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Trial registered on ANZCTR


Registration number
ACTRN12617000828325
Ethics application status
Approved
Date submitted
23/05/2017
Date registered
6/06/2017
Date last updated
6/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimising mealtime insulin bolusing algorithms for dietary fat to improve glycaemic control in adults with type 1 diabetes.
Scientific title
Optimising mealtime insulin bolusing algorithms for dietary fat to improve glycaemic control in adults with type 1 diabetes.
Secondary ID [1] 292026 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 303416 0
Condition category
Condition code
Metabolic and Endocrine 302826 302826 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1: Relationship Between Amount and Type of Dietary Fat and Postprandial Glycaemia
A randomised, within-subject trial comparing capillary postprandial glycaemia for meals of varying amounts and types of fat over 5h with the same insulin dose for all meals (based on the insulin: CHO ratio) in 20 adults with T1D using insulin pump therapy.
Dietary Fat:
* 4 amounts of fat (0g, 20g, 40g, 60g) added to 45g CHO
* 3 different types of fat (saturated, monounsaturated and polyunsaturated fat) added to 45g CHO

Part 2: Optimal Prandial Insulin Bolusing Strategy for Dietary Fat
A randomised, within-subject trial in the same participants to identify the optimal insulin bolus dose and delivery pattern, using the Model Predicted Bolus, for meals of varying fat content and amount in 20 adults with T1D using insulin pump therapy.
* 1 type of fat (Monounsaturated fat) x 3 amounts of fat (20g, 40g, 60g) added to 45g CHO

Design Rationale: The types and amounts of fat, for which the ICR did not provide adequate insulin coverage in Part 1 (assessed as blood glucose levels outside target range of 4-10mmol/L), will then receive the same test meals with a MPB in the same participants (Predicted to be meals B, C and D). Using a previously validated MPB to determine the optimised subcutaneous insulin dose allows us to achieve tight postprandial glycemic control that is directly applicable to the clinical setting. The bolus delivery pattern for the MPB will be derived from the data from Part 1.

Model Predicted Bolus (MPB): Our model uses ‘Model Predictive Control’ to identify the acute changes in physiological parameters affected by meal composition and insulin dosing and predicts the optimal insulin bolus amount and pattern to achieve the minimal area above 10 mmol/L and below 4 mmol/L. In simple terms, the known variables (the macronutrient content of the meal, the insulin dose given and resulting blood glucose results) are used to determine individual physiological parameters ( the unknown variable) in Part 1. The model then 'rearranges the formula' to predict the optimal insulin dose (i.e the MPB, unknown variable) for the known individual physiological parameters, meal macronutrient composition and desired blood glucose result. This MPB can then be validated in people with T1D to confirm the efficacy of the prediction. The model has been previously been validated for predicting T1D mealtime insulin in the following paper: Bell KJ, Toschi E, Steil GM, Wolpert HA. Optimized Mealtime Insulin Dosing for Fat and Protein in Type 1 Diabetes: Application of a Model-Based Approach to Derive Insulin Doses for Open-Loop Diabetes Management. Diabetes Care, 2016; 39(9):1631-4.

Test Meals & Insulin doses
Part 1: Insulin doses calculated using participants' insulin: CHO ratio (standard clinical practice).
Test Meal A: 0g monounsaturated fat with 45g of CHO (avocado on toast)
Test Meal B: 20g monounsaturated fat with 45g of CHO (avocado on toast)
Test Meal C: 40g monounsaturated fat with 45g of CHO (avocado on toast)
Test Meal D: 60g monounsaturated fat with 45g of CHO (avocado on toast)
Test Meal E: 20g polyunsaturated fat with 45g of CHO (margarine on toast)
Test Meal F: 20g saturated fat with 45g of CHO (butter on toast)

Part 2: Insulin doses calculated using the MPB.
Repeat Test Meal B: 20g monounsaturated fat with 45g of CHO (avocado on toast)
Repeat Test Meal C: 40g monounsaturated fat with 45g of CHO (avocado on toast)
Repeat: Test Meal D: 60g monounsaturated fat with 45g of CHO (avocado on toast)

Wash out period: All test sessions must be completed on separate days but may be consecutive days. There is no washout period between testing sessions in Part 1 and Part 2 (i.e the final session of part 1 and the first session of part 2 may be conducted on consecutive days).

