Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000472774
Ethics application status
Approved
Date submitted
21/01/2022
Date registered
25/03/2022
Date last updated
13/03/2023
Date data sharing statement initially provided
25/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessment of closed loop technology in young children with Type 1 Diabetes Aged 2-7
Scientific title
Assessment of the efficacy of closed loop technology for glucose control in young children with Type 1 Diabetes
Secondary ID [1] 304189 0
Nil known
Universal Trial Number (UTN)
Trial acronym
HyCLIP - RCT
Linked study record
The current study is a follow-up of ACTRN12622000455763.

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 321884 0
Condition category
Condition code
Metabolic and Endocrine 319615 319615 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The Randomised Controlled Trial (RCT) is a prospective multi-centre randomised controlled, two-arm unblinded, parallel study in free-living conditions, in young children with type 1 diabetes (T1D) on insulin pump therapy. Participants will be randomised in two groups; either the control group (standard therapy) or the intervention group (Advanced Hybrid Closed Loop, HCL). The control group will be participants on continuous subcutaneous insulin infusion (CSII) with or without CGM (continuous glucose monitoring). The study duration is for 3 months

Intervention arm: Medtronic Advanced HCL system for 3 months OR
Control arm: Standard care for 3 months

The Medtronic Advanced HCL (AHCL) system comprises of the Medtronic MiniMed 780G insulin pump containing the closed loop algorithm, a next generation glucose sensor and a glucose sensor transmitter. The MiniMed 780G system has the capability to operate in Manual Mode or SmartGuard Mode (also referred to as AHCL or Auto Mode). After randomisation, participants in the intervention group and their parents will be educated on the use of Auto Mode (which will adjust the insulin delivery based on their determined set threshold of either 5.5 mmol/L, 6.1 mmol/L, or 6.7 mmol/L) during a 2-hour pump and CGM (continuous glucose monitoring) training.

The information session will cover:
- Instructions for pump upload
- Instructions to log hypoglycaemia and hyperglycaemia in the record book provided
- Instructions to link the participant's CGM to the Medtronic 780G pump
Sensor naïve individuals will have familiarisation phase of 7 to 10 days to get used to wearing a sensor.

The blood glucose threshold will be set at the discretion of the participant's endocrinologist. The AHCL algorithm will calculate the insulin dose at five-minute intervals based on their CGM data, in order to achieve glycaemic control throughout the day. Participants will still need to bolus for meals like standard pump therapy; hence 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. The modifications to the closed loop algorithm include the addition of adjustable target set points (5.5 mmol/L, 6.1 mmol/L, and 6.7 mmol/L), an auto correction bolus without user input or acknowledgement and fine tuning of safeguards in order to reduce auto mode exits and improve user experience. The system will also have an additional Bluetooth capability which will make it possible to control the glucose level via a phone app and is therefore more suitable for this young cohort.

11 weeks after randomisation, participants in within the control group will attend the clinic for the insertion of a blinded CGM. This constitutes first of the two sensors, each sensor provides data for 7 days and parents will be instructed to test their children for a minimum of 3 to 4x /day using the study meter. Participants will return after 7 days to have the first sensor removed and the second sensor inserted. A minimum of 10 days of data will be requited from the 2 sensors. In participants who do not meet this requirement, repeat sensors will be offered till a maximum of 4 attempts of data collection.

All visits will be conducted by a Diabetes educator with the supervision of an endocrinologist. Participants will have weekly communication via phone call or email for support in between clinic visits

Intervention code [1] 320522 0
Treatment: Devices
Intervention code [2] 320523 0
Prevention
Intervention code [3] 320524 0
Lifestyle
Comparator / control treatment
Standard care is defined as the participant's current treatment on continuous subcutaneous insulin infusion (CSII). Participants will have no change to their current treatment regimen and will only undergo CGM (continuous glucose monitoring) if already doing so prior to commencement of the study.. Patients currently using closed loop therapy will not be eligible.
Control group
Active

Outcomes
Primary outcome [1] 327468 0
Percentage of time spent in target glucose range (3.9 - 10 mmol/L) measured at 5-minutely intervals by a blinded CGM over 2 weeks starting at 13-15 weeks post randomisation.

