [1] 308906 0
None
Name [1] 308906 0
Address [1] 308906 0
Country [1] 308906 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307611 0
Metro South Hospital and Health Service HREC
Ethics committee address [1] 307611 0
Centres for Health Research
Level 7, Translational Research Institute
37 Kent St
Woolloongabba, QLD 4102
Ethics committee country [1] 307611 0
Australia
Date submitted for ethics approval [1] 307611 0
14/01/2021
Approval date [1] 307611 0
12/03/2021
Ethics approval number [1] 307611 0
HREC/2021/QMS/72731

Summary
Brief summary
The overall objective of the study is to develop and implement a practical pathway (NAFLD-RRR pathway) for optimal care of NAFLD in “high-risk” patients with T2D.
The most important predictor of mortality in NAFLD is the extent of liver fibrosis as these patients are at risk of developing cirrhosis and its complications, including hepatocellular carcinoma (HCC). People with T2D have a high prevalence of NAFLD (40–70%), and are more likely to develop advanced fibrosis/cirrhosis and HCC.
This study will use transient elastography with FibroScan as a screening and risk stratification tool for NAFLD in people attending diabetes clinics. The test allows measurement of the controlled attenuation parameter (CAP), which assesses the presence and level of hepatic steatosis, at the same time as evaluating liver stiffness to determine the presence or absence of advanced fibrosis.
A referral pathway will be developed to facilitate patient access to required services.
Individuals at low risk of advanced fibrosis will be managed in primary care, with a focus on healthy lifestyle and weight reduction and minimizing cardiovascular risk. In contrast, patients at risk of advanced fibrosis will be referred to secondary care for investigation of liver disease and management of advanced fibrosis with surveillance for HCC and liver decompensation.

It is expected that more patients will be diagnosed with “high-risk” NAFLD than in usual diabetes care, and that a higher proportion of NAFLD referrals to Hepatology clinics will have clinically significant fibrosis. We anticipate that the study will produce new evidence about the economic benefits of a NAFLD detection/risk stratification pathway in patients with type 2 diabetes.
We anticipate that patients with NAFLD will have a high rate of unmet needs related to lifestyle changes and practical and physical needs, and that identifying these needs will permit us to tailor strategies to promote patient-centred care and facilitate timely interventions or referral to appropriate support services.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107858 0
Prof Elizabeth Powell
Address 107858 0
Department of Gastroenterology and Hepatology
Princess Alexandra Hospital
Ipswich Rd
Woolloongabba
Brisbane QLD 4102
Country 107858 0
Australia
Phone 107858 0
+61 7 3443 8015
Fax 107858 0
Email 107858 0
e.powell@uq.edu.au
Contact person for public queries
Name 107859 0
Prof Elizabeth Powell
Address 107859 0
Department of Gastroenterology and Hepatology
Princess Alexandra Hospital
Ipswich Rd
Woolloongabba
Brisbane QLD 4102
Country 107859 0
Australia
Phone 107859 0
+61 7 3443 8015
Fax 107859 0
Email 107859 0
e.powell@uq.edu.au
Contact person for scientific queries
Name 107860 0
Prof Elizabeth Powell
Address 107860 0
Department of Gastroenterology and Hepatology
Princess Alexandra Hospital
Ipswich Rd
Woolloongabba
Brisbane QLD 4102
Country 107860 0
Australia
Phone 107860 0
+61 7 3443 8015
Fax 107860 0
Email 107860 0
e.powell@uq.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?

TypeCitationLinkEmailOther DetailsAttachment
Other    Summary data will be available as supporting infor... [More Details]


Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseImplementing the right care in the right place at the right time for non-alcoholic fatty liver disease (NAFLD-RRR study): a study protocol for a community care pathway for people with type 2 diabetes.2022https://dx.doi.org/10.1186/s12913-022-07808-7
N.B. These documents automatically identified may not have been verified by the study sponsor.