Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000605099
Ethics application status
Approved
Date submitted
15/06/2010
Date registered
26/07/2010
Date last updated
10/11/2021
Date data sharing statement initially provided
10/11/2021
Date results information initially provided
10/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized controlled trial comparing the impact of continuous subcutaneous insulin infusion (CSII) therapy and multiple daily injection (MDI) regimens upon indices of behaviour, cognition and glycaemia in children and adolescents with type 1 diabetes.
Scientific title
A randomized controlled trial comparing the impact of continuous subcutaneous insulin infusion (CSII) therapy and multiple daily injection (MDI) regimens upon indices of behaviour, cognition and glycaemia in children and adolescents with type 1 diabetes.
Secondary ID [1] 252028 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 diabetes 257573 0
Condition category
Condition code
Metabolic and Endocrine 257741 257741 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Continuous subcutaneous insulin infusion (CSII) (also known as Insulin pump therapy) - this is a commonly employed means of intensive insulin therapy and routine clinical practices in the management of patients on CSII will be employed in this study. CSII uses a mechanical device to continuously deliver insulin subcutaneously with additional patient activated 'boluses' being administered intermittently over the course of the day to cover food and to correct hyperglycaemia. Insulin delivery settings for participants in this study will be individualised and adjusted based on blood glucose levels as is routine clinical practice.

All participants in this study will be recruited from the waiting list for commencement of CSII at their diabetes centre. This means they will already have been assessed as being suitable and willing candidates for CSII. At baseline, all participants in this study will be using multiple daily injections of insulin, giving individualised doses as prescribed by their diabetes team. Following baseline investigations, participants will be randomly assigned (1:1) to either commence CSII (the intervention group) or continue on multiple daily injections of insulin (the control / comparator group) for the 4 month study period. Those assigned to CSII will be started on this modality within one month of randomisation and continue on CSII thereafter. Commencement of CSII will follow standard practices at the diabetes centres involved in the study - this involves 1.5 days of intensive education around the pronciples of CSII and its use. Thereafter, patients will have standard diabetes care, which comprises routine outpatient assessemtns (3-4 monthly as is standard) and intermittent patient-initiated contact with the diabetes team to adjust insulin delivery settings. After 4 months of their assigned therapy, all participants will have repeat investigations. Participants in the MDI group will thereafter be commenced on CSII (since all were recruited from the CSII waiting list and therefore this was their intention).
Intervention code [1] 256666 0
Treatment: Devices
Intervention code [2] 256667 0
Treatment: Drugs
Comparator / control treatment
Multiple daily injections of insulin (MDI) - this is the alternative commonly employed means of intensive insulin therapy to CSII.
MDI regimens comprise up to 5 injections of insulin / day which include background / basal insulin (once or twice daily) and short/rapid acting insulin with meals (3-4/day). All patients recruited to this study will be using MDI prior to the study and so additional education will not be necessary for this study group.
Doses are individualised based on individual blood glucose profiles - this dose adjustment is done routinely at outpatient clinic visits (which occur 3-4 monthly as a routine and will not be scheduled more frequently for this study) or in response to patient-initiated calls to the diabetes team. This is standard diabetes care at the diabetes centres involved and this process will continue throughout this study.

As outlined above, following baseline investigations, participants will be randomly assigned (1:1) to either commence CSII (the intervention group) or continue on multiple daily injections of insulin (the control / comparator group) for the 4 month study period. After 4 months of their assigned therapy, all participants will have repeat study investigations. Participants in the MDI group will thereafter be commenced on CSII (since all were recruited from the CSII waiting list and therefore this was their intention).
Control group
Active

Outcomes
Primary outcome [1] 258624 0
Parental report of behaviour on the Behaviour Assessment System for Children- Second Edition (BASC-2) questionnaire
Timepoint [1] 258624 0
measured at 4 months.
Secondary outcome [1] 264564 0
Self-report and teacher-report of externalising behaviour
Timepoint [1] 264564 0
at 4 months
Secondary outcome [2] 264565 0
Parental, self and teacher report of internalising behaviour
Timepoint [2] 264565 0
at 4 months
Secondary outcome [3] 264566 0
Cognitive assessments.

