Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001454763
Ethics application status
Approved
Date submitted
8/11/2022
Date registered
14/11/2022
Date last updated
30/08/2023
Date data sharing statement initially provided
14/11/2022
Date results information initially provided
30/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The Co-Pilot trial: Closed loop in children and youth with type 1 diabetes and high-risk glycaemic control
Scientific title
Effect of advanced automated insulin delivery on glycaemia in children and young adults with type 1 diabetes and high-risk glycemic control
Secondary ID [1] 308363 0
0004-AHCL
Universal Trial Number (UTN)
U1111-1284-8452
Trial acronym
Co-Pilot
Linked study record
This record is a follow-up study of ACTRN12621000556842.

Health condition
Health condition(s) or problem(s) studied:
Type 1 diabetes 328155 0
Condition category
Condition code
Metabolic and Endocrine 325212 325212 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a 3-month randomized controlled trial (RCT) followed by a 9-month extension phase investigating advanced hybrid closed loop (AHCL) in children and youth with type 1 diabetes (T1D) and high-risk glycaemic control that have previously not been using closed loop therapy. Following baseline assessments of blinded continuous glucose monitoring (CGM) for 21 days (using Guardian 3 sensor and transmitter CGM system), participants will be randomized to AHCL use (intervention group) or their usual diabetes management care (control group). The intervention group will undergo a run-in period of 72 hours running as sensor augmented pump (SAP) with predictive low glucose monitoring (PLGM) to allow subjects to familiarize with the system and for control to be optimized, and will then enter into a 3-month study period of using the insulin pump in its trial settings in Auto mode. All participants will use the AHCL system in Auto mode for a further 9 months during the extension phase. While participants have the option to enable/disable Auto mode during the RCT and extension phase, the AHCL system provides optimal results in Auto mode and therefore participants are encouraged to keep the system in Auto mode during the study. Expected duration of subject participation is 13 months (21 days baseline assessments, 3 days run-in, 3 months RCT, 9 months extension).
The study intervention is the Medtronic MiniMed™ 780G AHCL insulin pump running in AHCL mode. In use with the continuous glucose monitoring (CGM) components (Guardian 4 Sensor and Guardian 4 transmitter, and Medtronic's newest Synergy CGM system), the MiniMed™ 780G AHCL pump is capable of continuous insulin delivery at set and variable rates, and the monitoring of glucose levels via a sensor that is inserted in the interstitial fluid under the skin, including the detection of possible low or high blood glucose episodes. The pump also displays glucose values, storing this data so that it can be retrospectively analysed. The MiniMed™ AHCL insulin pump also includes the closed loop algorithm as part of the SmartGuard™ collection of features. SmartGuard™ is comprised of Manual Mode Low Management, which includes the Suspend On Low feature (suspends insulin delivery when a pre-set low sensor glucose [SG] threshold is reached), the Suspend Before Low feature (enables insulin to suspend 30 minutes before a pre-set low SG threshold is reached) and Auto Mode (hybrid closed loop) feature. The pump can also be used as a simple pump without CGM or as a SAP without use of the SmartGuard™ features. When Auto Mode is enabled, the sensor glucose values (SGVs) received by the pump from the CGM system will be used to automatically calculate the required insulin dose. It will then deliver insulin to the patient, at five-minute intervals, to achieve glycaemic control. With the AHCL system, subjects must still deliver bolus insulin for meals. In addition, the setting for active insulin must be programmed. Basal rates are set for periods of open loop therapy. When Auto Mode is not enabled, the user may use the Smart Guard™ Low Management features. Here, basal rate delivery will be suspended either when the SG has reached a programmed low threshold (Suspend on Low) or before the SGV has reached the programmed low threshold (Suspend before Low).
At the start of the RCT, participants randomized to intervention group will receive face-to-face education at the study site by trained study staff (research nurses with diabetes knowledge who are insulin pump education specialists) based on the manufacturer's user guides. The initial educational session will take approximately 5-6 hours, including the device set-up of the pump. Participants’ pump data will be automatically uploaded to CareLinkTM through the MiniMed™ Clinical mobile phone app, which will be installed on participants’ phones and is connected with the pump via Bluetooth. The app uploads data every 24 hours into the cloud, where study staff can review the data and give feedback to refine pump settings if necessary. These refinements are personalised based on the participant’s uploaded data and will happen after each review of the uploaded pump data. Remote reviews will happen daily for 7 days after initiation of AHCL, then weekly for 6 weeks, then monthly until the end of the RCT phase. During the extension phase, remote reviews will be performed every 2 months. Personalised pump setting changes/refinements can be insulin basal rates and insulin-to-carbohydrate-ratios, if required, and will be verified by the investigative staff by way of electronic review of the pump upload with the new settings.
Intervention code [1] 324812 0
Treatment: Devices
Comparator / control treatment
The control group will continue their usual diabetes therapy during the 3-month RCT period (multiple daily injection therapy or continuous subcutaneous insulin infusion therapy) and will undergo 2 weeks of blinded CGM (Guardian 3 sensor and transmitter CGM system) at the end of the RCT phase (weeks 11-13). At the end of the 3-month RCT, the control group will cross over to AHCL use and follow the same schedule as the intervention group previously. Participants randomized to the control group will receive the same personalized therapy review and support schedule as the intervention group during the 3-month RCT, will undergo device training and the same educational sessions as described above at the start of the extension phase, and will use the AHCL system for a duration of 9 months during the extension phase.
Control group
Active