Timepoint [1] 327468 0
Baseline and at the last visit (13-15 weeks post randomisation)
Secondary outcome [1] 395217 0
Composite outcome: Psycho-social measure of parents' well-being - Functional health status
Assessed using Quality of life (QOL), WHO5 and EuroQol-5 (EQ5D) questionnaires
Timepoint [1] 395217 0
Baseline and at last visit (13-15 weeks post randomisation)
Secondary outcome [2] 395218 0
Psycho-social measure of parents' well-being - Fear of hypoglycaemia
Assessed using Hypoglycaemia Fear Survey (Parent)
Timepoint [2] 395218 0
Baseline and at last visit (13-15 weeks post randomisation)
Secondary outcome [3] 395220 0
Psycho-social measure of parents' well-being - Diabetes-related distress
Assessed using Problem Areas in Diabetes (PAID) scale for parents
Timepoint [3] 395220 0
Baseline and at last visit (13-15 weeks post randomisation)
Secondary outcome [4] 395221 0
Psycho-social measure of parents' well-being - Anxiety:
Assessed using the General Anxiety Disorder-7 (GAD-7) questionnaire
Timepoint [4] 395221 0
Baseline and at last visit (13-15 weeks post randomisation)
Secondary outcome [5] 395229 0
Psycho-social measure of parents' well being - Sleep quality
Assessed using the Pittsburgh Sleep Quality Index
Timepoint [5] 395229 0
Baseline and at last visit (13-15 weeks post randomisation)
Secondary outcome [6] 407349 0
Psycho-social measure of parents' well being - Technology acceptance and satisfaction
Assessed using the Disclosure of Trauma Questionnaire (DTQ)
Timepoint [6] 407349 0
Baseline and at last visit (13-15 weeks post randomisation)
Secondary outcome [7] 407350 0
Experience of using new technology to manage Type 1 diabetes
Assessed using a semi-structured one-on-one audio-recorded interview
Timepoint [7] 407350 0
At last visit (13-15 weeks post randomisation)
Secondary outcome [8] 407351 0
Glycaemic outcomes
Assessed using HbA1c levels from blood samples
Timepoint [8] 407351 0
Baseline and at last visit (13-15 weeks post randomisation)
Secondary outcome [9] 407352 0
Nutritional adequacy of child’s diet, measured using:
24- hour food recall to identify the proportion of children meeting (1) current macronutrient ratios (for fat, protein and carbohydrate expressed as % of total energy intake) as per International Society for Pediatric and Adolescent Diabetes (ISPAD) Nutrition Guidelines on any given day, and (2) food group serves as per the NHMRC’s Australian Guide to Healthy Eating for Children and Adolescents recommendations.
Timepoint [9] 407352 0
At last visit (13-15 weeks post randomisation
Secondary outcome [10] 407353 0
Composite outcome:
Health-economic impact of the AHCL system vs standard therapy

Assessed using:
- Quality Adjusted Life Year (QALY) calculated from the EQ-5D questionnaire,
- HbA1c levels collected in the study,
- Participants' self-reported measures captured on the participants Case Report Form (CRF):
Number of hypoglycaemic events, number of reported admission to hospital due to diabetes-related events, reported parental work interruption and leave due to child’s diabetes, reported child’s school absenteeism due to diabetes,
- Investigator's reported time spent on training, education and support by the type of health professional resource used, and
- Cost of diabetes management consumables (glucose strips, ketone strips, batteries, sensors, site dressings, lancets, needles, insulin)
Timepoint [10] 407353 0
At the last visit (13 -15 weeks post randomisation)
Secondary outcome [11] 407354 0
Composite outcome:
Human factors.
Participant technology interaction and adherence patterns with the use of AHCL will be determined from closed loop monitor analytics.
Timepoint [11] 407354 0
Baseline and at the last visit (13-15 weeks post randomisation)
Secondary outcome [12] 407897 0
Glycaemic Outcome
Assessed using percentage CGM Time from closed loop monitor analytics
Timepoint [12] 407897 0
Baseline and at the last visit (13-15 weeks post randomisation)
Secondary outcome [13] 407898 0
Glycaemic Outcome
Assessed using Glycaemic variability (Standard Deviation and Coefficient of Variation of CGM values) from closed loop monitor analytics
Timepoint [13] 407898 0
Baseline and at the last visit (13-15 weeks post randomisation)