Study Procedure:
Participants will be instructed to avoid alcohol and exercise for 24h prior to the session and not make any manual insulin adjustments (correction bolus or temporary basal rate) after midnight. In the case of hypoglycaemia, participants will be instructed to treat their hypoglycaemia according to their usual clinical care and their test session will be rescheduled.
On the day of the test session, participants will arrive at the metabolic kitchen at the Charles Perkins Centre, University of Sydney between 6:30-8:30am after an overnight fast. Two baseline capillary blood glucose tests will be performed on arrival to confirm eligibility to commence the testing session. The fasting BGL must be between 4-10 mmol/L for the session to be commenced. If eligible, capillary blood samples will taken 30, 15 and 0 minutes prior to the consumption of the test meal. The allocated insulin dose will be administered subcutaneously via an insulin pump by the CDE 15 minutes immediately prior to the consumption of the test meal. The test food will be served with 250mL of plain water and participants will be given 12 minutes to consume both the food and water and then no other food or drink will be provided for the remainder of the 5h test session (except water). Capillary blood samples will be collected at 15 min, 30 min, 45 min, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h and 5h. If hypoglycaemia occurs (> 3.5 mmol/L), the test session will be terminated, the event recorded and the participant treated appropriately.
Intervention code [1] 298154 0
Treatment: Other
Comparator / control treatment
This is a within subject trial and thus subjects serve as their own control. Blood glucose levels and insulin doses for different test meals will be compared within each individual.
Control group
Active

Outcomes
Primary outcome [1] 302217 0
Differences in 5hr iAUCglucose (Part 1)
Timepoint [1] 302217 0
The 5hr iAUCglucose will be calculated from capillary blood glucose level measurements taken at 15-30 minute intervals for 5 hrs (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes).
Primary outcome [2] 302218 0
Mean insulin dose (Part 2)
Timepoint [2] 302218 0
Insulin dose administered for the study session is recorded at the time the insulin dose is given (t = 0)
Primary outcome [3] 302248 0
Mean insulin dose dual-wave split (Part 2)
Timepoint [3] 302248 0
Insulin dose dual-wave split administered for the study session is recorded at the time the insulin dose is given (t = 0)
Secondary outcome [1] 335182 0
Incidence of hypoglycaemia (< 3.5mmol/L)
Timepoint [1] 335182 0
The incidence of hypoglycaemia will be recorded from capillary blood glucose level measurements taken at 15-30 minute intervals for 5 hrs (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes).
Secondary outcome [2] 335183 0
Mean postprandial blood glucose level
Timepoint [2] 335183 0
The mean postprandial blood glucose level will be calculated from capillary blood glucose level measurements taken at 15-30 minute intervals for 5 hrs (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes).
Secondary outcome [3] 335184 0
Standard deviation around mean postprandial blood glucose level
Timepoint [3] 335184 0
The standard deviation around the mean postprandial blood glucose level will be calculated from capillary blood glucose level measurements taken at 15-30 minute intervals for 5 hrs (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes).
Secondary outcome [4] 335185 0
Coefficient of Variation in blood glucose levels
Timepoint [4] 335185 0
The Coefficient of Variation will be calculated from capillary blood glucose level measurements taken at 15-30 minute intervals for 5 hrs (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes).
Secondary outcome [5] 335186 0
J-Index of blood glucose levels
Timepoint [5] 335186 0
The J-Index will be calculated from capillary blood glucose level measurements taken at 15-30 minute intervals for 5 hrs (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes).
Secondary outcome [6] 335187 0
Mean Amplitude of Glycaemic Excursion (MAGE)
Timepoint [6] 335187 0
The Mean Amplitude of Glycaemic Excursion (MAGE) will be calculated from capillary blood glucose level measurements taken at 15-30 minute intervals for 5 hrs (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes).
Secondary outcome [7] 335291 0
Insulin dose dual-wave duration (Primary outcome for Part 2)
Timepoint [7] 335291 0
Insulin dose dual-wave duration administered for the study session is recorded at the time the insulin dose is given (t = 0)
Secondary outcome [8] 337493 0
Satiety
Timepoint [8] 337493 0
Measured using 17 point likert scale at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270 and 300 minutes