Cognitive assessments will comprise the standardised and commonly used cognitive tests listed below. These will be administered at baseline and end of study (by a trained research psychologist).
Alternative versions will be used at each time point to eliminate any bias from 'practise-effects'.

Vocabulary will be assessed using: Vocabulary measure from Wechsler Intelligence Scale for Children's Fourth Edition(WISC-1V) and an alternate version from the Wechsler Abbreviated Scale of Intelligence (WASI).
Perceptual reasoning will be assessed using: Block design (WISC-IV) and an alternative version from WASI.
Immediate attention span will be assessed using: Digit span subtest (WISC-IV). Alternative version from Children's Memory Scale (CMS).
Selective attention, divided attention and sustained attention will be assessed using TEA-Ch. TEA-Ch is a standardised test of attention, with different subtests from the overall test measuring different aspects of attention e.g sustained attention, divided attention etc. Alternative versions are available within this test instrument.
Cognitive flexibility will be assessed using the Contingency Naming test.
Concept formation will be assessed using the Verbal fluency test of the Delis-Kaplan Executive Function System (DKEFS).
Organisation will be assessed using the Rey complex figure.
Working memory will be assessed using Letter number sequencing from WISC-IV.
New learning will be assessed using Paired associative learning.
Timepoint [3] 264566 0
at 4 months
Secondary outcome [4] 264567 0
Glycated haemoglobin (HbA1c). This will be recorded at baseline and at the end of study by capillary blood sampling. Measurement will be by High Performance Liquid Chromatography using the Bio-Rad D-10TM Haemoglobin Testing System (Bio-Rad Laboratories Inc., Hercules, CA, USA). A 5 microlitre capillary blood sample is required to perform the analysis. Normal (non-diabetic) reference range for HbA1c assessed using this method is quoted at 4.5-5.7%.
Timepoint [4] 264567 0
at 4months
Secondary outcome [5] 264568 0
Indices of glycaemia as calculated using data collected over a 6 day period of continuous glucose monitoring (CGM).

The continuous glucose monitoring system uses a glucose oxidase sensor that is inserted subcutaneously and records interstitial glucose levels every 5 minutes for up to 6 days. The wearer does not have access to the data in real-time as they can only be downloaded from the device at the end of the 6 day period. Each participant will wear a CGM device for 6 days at baseline (prior to randomisation) and again at the end of the 4 month trial period.

Indices assessed will include:
Percent time in target range (4.0-10.0 mmol/l)
Percent time in hyperglycaemic range (>10.0 mmol/l)
Percent time in hypoglycaemic range (<4.0 mmol/l)
Glycaemic variation as measured by continuous overlapping net glycaemic action CONGA).

Percent time in various glycaemic categories (target, hyperglycaemic, or hypoglycaemic) will be assessed by calculating the sum of the time in minutes spent in each range over the 6 day trace as a percentage of the total time recorded.


Glycaemic variation will be assessed using CONGA, a measurement tool specifically designed by statisticians and clinicians at the Royal Children's Hospital Melbourne to assess the variation of CGM-derived data over various time intervals (e.g 1 hour, 4 hours etc). This measurement is described in detail in the following reference:
A novel approach to continuous glucose analysis utilizing glycemic variation.
Diabetes Technol Ther. 2005 Apr;7(2):253-63.
McDonnell CM, Donath SM, Vidmar SI, Werther GA, Cameron FJ.
Timepoint [5] 264568 0
at 4 months

Eligibility
Key inclusion criteria
Youth aged 9-15.5 years with type 1 diabetes mellitus. Most children younger than 9 are unable or unwilling to use an MDI regimen, as this involves a lunchtime injection of insulin at school, which can be practically difficult for young children. Sixteen is the older end of the validated age range for the selected cognitive tests employed; therefore adolescents recruited at 15.5y will still be <16y at the end of study.

Naïve to CSII therapy

Currently using MDI regimen for at least 1 month duration

Previously assessed as suitable for CSII (by their own diabetes physician and care team) and already on the waiting list to commence CSII at their institution. This inclusion criterion is necessary as not all youth will be willing or deemed suitable to commence CSII (e.g. if not performing self monitoring of blood glucose levels at least 4 times / day).

Have access to an insulin pump device through private health insurance, self-pay or local loan scheme
Minimum age
9 Years
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Non-English speaking (as behavioural questionnaires and cognitive tests are conducted in English)

Co-existent developmental delay or pervasive neurological disorders such as autism that would interfere with a participant’s ability to perform psychometric testing

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)
Eligible patients will be identified using department records from the diabetes clinic (CSII waiting list and database records of current insulin regimen) at each site. All eligible participants will be invited to take part in the project. Potential participants will be approached either in person or by telephone and the project will be verbally explained to them by a member of the research team at each site. Individuals who express interest in learning more about the project will be provided with a written participant information statement that will explain the project in detail and formally invite individuals to participate. A corresponding parent/guardian information statement will also be supplied.
Patients (and their parents/guardians) agreeing to participate will be asked to sign an informed consent form indicating that they understand the aims and procedures involved in the project. The signed consent form will also indicate that by agreeing to take part they are aware that they will be randomly assigned to either study group. Randomisation will be performed using a computer generated randomisation schedule with participant allocation using sealed envelope which will be supplied by the Clinical Epidemiology and Biostatistics Unit (CEBU) at the Royal Children's Hospital (RCH), Melbourne.
Once recruited, all participants will have baseline assessments of glycaemia, behaviour and cognition. Thereafter, each participant will be randomised into one of the 2 study groups for the duration of the study; starting CSII or continuing MDI. Participants randomised to MDI will be offered CSII after the end of the study (4 months).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using a computer generated randomisation schedule with participant allocation using sealed envelope which will be supplied by the Clinical Epidemiology and Biostatistics Unit (CEBU) at the Royal Children's Hospital (RCH), Melbourne. These sealed envelopes will be sent to each site by a biostatistician (Dr K Lee of CEBU) who will not be directly involved in the medical care of any participants in the study. To ensure the study is balanced across both sites, randomisation will be stratified by site, with the expectation that each site will recruit approximately half of the participants. Following completion of baseline investigations, participants will be assigned a site-specific study number in chronological order within each site. Each envelope will be marked with a study number and will contain the study group allocation (as randomly assigned by the computer generated schedule) for the participant allocated that number.
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

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/08/2010
Actual
4/10/2010
Date of last participant enrolment
Anticipated
Actual
2/10/2014
Date of last data collection
Anticipated
Actual
27/05/2016
Sample size
Target
110
Accrual to date
Final
101
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 257139 0
Charities/Societies/Foundations
Name [1] 257139 0
Australian Diabetes Society (ADS) Servier Grant 2009
Country [1] 257139 0
Australia
Funding source category [2] 257340 0
Government body
Name [2] 257340 0
NHMRC Centre of Clinical Research Excellence in Clinical Science in Diabetes
Country [2] 257340 0
Australia
Primary sponsor type
Hospital
Name
The Royal Children's Hospital Melbourne
Address
Flemington Road, Parkville, Vic 3052
Country
Australia
Secondary sponsor category [1] 256399 0
None
Name [1] 256399 0
Address [1] 256399 0
Country [1] 256399 0
Other collaborator category [1] 1319 0
Hospital
Name [1] 1319 0
The Children's Hospital at Westmead
Address [1] 1319 0
Cnr Hawkesbury Rd and Hainsworth St, Westmead, NSW. Postal address: Locked Bag 4001, Westmead 2145
Country [1] 1319 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259175 0
The Royal Children's Hospital
Ethics committee address [1] 259175 0
Flemington Road, Parkville, Vic 3052
Ethics committee country [1] 259175 0
Australia
Date submitted for ethics approval [1] 259175 0
19/04/2010
Approval date [1] 259175 0
09/07/2010
Ethics approval number [1] 259175 0
30043

Summary
Brief summary
Studies have also shown that children with Type 1 diabetes mellitus (T1DM) have much higher rates of problems with behaviour and cognition (learning, understanding, attention, memory etc) which can affect their health and quality of life. In particular, youth who have more problems with behaviours such as aggression and conduct (called ‘externalising’ behaviours) have been shown to have much higher rates of poorer mental health outcomes and poor long-term diabetes control.
It is known that despite having regular insulin injections, individuals with T1DM can have large swings in blood glucose levels (from very high to very low or vice versa) over the course of a day. These high and low levels of glucose not only give rise to uncomfortable symptoms, but have also been shown to result in an increase in externalising behaviours and impaired mental functioning.
‘Intensive insulin therapy’ regimens involve either multiple daily injections (MDI) of insulin or continuous subcutaneous insulin infusion (CSII) using an insulin pump. These regimens aim to better mimic the work of the pancreas and therefore to reduce the large swings in glucose found in T1DM. A previous study that followed up 32 youth who commenced use of CSII showed significant improvements in their scores of behaviour & cognition after 6-8 wks. Improvements in behaviour have persisted to 2 years in those using CSII. Of note however, there was no control group in this pilot study and so results can not be generalised. If however, similar results were found when comparing CSII and MDI, then CSII would offer additional health and wellbeing benefits for youth with T1DM.
The aim of this randomised controlled trial is to assess whether, in a group of youth already using MDI, commencement and continued use of CSII results in improvements in indices of behaviour and cognition, and if so, whether these changes are as a result of improved glucose profiles. The study will run at both the Royal Children’s Hospital Melbourne (VIC) and the Children’s Hospital Westmead, (NSW). Children and adolescents aged 9-16 years who are on the waiting list to commence CSII (i.e willing to use CSII and assessed by the diabetes team as capable of doing so) will be invited to participate. Assessments performed will include standardised behaviour questionnaires and cognitive tests (supervised and scored by a trained psychologist) as well as 6 days of continuous glucose monitoring (using a probe inserted under the skin which continuously records glucose measurements) and HbA1c (a standard monitoring test of glucose control).
Following baseline assessments, 110 youth will be randomly assigned to either continue MDI or to commence and continue CSII. All participants will then have standard diabetes care until assessments are repeated at the end of a 4month period. Differences between outcomes in the 2 study groups at 4 months will be compared. Between group difference in scores of externalising behaviour at 4 months is the primary outcome of interest. Differences in scores of mood, cognition and markers of glucose control at 4 months are secondary outcomes of interest. Since all participants will be recruited from the CSII waiting list, at the end of the 4 month study period, those randomised to continue MDI will be commenced on CSII.
Trial website
Trial related presentations / publications
International Society for Pediatric and Adolescent Diabetes, Innsbruck, Austria, Oct 2017. Oral Presentations entitled: (i) Is insulin pump therapy associated with longer-term improvement in behaviour, mood and glycaemia in children and adolescents with Type 1 diabetes?
Public notes

Contacts
Principal investigator
Name 31294 0
Address 31294 0
Country 31294 0
Phone 31294 0
Fax 31294 0
Email 31294 0
Contact person for public queries
Name 14541 0
Dr Michele O'Connell
Address 14541 0
Department of Endocrinology and Diabetes,
The Royal Children's Hospital Melbourne, Flemington Road,
Parkville, Vic 3052
Country 14541 0
Australia
Phone 14541 0
+61 3 9345 5951
Fax 14541 0
+61 3 9347 7763
Email 14541 0
[email protected]
Contact person for scientific queries
Name 5469 0
Dr Michele O'Connell
Address 5469 0
Dept of Endocrinology and Diabetes,
The Royal Children's Hospital Melbourne, Flemington Road,
Parkville, Vic 3052
Country 5469 0
Australia
Phone 5469 0
+61 3 9345 5951
Fax 5469 0
Email 5469 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
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.