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. CSII therapy for at least 3 months
3. Age 2 to 7 years (inclusive)
4. Total daily insulin of greater or equal 8 units/day in last 2 weeks
5. Participant and parent willing to follow study instructions
6. Living in an area with internet and cellular coverage
Minimum age
2 Years
Maximum age
7 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Commenced CGM in the 3 months prior to screening visit
2. Using advanced hybrid closed loop system: Control IQ
3. Uncontrolled coeliac disease
4. Uncontrolled thyroid disease
5. Inability or unwillingness to meet protocol requirements
6. Unwilling to perform 3 to 4 finger stick blood glucose measurements daily
7. Use of Hydroxyurea medication
8. Poor vision (of primary caregiver) precluding the use of investigational technology

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)
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
Efficacy
Statistical methods / analysis
Data collected at baseline and at the end of the RCT (13 - 15 weeks post randomisation) will be used to assess the effectiveness of AHCL therapy as compared to standard therapy.
To test for an effect of treatment group on the primary outcome, an ANCOVA including treatment, baseline percent time in range adjusting for minimisation factors will be conducted on an intention to treat basis. Multiple imputations will be used to handle missing data: a multivariate normal imputation approach will be taken. Results will be presented as the mean difference in the percent time in target range at the end of the study between treatment arms with 95% confidence interval and p value.
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. The same assessment of model residuals will be conducted, and the appropriate analysis approach utilised. Where parametric methods are employed using the untransformed outcome measure, mean difference with 95% CI will be presented; where data are transformed, the retransformed effect with 95% confidence intervals will be presented as an indication of the relative effect of the intervention; where non-parametric methods are employed, Hodges-Lehmann median difference with robust 95% CI will be presented.

Secondary count outcomes will be analysed using Poisson regression or, where overdispersion is apparent, negative binomial model with a maximum likelihood-estimated dispersion parameter. ‘Exposure’ will be the number of hours wearing the sensor for CGM-derived outcomes and total number of days enrolled in the study for non-CGM-derived outcomes.

To assess the cost effectiveness of the intervention, the ‘cost per quality of life year (QALY)’ will be calculated using an incremental cost effectiveness ratio.