Eligibility
Key inclusion criteria
Aged 18-70y, T1D diagnosed for less than or equal to 1 year, CSII for less than or equal to 3 months, HbA1c for less than or equal to 8.5% (69 mmol/mol), reliably performing self-monitoring of blood glucose at least four times daily and fluency in English.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Concurrent medical issues including coeliac disease and gastroparesis, food allergies, intolerances or eating disorders or use of other medication that may influence blood glucose levels, pregnancy or lactation.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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)
The order of the first 6 meals will be randomised as each corresponding insulin dose will be determined by their existing clinically-prescribed insulin:carbohydrate ratio (Part 1). The following 3 test meals using the 'model predicted bolus' will also be given in random order, with each test meal repeated directly after if target blood glucose level not reached on the first attempt (Part 2). The randomisation sequence will be generated using a computerised sequence generator.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
17 participants will provide >80% power to detect an effect size of 20-25% in 5h iAUCglucose, allowing for a standard deviation (SD) of 27 mmol.hr/L. To allow for a 15% margin for dropouts, a total of 20 participants will be recruited.
If the session is stopped due to hypoglycaemia, the last recorded value will be carried forward. A general linear model with preprandial blood glucose level as a covariate will be used to analyse the parameters for the test conditions. The number of episodes of hypoglycaemia will be expressed as a proportion of all test sessions and compared by Chi-Square test and a Kaplan-Meier survival plot. Differences in coefficients will be considered statistically significant if p is < 0.05, and highly significant if p is < 0.01 (two-tailed).

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 8113 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 8114 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 16170 0
2050 - Camperdown
Recruitment postcode(s) [2] 16171 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 296556 0
Charities/Societies/Foundations
Name [1] 296556 0
ADEA Diabetes Research Foundation
Address [1] 296556 0
PO Box 163
Woden, ACT 2606
Country [1] 296556 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Level 6, Jane Foss Russell Building G02,
The University of Sydney NSW 2006
Country
Australia
Secondary sponsor category [1] 295510 0
None
Name [1] 295510 0
Address [1] 295510 0
Country [1] 295510 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297770 0
Sydney Local Health District Ethics Review Committee
Ethics committee address [1] 297770 0
Research Ethics and Governance Office
Royal Prince Alfred Hospital
Missenden Rd
Camperdown NSW 2050
Ethics committee country [1] 297770 0
Australia
Date submitted for ethics approval [1] 297770 0
22/02/2017
Approval date [1] 297770 0
04/04/2017
Ethics approval number [1] 297770 0
HREC/17/RPAH/75

Summary
Brief summary
We will systematically assess the dose-response relationship between dietary fat and postprandial glycaemia in adults with type 1 diabetes. Optimal insulin bolusing algorithms for dietary fat will be derived through predictive modelling of the data and validated in adults with type 1 diabetes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75066 0
Dr Kirstine Bell
Address 75066 0
Charles Perkins Centre
The University of Sydney NSW 2006
Country 75066 0
Australia
Phone 75066 0
+61 2 8627 4250
Fax 75066 0
Email 75066 0
Kirstine.Bell@sydney.edu.au
Contact person for public queries
Name 75067 0
Dr Kirstine Bell
Address 75067 0
Charles Perkins Centre
The University of Sydney NSW 2006
Country 75067 0
Australia
Phone 75067 0
+61 2 8627 4250
Fax 75067 0
Email 75067 0
Kirstine.Bell@sydney.edu.au
Contact person for scientific queries
Name 75068 0
Dr Kirstine Bell
Address 75068 0
Charles Perkins Centre
The University of Sydney NSW 2006
Country 75068 0
Australia
Phone 75068 0
+61 2 8627 4250
Fax 75068 0
Email 75068 0
Kirstine.Bell@sydney.edu.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary