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Trial registered on ANZCTR


Registration number
ACTRN12624000306516
Ethics application status
Approved
Date submitted
31/10/2023
Date registered
22/03/2024
Date last updated
22/03/2024
Date data sharing statement initially provided
22/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Mixed Meal Challenge and Insulin Resistance
Scientific title
Early detection of insulin resistance with a mixed meal challenge in healthy adults at-risk of insulin resistance - The REFINE Study
Secondary ID [1] 310801 0
Nil
Universal Trial Number (UTN)
Trial acronym
REFINE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Insulin Resistance 331784 0
Condition category
Condition code
Metabolic and Endocrine 328522 328522 0 0
Metabolic disorders
Cardiovascular 328523 328523 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is to evaluate whether a mixed meal challenge (milk drink comprising 55 grams carbohydrates, 35 grams protein and 7 grams fat; one dose given orally) is more sensitive at detecting insulin resistance than traditional clinical tests (fasting blood sample or the oral glucose tolerance test containing 75 grams glucose).

Participants at-risk of insulin resistance will have their insulin sensitivity (i.e., level of insulin resistance) measured by a fasting blood sample (control), a mixed meal challenge (intervention) and an oral glucose tolerance test (control) compared to the gold standard hyperinsulinemic euglycemic clamp (40 mU/m2/min; control) in a randomised cross-over order. Each test will be conducted 1-4 weeks apart.

Participants will have their diet (3-day food diary) and level of physical activity (questionnaire and accelerometer worn for 7 days) assessed once in the 7 day baseline period. Participants will be asked to fast overnight (10-12 hours) before coming in to the laboratory in the morning for each test/challenge. Participants will have their fasting blood biochemistries measured (glucose, HbA1c, total cholesterol, low density lipoprotein, high density lipoprotein, triglyceride and insulin concentrations). Participants will undergo metabolic (blood glucose, plasma insulin and cardiometabolic hormone concentrations) and blood pressure testing before and during a mixed meal challenge, oral glucose tolerance test and hyperinsulinemic euglycemic clamp. Consumption of the glucose or milk drink will occur within 5 minutes and supervised by research staff. Body composition (weight, height and dual x-ray absorptiometry) will assessed in the fasting state at one of the testing visits. Participants also have the 'option' to undergo state-of-the art cardiovascular testing [cardiac function, vascular stiffness, central blood pressure, femoral artery blood flow and skeletal muscle/adipose tissue microvascular blood flow].
Intervention code [1] 327212 0
Early detection / Screening
Comparator / control treatment
1. Fasting blood sample. Participants will be asked to fast overnight (10-12 hours) before coming in to the laboratory in the morning for the blood test.
2. Oral glucose tolerance test (75 grams glucose as a liquid drink; one dose given orally). Participants will be asked to fast overnight (10-12 hours) before coming in to the laboratory in the morning for the test.
3. Hyperinsulinemic euglycemic clamp (40 mU/m2/min of insulin infused intravenously while simultaneously infusing a glucose solution intravenously at a variable rate to maintain blood glucose concentrations at ~5mM for 2hrs). Participants will be asked to fast overnight (10-12 hours) before coming in to the laboratory in the morning for the test.
Control group
Active

Outcomes
Primary outcome [1] 336343 0
Proportion of people considered insulin resistant with each test/challenge.
Timepoint [1] 336343 0
At the conclusion of the study.
Secondary outcome [1] 427925 0
Differences in the sensitivity and specificity between each test/challenge to detect insulin resistance.
Timepoint [1] 427925 0
At the conclusion of the study.
Secondary outcome [2] 432183 0
Differences in skeletal muscle microvascular blood flow between individuals that are insulin resistant and insulin sensitive.
Timepoint [2] 432183 0
Assessed at baseline (fasting) and repeated 1hr into each test/challenge. Outcomes in relation to the degree of insulin resistance/sensitivity will be assessed at the conclusion of the study.
Secondary outcome [3] 432184 0
Differences in adipose tissue microvascular blood flow between individuals that are insulin resistant and insulin sensitive.
Timepoint [3] 432184 0
Assessed at baseline (fasting) and repeated 1hr into each test/challenge. Outcomes in relation to the degree of insulin resistance/sensitivity will be assessed at the conclusion of the study.
Secondary outcome [4] 433006 0
Differences in femoral artery blood flow between individuals that are insulin resistant and insulin sensitive.
Timepoint [4] 433006 0
Assessed at baseline (fasting) and repeated 1hr into each test/challenge. Outcomes in relation to the degree of insulin resistance/sensitivity will be assessed at the conclusion of the study.
Secondary outcome [5] 433007 0
Differences in blood pressure between individuals that are insulin resistant and insulin sensitive.
Timepoint [5] 433007 0
Assessed at baseline (fasting) and repeated 1hr and 2hr into each test/challenge. Outcomes in relation to the degree of insulin resistance/sensitivity will be assessed at the conclusion of the study.

Eligibility
Key inclusion criteria
1. Fasting blood glucose <= 6.0 mM
2. 35-75 years old

PLUS at least one of the below risk factors for insulin resistance:
i). Overweight/obese (body mass index >=25 kg/m2).
ii). Elevated blood pressure (defined as seated blood pressure >130/85 mmHg, or on medication to control blood pressure).
iii). Abnormal blood lipids (fasting triglycerides >1.7 mM, total cholesterol >5.5 mM or high density lipoproteins <1.0 mM for males or <1.3 mM for females, or on medication to treat their lipids).
iv). Have a parent with type 2 diabetes or a parent with premature onset cardiovascular disease (males <=55 years, females <=65 years).
v). Prior history of gestational diabetes (for females).
Minimum age
35 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Have type 2 diabetes or elevated fasting blood glucose (> 6.0 mM).
2. <35 or >75 years old.
3. On medication known to alter insulin sensitivity or blood glucose levels
(e.g. metformin, glucocorticoids).
4. Have cardiovascular disease (e.g. previous heart attack, stroke, pacemaker etc).
5. Pregnant or lactating.
6. Lactose/dairy intolerance or people abstaining from dairy.

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)
Randomisation by computer. Randomisation will be centralised at the Deakin University site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation for each site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical methods will be performed by a qualified biostatistician.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2024
Actual
Date of last participant enrolment
Anticipated
1/09/2027
Actual
Date of last data collection
Anticipated
31/12/2027
Actual
Sample size
Target
255
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
TAS,VIC

Funding & Sponsors
Funding source category [1] 315038 0
Government body
Name [1] 315038 0
National Health and Medical Research Council (Medical Research Future Fund Cardiovascular Mission)
Country [1] 315038 0
Australia
Primary sponsor type
University
Name
Deakin University
Address
Deakin University, 221 Burwood Highway, Burwood, VIC 3125
Country
Australia
Secondary sponsor category [1] 317061 0
None
Name [1] 317061 0
Address [1] 317061 0
Country [1] 317061 0
Other collaborator category [1] 282861 0
Other
Name [1] 282861 0
Baker Heart and Diabetes Institute
Address [1] 282861 0
75 Commercial Road, Melbourne, VIC 3004
Country [1] 282861 0
Australia
Other collaborator category [2] 282862 0
University
Name [2] 282862 0
Victoria University
Address [2] 282862 0
Footscray, VIC 3011
Country [2] 282862 0
Australia
Other collaborator category [3] 282863 0
University
Name [3] 282863 0
Menzies Institute for Medical Research
Address [3] 282863 0
17 Liverpool St, Hobart, TAS 7000
Country [3] 282863 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313999 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 313999 0
Alfred Hospital, 55 Commercial Rd, Melbourne, VIC 3004
Ethics committee country [1] 313999 0
Australia
Date submitted for ethics approval [1] 313999 0
24/07/2023
Approval date [1] 313999 0
03/10/2023
Ethics approval number [1] 313999 0
95584

Summary
Brief summary
Heart disease and stroke is accelerated in people with type 2 diabetes. More recently insulin resistance, even in those without diabetes, has been identified as a major driver. People can have insulin resistance, with normal blood glucose levels, for years and be unaware they are at-risk of heart disease and stroke. It is important to identify these people because early intervention can prevent development of type 2 diabetes, heart disease and stroke. The standard clinical assessments are not effective at identifying insulin resistance at its earliest time point. We aim to do a community screen to determine whether the mixed meal challenge (a milk drink with fat, protein and carbohydrate) can identify insulin resistance in the population that would otherwise be undetected using conventional testing. We hypothesise that the mixed meal challenge will be a new low-cost, easy to perform, diagnostic test, forming a necessary and fundamental strategy for the prevention of type 2 diabetes, heart disease and stroke in routine practice.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130074 0
Prof Michelle Keske
Address 130074 0
Deakin University, 221 Burwood Highway, Burwood, VIC 3125
Country 130074 0
Australia
Phone 130074 0
+61 3 9246 8850
Fax 130074 0
Email 130074 0
Michelle.Keske@deakin.edu.au
Contact person for public queries
Name 130075 0
Prof Michelle Keske
Address 130075 0
Deakin University, 221 Burwood Highway, Burwood, VIC 3125
Country 130075 0
Australia
Phone 130075 0
+61 3 9246 8850
Fax 130075 0
Email 130075 0
Michelle.Keske@deakin.edu.au
Contact person for scientific queries
Name 130076 0
Prof Michelle Keske
Address 130076 0
Deakin University, 221 Burwood Highway, Burwood, VIC 3125
Country 130076 0
Australia
Phone 130076 0
+61 3 9246 8850
Fax 130076 0
Email 130076 0
Michelle.Keske@deakin.edu.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?
De-identified published data may be made available with an approval from the relevant ethics committee in a related area.
When will data be available (start and end dates)?
Immediately following publication and available for 5 years after publication.
Available to whom?
De-identified published data may be made available upon request to the Principal Investigator with i) evidence that ethics approval has been obtained ii) the data request is consistent with the aims of their approved proposal and iii) the project is in a related area.
Available for what types of analyses?
Only to achieve the aims of the approved proposal in a related area.
How or where can data be obtained?
Access subject to approval by the Principal Investigator Professor Michelle Keske (Michelle.Keske@deakin.edu.au).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
20689Ethical approval    386754-(Uploaded-19-10-2023-12-06-25)-Study-related document.pdf



Results publications and other study-related documents

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