All hypothesis testing will be two-sided with an a of 0.05. No corrections for multiplicity are planned to control Type I error; rather, the effectiveness of the intervention will be assessed based on the clearly specified primary outcome; secondary outcomes are exploratory in nature and will be labelled as such in publications arising from the study.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Participant recruitment difficulties
Other reasons/comments
Other reasons
- Delays in acquiring Governance approval, timely availability of investigational pumps and COVID resulted in delay in commencement of the feasibility study (ACTRN12622000455763).
- Availability of closed loop systems in the younger age group and Medtronic initiative to upgrade all users to 780G pumps lead to longer recruitment period for the feasibility study and has impacted the viability of the RCT
- A European study, with similar protocol, is currently underway
Date of first participant enrolment
Anticipated
1/09/2022
Actual
Date of last participant enrolment
Anticipated
31/08/2023
Actual
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
70
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA,VIC
Recruitment hospital [1] 19392 0
Perth Children's Hospital - Nedlands
Recruitment hospital [2] 19393 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 19394 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [4] 19395 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 33971 0
6009 - Nedlands
Recruitment postcode(s) [2] 33972 0
3052 - Parkville
Recruitment postcode(s) [3] 33973 0
5006 - North Adelaide
Recruitment postcode(s) [4] 33974 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 308566 0
Charities/Societies/Foundations
Name [1] 308566 0
Juvenile Diabetes Research Foundation (JDRF) Australia
Country [1] 308566 0
Australia
Funding source category [2] 310605 0
Commercial sector/Industry
Name [2] 310605 0
Medtronic Diabetes
Country [2] 310605 0
United States of America
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] 309419 0
None
Name [1] 309419 0
Address [1] 309419 0
Country [1] 309419 0
Other collaborator category [1] 282136 0
Hospital
Name [1] 282136 0
Women's and Children's Hospital
Address [1] 282136 0
Endocrinology & Diabetes Centre
Women's and Children's Hospital
72 King William Road
North Adelaide, SA 5006
Country [1] 282136 0
Australia
Other collaborator category [2] 282137 0
Hospital
Name [2] 282137 0
Royal Children's Hospital
Address [2] 282137 0
MCRI, East Level 5
Diabetes Research
The Royal Children's Hospital
50 Flemington Road
Parkville, VIC 3052
Country [2] 282137 0
Australia
Other collaborator category [3] 282138 0
Hospital
Name [3] 282138 0
The Children's Hospital Westmead
Address [3] 282138 0
Institute of Endocrinology and Diabetes
The Children's Hospital at Westmead
Cnr Hawkesbury Rd and Hainsworth St
Locked Bag 4001
Westmead, NSW 2145
Country [3] 282138 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308509 0
Child and Adolescent Health Service HREC
Ethics committee address [1] 308509 0
Perth Children’s Hospital
15 Hospital Avenue
Nedlands WA 6009
Ethics committee country [1] 308509 0
Australia
Date submitted for ethics approval [1] 308509 0
19/05/2020
Approval date [1] 308509 0
11/12/2020
Ethics approval number [1] 308509 0
RGS0000003688

Summary
Brief summary
This study will explore the hypothesis that the advanced HCL (AHCL) system will reduce the glycaemic variability and thereby improve the glycaemic outcomes of children and improve the wellbeing of parents/caregivers.
This proposed study is a 3-month multicentre randomised controlled study in children aged 2 to 7 years with Type 1 Diabetes (T1D) on insulin pump therapy. The participants will be randomly assigned to two groups: control group on standard therapy and the intervention group on AHCL system in the Medtronic 780G pumps.
The primary objective is to compare the proportion of time in target range (sensor glucose 3.9-10mmol/l) in young children with T1D while using AHCL or standard insulin pump therapy. The secondary aims are to determine the effect of AHCL on hypoglycaemia and hyperglycaemia and to determine the psychological and social well-being of caregivers compared to standard care.
The age of the participants means that this is placed in a category more than low risk although the level of parental supervision at this age and the use of a system that allows 24/7 glucose monitoring in reality more than mitigates this theoretical consideration. There are no potential ethical issues in the proposed study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110950 0
Prof Timothy W Jones
Address 110950 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 110950 0
Australia
Phone 110950 0
+61 864565033
Fax 110950 0
Email 110950 0
[email protected]
Contact person for public queries
Name 110951 0
Miss Julie Dart
Address 110951 0
Telethon Kid's Institute
Northern Entrance
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 110951 0
Australia
Phone 110951 0
+61 864564608
Fax 110951 0
Email 110951 0
[email protected]
Contact person for scientific queries
Name 110952 0
Dr Mary Abraham
Address 110952 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands WA 6009
Country 110952 0
Australia
Phone 110952 0
+61 864565027
Fax 110952 0
Email 110952 0
[email protected]

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 bodies, JDRF and Medtronic Diabetes, 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 July 2023 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 [email protected]. Guidelines for application will be made available closer to study completion.


What supporting documents are/will be available?




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.