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Trial registered on ANZCTR


Registration number
ACTRN12624001025527
Ethics application status
Approved
Date submitted
12/06/2024
Date registered
23/08/2024
Date last updated
5/10/2024
Date data sharing statement initially provided
23/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Redefining Glucose thresholds for Hypo Treatment in Children with Type 1 Diabetes on Closed loop Therapy
Scientific title
Redefining Glucose Thresholds for Hypoglycaemia Management in Children with Type 1 Diabetes on Closed Loop Therapy: A Cross-over Clinical Trial
Secondary ID [1] 312269 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 333985 0
Condition category
Condition code
Metabolic and Endocrine 330650 330650 0 0
Diabetes
Public Health 330818 330818 0 0
Health service research

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study aims to determine if reducing the cut-off of initiating treatment will be an acceptable hypoglycaemia threshold and will not be associated with an increase in time spent in hypoglycaemia <3.0 mmol/L with worsening of glycaemic outcomes.

A two-treatment, two-period cross-over randomised controlled non-inferiority trial design will be used. Participants will be randomised to sequence A (‘Standard Hypo Rx First’), or sequence B (‘Revised Hypo Rx First’).
‘Standard Hypo Rx First’ participants will use the standard hypo treatment (i.e. Hypoglycaemia treatment initiated with glucose level <3.9 mmol/L) for 4 weeks (Period 1) after which they will switch to revised hypo treatment plan for 4 weeks (Hypoglycaemia treatment initiated at lower revised threshold of less than or equal to 3.6 mmol/L) (Period 2). The revised hypo treatment plan will consist of the same hypo treatment as clinically recommended (i.e. 10-15g of fast-acting carbohydrates, or 5.0-7.5g of fast-acting carbohydrates if on closed loop therapy) and does not change between the two arms.
‘Revised Hypo Rx First’ participants will start with revised hypo treatment plan for 4 weeks (Period 1) and cross over to standard hypo Rx plan for 4 weeks (Period 2). The 4-week duration is chosen to capture adequate number of hypoglycaemic episodes. Most children are expected to experience at least 2 or more episodes per week.
There will be a wash-out phase of at least 2 weeks to prevent carryover effects.
Participants will be randomised to one of the two treatment sequences using https://sealedenvelope.com/ into a) Standard Hypo Rx First’ or b) Revised Hypo Rx First’.
All participants will receive weekly review with email/phone calls by our team to ensure adherence and address any concerns or questions participants may have. If time spent <3.0 mmol/L has doubled from baseline and/or is >1%, research staff (doctor and research diabetes educator) will review the participant to ensure 1) if they are ‘true’ hypoglycaemic events 2) explore the reason if ‘true’ hypoglycaemic.
Adherence to hypo management will be monitored using a participant Logbook that asks for the date and time the hypo occurred, the glucose level (in mmol/L), the amount of carbohydrates given as treatment, and whether they are in the revised or standard treatment plan arms at the time of the hypo occurring.
Potential participants will be identified from the Western Australian Children’s Diabetes Database by a Child and Adolescent Health Service employee and invited via email to partake in this study. Participants must attend the Diabetes Clinics at Perth Children’s Hospital to be eligible.
Intervention code [1] 328726 0
Treatment: Other
Comparator / control treatment
As this is a cross-over randomised control study, the intervention participants will be their own control. The ‘Standard Hypo Rx First’ arm/study period will be acting as the control/comparator.
Control group
Active

Outcomes
Primary outcome [1] 338465 0
Time spent in hypoglycaemia <3.0 mmol/l
Timepoint [1] 338465 0
During the 10-week period (4 weeks intervention, 2 weeks washout, 4 weeks standard)
Secondary outcome [1] 436048 0
Time in range 3.9-10.0 mmol/l
Timepoint [1] 436048 0
During the 10-week period (4 weeks intervention, 2 weeks washout, 4 weeks standard)
Secondary outcome [2] 436049 0
Time spent in hyperglycaemia >10.0 mmol/l
Timepoint [2] 436049 0
During the 10-week period (4 weeks intervention, 2 weeks washout, 4 weeks standard)
Secondary outcome [3] 436050 0
Time spent in hyperglycaemia >13.9 mmol/l
Timepoint [3] 436050 0
During the 10-week period (4 weeks intervention, 2 weeks washout, 4 weeks standard)
Secondary outcome [4] 436051 0
Participant’s acceptability of revised hypoglycaemia cut-off
Timepoint [4] 436051 0
At the end of the 10 weeks of study participation

