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Trial registered on ANZCTR


Registration number
ACTRN12619001452189
Ethics application status
Approved
Date submitted
25/09/2019
Date registered
18/10/2019
Date last updated
18/10/2019
Date data sharing statement initially provided
18/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Use of a Hybrid Closed Loop System in the Management of Individuals with Type 1 Diabetes and Poor Glycaemic Control Aged 12-25
Scientific title
The Use of a Hybrid Closed Loop System in the Management of Individuals with Type 1 Diabetes and Poor Glycaemic Control
Secondary ID [1] 299409 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 314582 0
Poor Glycaemic Control 314685 0
Condition category
Condition code
Metabolic and Endocrine 312924 312924 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective multicentre randomized controlled, two-arm unblinded, parallel study in free-living conditions, in adolescents with type 1 diabetes on insulin pump therapy.

Participants are randomized in two groups; either the control group (standard therapy) or the intervention group (hybrid closed loop, HCL). The control group will be participants on insulin pump therapy with or without continuous glucose monitoring (CGM).

Intervention arm: Medtronic Advanced HCL system for 6 months (8 in-clinic visits in 6 months)
OR
Control arm: Standard care for 6 months (7 in-clinic visits in 6 months)

This will be followed by an optional extension phase for another 6 months when those in the control arm would crossover to the intervention arm.

Study participants in the intervention arm will use the Medtronic Advanced HCL (AHCL) system. The system includes the advanced Medtronic insulin pump with the compatible transmitter and sensor. The pump works in Manual Mode (comparable to current insulin therapy with the Medtronic 640G pump) and Auto Mode (hybrid closed loop therapy). Participants will be educated on the use of Auto Mode, an option available in the pump, which will adjust the insulin delivery based on the sensor glucose level. The user will still need to bolus for meals like standard pump therapy and hence this is described as a hybrid closed loop system. The advanced algorithm will be more robust in correcting hyperglycaemia as compared to the currently available Medtronic 670G system.
Intervention code [1] 315657 0
Prevention
Intervention code [2] 315658 0
Behaviour
Intervention code [3] 315659 0
Lifestyle
Comparator / control treatment
Standard care for 6 months follow by an optional extension phase for another 6 months crossover to the intervention arm. Standard care is defined as the current treatment (insulin pump therapy with or without CGM) which the patient is on for at least six months and yet continues to have mean and recent HbA1c above 9%. Patients already on Medtronic 670G hybrid closed loop system will not be eligible.
Control group
Active

Outcomes
Primary outcome [1] 321523 0
Glycaemic control as measured by HbA1c collected via blood test.
Timepoint [1] 321523 0
At baseline and 6 months post randomisation.
Secondary outcome [1] 375221 0
Changes in retinopathy scores from retinal photography.
Timepoint [1] 375221 0
At randomisation
Endpoint - 6 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [2] 375222 0
Changes in retinal microvascular structure (arteriolar or venular dilation, increased vascular fractal dimension, branching and tortuosity) from retinal photography. This is a composite secondary outcome.
Timepoint [2] 375222 0
At randomisation
Endpoint - 6 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [3] 375223 0
Health economic impact of the AHCL system vs standard therapy by collecting the following data during the study:
a) Calculate number of hypoglycaemic events
b) Changes in HbA1c
c) Amount of time spent by investigators with participants (training, education, support)
d) Calculating amount of diabetes management consumables used by participants (glucose strips, ketone strips, batteries, sensors, site dressings, lancets, needles, insulin)
Timepoint [3] 375223 0
Baseline
At randomisation
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [4] 375485 0
Human factors: adherence patterns as measured by assessing AHCL system data upload completion.
Timepoint [4] 375485 0
At randomisation
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [5] 375857 0
Psychosocial well-being measured via validated diabetes distress scales: Problem Areas in Diabetes questionnaires
Timepoint [5] 375857 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [6] 375858 0
Psychosocial well-being measured via validated fear of hypoglycaemia scales: Hypoglycaemia Fear Survey II questionnaires
Timepoint [6] 375858 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [7] 375859 0
Psychosocial well-being measured via validated general anxiety scales: Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9 questionnaires

This is a composite secondary outcome.
Timepoint [7] 375859 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [8] 375860 0
Psychosocial well-being measured via validated health status questionnaires: EQ-5D-Y
Timepoint [8] 375860 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [9] 375861 0
Psychosocial well-being measured via validated diabetes-specific quality of life questionnaires: PedsQL
Timepoint [9] 375861 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [10] 375862 0
Psychosocial well-being measured via validated treatment satisfaction questionnaires: INSPIRE and Diabetes Technology Questionnaires