Outcomes
Primary outcome [1] 333049 0
Glycaemic control as measured by glycated hemoglobin (HbA1C) from blood samples.
Timepoint [1] 333049 0
At baseline, at 3 months post-RCT commencement (primary endpoint), and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [1] 415617 0
Glycaemic control as measured by percentage of time in range (3.9 – 10mmol/L), by way of CGM data analysis.
Timepoint [1] 415617 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [2] 415618 0
Glycaemic outcomes via CGM data for % CGM time below 3.0mmol/L
Timepoint [2] 415618 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [3] 415619 0
Glycaemic outcomes via CGM data for % CGM time below 3.9mmol/L
Timepoint [3] 415619 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [4] 415620 0
Glycaemic outcomes via CGM data for % CGM time above 10.0mmol/L
Timepoint [4] 415620 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [5] 415621 0
Glycaemic outcomes via CGM data for % CGM time above 13.9mmol/L
Timepoint [5] 415621 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [6] 415622 0
Glucose levels during the day (0600-2359 hours), determined from CGM data.
Timepoint [6] 415622 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [7] 415623 0
Glucose levels during the night (0000-0559 hours), determined from CGM data.
Timepoint [7] 415623 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [8] 415624 0
Safety of AHCL system, as determined by occurrence of episodes of diabetic ketoacidosis from participant self-reports and data linkage to medical records.
Timepoint [8] 415624 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [9] 415625 0
Safety of AHCL system, as determined by occurrence of episodes of severe hypoglycaemia defined as coma or convulsion requiring assistance from others, from participant self-reports and data linkage to medical records.
Timepoint [9] 415625 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [10] 415626 0
Qualitative interview-based assessment of participant experience using AHCL. Semi-structured, one-on-one interviews with trained members of the study team will be conducted face-to-face in private clinic rooms, or via videoconference (Zoom). Interviews will take approximately 45-60 minutes, will be digitally recorded and transcribed verbatim.
Timepoint [10] 415626 0
After 13 weeks of pump use in Auto mode
Secondary outcome [11] 415627 0
The change in fear of hypoglycaemia as measured by the Hypoglycaemia Fear Survey (HFS)
Timepoint [11] 415627 0
At baseline, and at 3 months post-RCT commencement.
Secondary outcome [12] 415628 0
The change in diabetes treatment satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire-status (DTSQs)
Timepoint [12] 415628 0
At baseline, at 3 months post-RCT commencement.
Secondary outcome [13] 415629 0
The change in sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI)
Timepoint [13] 415629 0
At baseline, at 3 months post-RCT commencement.
Secondary outcome [14] 415630 0
The change in feelings towards automated insulin dosing systems as measured by the INSPIRE survey.
Timepoint [14] 415630 0
At baseline, at 3 months post-RCT commencement.
Secondary outcome [15] 415631 0
Platform performance as measured by percentage of time spent in automode, determined by accessing device analytics via the CareLinkTM software.
Timepoint [15] 415631 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [16] 415633 0
Platform performance as measured by percentage of time of sensor wear, determined by accessing device analytics via the CareLinkTM software.
Timepoint [16] 415633 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.
Secondary outcome [17] 415634 0
Platform performance as measured by percentage of insulin delivery distribution, determined by accessing device analytics via the CareLinkTM software.
Timepoint [17] 415634 0
At baseline, at 3 months post-RCT commencement, and at 3, 6, and 9 months post-extension phase commencement.

Eligibility
Key inclusion criteria
1. Male or female aged 7 – 25 years inclusive.
2. Type I diabetes as per the American Diabetes Association Classification, diagnosed at least 1 year prior to Study Day 1.
3. Current HbA1c level of greater than or equal to 8.5% (69mmol/mol).
4. Minimum daily insulin requirement of greater than or equal to 8 units of insulin/day.
5. Willing and able to adhere to the study protocol.
6. Access to the internet and a computer system that meets requirements for uploading the study pump.
Minimum age
7 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous use of closed loop technology prior to Baseline visit.
2. Previous significant adverse event at investigator discretion that precludes the participant safely using advanced diabetes technology/sensors e.g., unable to wear glucose sensors due to prior cutaneous adverse events.
3. Use of a medication indicative of moderate/severe diabetes complications (ACE inhibitors and statins are permitted).
4. Use of systemic glucocorticoids within 2 weeks prior to the Baseline visit.
5. Current use of Metformin, SGLT-2 or GLP-1 medications.
6. History or current evidence of severe psychiatric disorder, uncontrolled seizure disorder, renal impairment or cardiovascular disease (including uncontrolled hypertension), that in the opinion of the Investigator would limit study involvement or be a safety issue.
7. For diabetic retinopathy (DR) or other visual impairment, the following criteria apply:
A. Nil or Minimal retinopathy (less than or equal to R1/M1) – no restriction on study entry. To follow established ISPAD screening guidelines as below.
B. If Grade 1 / Mild retinopathy (R2/M2) and HbA1c less than 10% (86mmol/mol) – no restriction to study entry.
C. If Grade 1 / Mild retinopathy (R2/M2) and HbA1c equal to or greater than 10% (86mmol/mol) – DR screening to be performed during the study pre-screening phase (not greater than 4 weeks prior to initiation of blinded CGM). If subject remains at Grade 1 / Mild retinopathy (R2/M2) and frequency of screening is equal to or more than 1 year (indicating less clinical concern), subject meets inclusion. If subject has progressed to Moderate (Grade 2) or Severe (Grade 3) DR, to be excluded as per below exclusion criteria.
D. Absolute exclusion: Any DR classed as Moderate (Grade 2) or Severe (Grade 3) non-proliferative retinopathy (known as equal to or more than R3/M3) is exclusive.
NB: ISPAD guidelines (2022) for who needs retinopathy screening to be followed while in study care. These are: Screening from age 11 years with 2-5years diabetes duration. Subsequent monitoring frequency 2-3 yearly (or as locally recommended/available).
E. History of severe visual impairment (which in the opinion of the Investigator would limit their successful involvement), is exclusive.
8. If female, is pregnant or plans to become pregnant while participating in the study. A positive urine pregnancy test at Screening is exclusionary.
9. Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this 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 will be done by a biostatistician blinded to allocation arm and will use non-informative group codes until all planned analyses are completed. Once the REDCap (Research Data Capture) project is moved to production, the randomisation list is locked and becomes unmodifiable and inaccessible to the study team preserving allocation concealment. The study statistician will have no contact with potential participants or be able to influence enrolment in any way.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The study statistician will prepare a computer-generated randomisation list with an allocation ratio of 1:1 and permutated blocks of random size. The randomisation list will be stratified by;
1. Baseline HbA1c (below 100mmol/mol; equal to or above 100mmol/mol)
2. Age (7-15 years inclusive; 16-25 years inclusive)
The randomisation list will be loaded into the REDCap database by the study statistician immediately prior to moving the project to production status.
Participants who give consent for participation, and fulfil the eligibility criteria, will be enrolled in the study and given a unique study identifier. After stratification variables have been entered into REDCap, research staff with authorisation to randomise participants may click the ‘randomise’ button, which will assign the treatment to the study number according to the randomisation list and lock the fields containing the treatment group and stratification variables.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Assignment during the 3-month RCT phase is parallel (intervention group and control group), followed by a 9-month extension phase where those previously in the control group cross over into the intervention group and all participants (intervention and former control group) use the AHCL system during the extension phase.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
To estimate the effect of AHCL on outcome measures, mixed regression models will be used to determine mean differences, 95% CIs, and p-values, adjusted for baseline, between the two groups at 3 months. A random effect for site with be included, and adjustment for stratification variables. Analyses will be undertaken in Stata (StataCorp, Texas) by the study biostatistician (or supervised by the study biostatistician) and results will be reported in line with the CONSORT statement.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/03/2023
Actual
13/03/2023
Date of last participant enrolment
Anticipated
Actual
8/08/2023
Date of last data collection
Anticipated
16/08/2024
Actual
Sample size
Target
80
Accrual to date
Final
81
Recruitment outside Australia
Country [1] 25108 0
New Zealand
State/province [1] 25108 0
Otago
Country [2] 25109 0
New Zealand
State/province [2] 25109 0
Canterbury
Country [3] 25110 0
New Zealand
State/province [3] 25110 0
Waikato
Country [4] 25111 0
New Zealand
State/province [4] 25111 0
Wellington
Country [5] 25112 0
New Zealand
State/province [5] 25112 0
Auckland

Funding & Sponsors
Funding source category [1] 312605 0
Charities/Societies/Foundations
Name [1] 312605 0
Otago Southland Diabetes Research Trust
Country [1] 312605 0
New Zealand
Funding source category [2] 312607 0
Charities/Societies/Foundations
Name [2] 312607 0
Rotary New Zealand
Country [2] 312607 0
New Zealand
Funding source category [3] 312608 0
Charities/Societies/Foundations
Name [3] 312608 0
Spinal Cord Society NZ
Country [3] 312608 0
New Zealand
Funding source category [4] 312609 0
University
Name [4] 312609 0
University of Otago
Country [4] 312609 0
New Zealand
Funding source category [5] 312610 0
Commercial sector/Industry
Name [5] 312610 0
Medtronic
Country [5] 312610 0
United States of America
Funding source category [6] 314708 0
Charities/Societies/Foundations
Name [6] 314708 0
Lions Clubs District 202F
Country [6] 314708 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
362 Leith Street
Dunedin North
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 314218 0
None
Name [1] 314218 0
Address [1] 314218 0
Country [1] 314218 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311930 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 311930 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 311930 0
New Zealand
Date submitted for ethics approval [1] 311930 0
03/11/2022
Approval date [1] 311930 0
10/01/2023
Ethics approval number [1] 311930 0
2022 FULL 13508

Summary
Brief summary
Long-term health complications and increased mortality due to suboptimal glycaemic control are great concerns for patients with type 1 diabetes (T1D). Unfortunately, less than a third of patients meet glycaemic control targets recommended to prevent long-term complications. Evidence suggests that automation of insulin delivery through advanced hybrid closed loop (AHCL) systems may lead to improved health outcomes. This 3-month randomised controlled trial, followed by a 9-month period where control subjects cross over to the intervention arm, will explore the ability of the AHCL system to improve glucose levels and reduce disease burden in children and youth struggling with the maintenance of healthy diabetes control. This study will enrol 80 participants aged 7–25 years at 5 study sites in Aotearoa New Zealand. Baseline data will be collected from eligible subjects. After baseline assessments, subjects will be randomised and either commence use of the AHCL system (intervention arm), or continue their usual diabetes care (control arm) for 3 months. Subsequently, those in the control arm commence use of the AHCL system, and all participants use the system during the 9-month extension phase. The study will conclude after approximately 13 months.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122878 0
Prof Benjamin J Wheeler
Address 122878 0
Department of Women's and Children's Health
Otago Medical School - Dunedin Campus
PO Box 56
Dunedin 9054
New Zealand
Country 122878 0
New Zealand
Phone 122878 0
+64 3 470 9189
Fax 122878 0
Email 122878 0
ben.wheeler@otago.ac.nz
Contact person for public queries
Name 122879 0
Prof Benjamin J Wheeler
Address 122879 0
Department of Women's and Children's Health
Otago Medical School - Dunedin Campus
PO Box 56
Dunedin 9054
New Zealand
Country 122879 0
New Zealand
Phone 122879 0
+64 3 470 9189
Fax 122879 0
Email 122879 0
ben.wheeler@otago.ac.nz
Contact person for scientific queries
Name 122880 0
Prof Benjamin J Wheeler
Address 122880 0
Department of Women's and Children's Health
Otago Medical School - Dunedin Campus
PO Box 56
Dunedin 9054
New Zealand
Country 122880 0
New Zealand
Phone 122880 0
+64 3 470 9189
Fax 122880 0
Email 122880 0
ben.wheeler@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data related to the primary and secondary outcomes.
When will data be available (start and end dates)?
Data will be available prior to submitting the first manuscript for publication (approximately February 2024) through 10 years after the youngest participant has turned 16 (approximately January 2042).
Available to whom?
Those involved in the peer review process for publication in a scientific journal, upon request.
Available for what types of analyses?
Those analyses performed to report the study findings.
How or where can data be obtained?
By emailing the lead investigator A/Prof Ben Wheeler (ben.wheeler@otago.ac.nz)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17564Informed consent form  ben.wheeler@otago.ac.nz
17565Ethical approval  ben.wheeler@otago.ac.nz



Results publications and other study-related documents

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