Eligibility
Key inclusion criteria
1. Diagnosis of Type 1 diabetes
2. 6 to 18 years
3. Duration of diabetes of >12 months
4. On advanced closed loop therapy
4.1 for at least 4 weeks and
4.2 using the system optimally for >80% in last 2 weeks.
Minimum age
6 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Impaired hypoglycaemia awareness. Self-reported Gold score greater than or equal to 4 (these patients need higher glucose targets). For young children (age 6 to 10 years or if the child is developmentally young to self-report), parent-reported response will be used.
2. Increased time spent in hypoglycaemia as documented on CGM (>2% of time spent <3.0 mmol/L and/or >6% of time spent <3.9 mmol/L) for last two weeks
3. Families not willing to try lower cut-off due to fear of hypoglycaemia.
4. Severe hypoglycaemia (coma, convulsion or altered consciousness requiring third party assistance) in last 12 months.
5. Any medical or psychological disease state of the child and/or caregiver that limits capacity to participate in the study.

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)
Participants will be randomised to one of the two treatment sequences using https://sealedenvelope.com/ into a) 'Standard Hypo Rx First’ or b) 'Revised Hypo Rx First’.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A non-inferiority limit was identified based on discussions with clinicians and was set at a 75% increase in time spent in hypoglycaemia. This equates to a difference of 0.56 in the log-transformed time <3.0 mmol/L.
A sample of 36 participants would provide over 90% power for the boundary of a one-sided 97.5% confidence interval (one sided alpha of 0.025) to fall below the non-inferiority limit of 0.56. Allowing for 10% drop-out, we will recruit 40 participants.

The primary analysis will assess the difference in time spent in clinically significant hypoglycaemia (<3.0 mmol/L) between the ‘standard hypo Rx’ and ‘revised hypo Rx’ conditions measured over four weeks. A linear mixed model including terms for treatment, period and sequence will be conducted on the log-transformation of ‘time spent < 3.0 mmol/L’. The ‘treatment’ effect along with 95% confidence intervals will be produced. To demonstrate non-inferiority, the lower limit of the one-sided 95% confidence interval must fall below the pre-specified non-inferiority limit.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
21/10/2024
Actual
Date of last participant enrolment
Anticipated
30/04/2025
Actual
Date of last data collection
Anticipated
31/07/2025
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 26664 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 42703 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 316654 0
Charities/Societies/Foundations
Name [1] 316654 0
Perth Children's Hospital Foundation
Country [1] 316654 0
Australia
Primary sponsor type
Hospital
Name
Perth Children's Hospital
Address
Country
Australia
Secondary sponsor category [1] 318906 0
None
Name [1] 318906 0
Address [1] 318906 0
Country [1] 318906 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315433 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 315433 0
[email protected]
Ethics committee country [1] 315433 0
Australia
Date submitted for ethics approval [1] 315433 0
28/11/2023
Approval date [1] 315433 0
29/11/2023
Ethics approval number [1] 315433 0
RGS0000006405

Summary
Brief summary
Hypoglycaemia (hypo) education is provided at the time of type 1 diabetes diagnosis and knowledge reviewed in the clinic as required. The current threshold for initiating hypo treatment at glucose level < 3.9 mmol/L is on expert opinion, rather than evidence based, which was chosen to avoid glucose levels from dropping even further (<3.0 mmol/L), considered as significant hypoglycaemia below which neurocognitive decline occurs. However, it needs to be appreciated that levels between 3.0 and 3.9 mmol/L are considered as normal in healthy individuals with no diabetes. With the availability of continuous glucose monitoring (CGM) and closed loop therapy as standard care in management of T1D, there is ability to support lower glucose thresholds for treatment as basal insulin delivery is suspended with prediction of a hypo. This will avoid overtreatment of hypos and resultant high glucose levels.
The study aims to determine if reducing the cut-off of initiating treatment will be an acceptable hypo threshold and will not be associated with an increase in time spent in hypos <3.0 mmol/L with worsening of glycaemic outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134686 0
Dr Mary Abraham
Address 134686 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009
Country 134686 0
Australia
Phone 134686 0
+61 8 6456 5027
Fax 134686 0
Email 134686 0
[email protected]
Contact person for public queries
Name 134687 0
Dr Mary Abraham
Address 134687 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009
Country 134687 0
Australia
Phone 134687 0
+61 8 6456 5027
Fax 134687 0
Email 134687 0
[email protected]
Contact person for scientific queries
Name 134688 0
Dr Mary Abraham
Address 134688 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009
Country 134688 0
Australia
Phone 134688 0
+61 8 6456 5027
Fax 134688 0
Email 134688 0
[email protected]

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?

No Supporting Document Provided



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.