This is a composite secondary outcome.
Timepoint [10] 375862 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [11] 375863 0
Psychosocial well-being measured via validated hypoglycaemia awareness questionnaire: Gold Score Hypoglycaemic Awareness
Timepoint [11] 375863 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [12] 375864 0
Glycaemic outcomes via CGM data for % CGM time <2.8 mmol/L
Timepoint [12] 375864 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [13] 375865 0
Glycaemic outcomes via CGM data for % CGM time <3.3 mmol/L
Timepoint [13] 375865 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [14] 375866 0
Glycaemic outcomes via CGM data for % CGM time <3.9 mmol/L
Timepoint [14] 375866 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [15] 375867 0
Glycaemic outcomes via CGM data for % CGM time 3.9-7.8 mmol/L
Timepoint [15] 375867 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [16] 375868 0
Glycaemic outcomes via CGM data for % CGM time 3.9-10.0mmol/L
Timepoint [16] 375868 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [17] 375869 0
Glycaemic outcomes via CGM data for % CGM time >10.0 mmol/L
Timepoint [17] 375869 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [18] 375870 0
Glycaemic outcomes via CGM data for % CGM time >13.9 mmol/L
Timepoint [18] 375870 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [19] 375871 0
Glycaemic outcomes via CGM data for % CGM time >16.7 mmol/L
Timepoint [19] 375871 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline
Secondary outcome [20] 375872 0
Glycaemic outcomes using Standard Deviation and Coefficient of Variation of CGM values
Timepoint [20] 375872 0
Baseline
Midpoint - 3 months post-baseline
Endpoint - 6 months post-baseline
Midpoint optional extension phase - 9 months post-baseline
Endpoint optional extension phase - 12 months post-baseline

Eligibility
Key inclusion criteria
1. Type 1 diabetes (diagnosis consistent with American Diabetes Association Classification of Diabetes Mellitus, diagnosed at least 1 year ago)
2. Fasting C peptide less than 0.1nmol/L (in the absence of hypoglycaemia)
3. Pump therapy for at least 6 months
4. Age 12 to 25 years
5. Recent HbA1c above 9% in the last 3 months
6. Mean HbA1c above 9% for 6 months
7. Willing to follow study instructions
8. Willing to perform at least 3 finger stick blood glucose measurements daily
9. Willing to perform required sensor calibrations
10.Capable of reading and understand instructions in English
11.Living in an area with internet and cellular phone coverage
Minimum age
12 Years
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Severe DKA in the 6 months prior to the screening visit
2. Use of any non-insulin glucose-lowering agent within the past 3 months
3. Commenced CGM in the 3 months prior to the screening visit
4. Pregnancy or planned pregnancy within the study period
5. Uncontrolled coeliac disease (not following a gluten free diet), or other untreated malabsorption
6. Uncontrolled thyroid disease
7. Clinically-significant gastroparesis
8. Poor visual acuity precluding use of the investigational technology
9. Inability or unwillingness to meet protocol requirements

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Dynamic (adaptive) random allocation methods - minimisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
The power calculation is for a parallel study design with two groups of equal size. Based on information in the WA population based database and current data (de Bock et al, accepted JDST 2018), we expect a between group difference of 1.5% in HbA1c at 6 months with a SD of 1.7% for both groups. With alpha set at 0.05, 22 subjects would be required in each group to have 80% power to detect a difference of 1.5%. It is assumed the total dropout rate will be up to 15%, so we plan to recruit 50 subjects in total.

The primary analysis will assess differences in HbA1c (%) with AHCL versus standard therapy, measured six months post-randomisation using analysis of covariance (ANCOVA) with adjustment for baseline HbA1c. Least square means and least square mean differences and their associated 95% confidence intervals will be presented for each treatment group and between groups.

Model residuals will be used to assess model fit. If the residuals indicate poor model fit, the outcome variable will be transformed and the model refitted and evaluated. If poor model fit cannot be addressed, nonparametric analysis will be performed. In the event that residuals are not normally distributed: the Mann–Whitney–Wilcoxon (Wilcoxon Rank-Sum) Test will be employed if raw data are symmetric; if raw data are non-symmetric, bootstrap methods will be used to test the difference between groups.

Continuous secondary outcomes (glycaemic, auxological, clinical, psychosocial) will be analysed using the ANCOVA approach described above.

Secondary analysis for outcomes collected at multiple time points will be conducted using linear mixed models including random effects and various variance-covariance structures to account for non-independence. Akaike information criterion (AIC) will be used to determine the most appropriate model.

Recruitment
Recruitment status
Not yet 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,SA,WA,VIC
Recruitment hospital [1] 14854 0
Perth Children's Hospital - Nedlands
Recruitment hospital [2] 14855 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 14856 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [4] 14857 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 28120 0
6009 - Nedlands
Recruitment postcode(s) [2] 28121 0
3052 - Parkville
Recruitment postcode(s) [3] 28122 0
5006 - North Adelaide
Recruitment postcode(s) [4] 28123 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 303914 0
Charities/Societies/Foundations
Name [1] 303914 0
JDRF Australia
Address [1] 303914 0
Level 4, 80 Chandos Street
St Leonards NSW 2065
Country [1] 303914 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Telethon Kids Institute
Address
Perth Children's Hospital
15 Hospital Avenue
Nedlands 6009 WA
Country
Australia
Secondary sponsor category [1] 304066 0
None
Name [1] 304066 0
Address [1] 304066 0
Country [1] 304066 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304418 0
Child and Adolescent Health Service HREC
Ethics committee address [1] 304418 0
Perth Children’s Hospital
15 Hospital Avenue
Nedlands WA 6009
Ethics committee country [1] 304418 0
Australia
Date submitted for ethics approval [1] 304418 0
Approval date [1] 304418 0
09/05/2018
Ethics approval number [1] 304418 0
RGS0000000886

Summary
Brief summary
This is a 6 month multi-centre randomized controlled trial assessing the effect of advanced hybrid closed loop (AHCL) in adolescents with poor glycaemic control and comparing this technology with their standard care. The purpose of this project is to utilize an automated insulin delivery system to improve glycaemic control which has been shown during in-home use by adolescents and adults with increased time in target, and reductions in HbA1c, hyperglycaemia and hypoglycaemia, compared to baseline. Hence, it would be valuable to test the effectiveness of AHCL in patients with poor glycaemic control.

We hypothesize that AHCL system will circumvent the significant glycaemic excursion associated with conventional therapy in patients with poor glycaemic control. Reduced adherence to diabetes self-management tasks is often associated with poor glycaemic control and this trial will address, in effect, whether the challenge of managing AHCL is less than the challenge of routine treatment and will generate data that will inform approaches to enhance adherence.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96886 0
Prof Timothy W Jones
Address 96886 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 96886 0
Australia
Phone 96886 0
+61 864562222
Fax 96886 0
Email 96886 0
tim.jones@health.wa.gov.au
Contact person for public queries
Name 96887 0
Miss Julie Dart
Address 96887 0
Telethon Kid's Institute
Northern Entrance
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 96887 0
Australia
Phone 96887 0
+61 864564608
Fax 96887 0
Email 96887 0
julie.dart@health.wa.gov.au
Contact person for scientific queries
Name 96888 0
Dr Mary Abraham
Address 96888 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 96888 0
Australia
Phone 96888 0
+61 864565027
Fax 96888 0
Email 96888 0
mary.abraham@health.wa.gov.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?
All de-identified data will be shared as per contract with funding body JDRF as well as sponsoring institution's regulation and policies according to GCP.
When will data be available (start and end dates)?
At completion of the study and publications of primary and secondary outcomes - tentative after Dec 2022 and up to 15 years thereafter.
Available to whom?
Investigators external to the trial will need to submit an application to request for participant data. Guidelines for application will be made available closer to study completion.
Available for what types of analyses?
Translational analyses with proven scientific and ethical rigor identified through the application process.
How or where can data be obtained?
Please submit a data request application to Children's Diabetes Centre at Telethon Kids Institute via email diabetes.research@health.wa.gov.au. Guidelines for application will be made available closer to study completion.
What supporting documents are/will be available?
Study protocol
Ethical approval
How or where can supporting documents be obtained?
Type [1] 5076 0
Study protocol
Citation [1] 5076 0
Link [1] 5076 0
Email [1] 5076 0
mary.abraham@health.wa.gov.au
Other [1] 5076 0
Attachment [1] 5076 0
Type [2] 5077 0
Ethical approval
Citation [2] 5077 0
Link [2] 5077 0
Email [2] 5077 0
julie.dart@health.wa.gov.au
Other [2] 5077 0
Attachment [2] 5077 0
Summary results
No Results