Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000360819
Ethics application status
Approved
Date submitted
3/02/2021
Date registered
30/03/2021
Date last updated
30/03/2021
Date data sharing statement initially provided
30/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimizing outcomes in Advanced hybrid closed loop in children and adults with type 1 diabetes aged 2-80
Scientific title
Optimizing outcomes in Advanced hybrid closed loop in children and adults with type 1 diabetes
Secondary ID [1] 303323 0
Nil known
Universal Trial Number (UTN)
U1111-1261-3657
Trial acronym
Nil known
Linked study record
Nil known

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 320562 0
Poor Glycaemic Control 320959 0
Condition category
Condition code
Metabolic and Endocrine 318416 318416 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single arm longitudinal study investigating advanced hybrid closed loop insulin therapy (AHCL) combined with an optimisation protocol. For the duration of the study participants will be provided with a Medtronic AHCL pump.
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 using both face to face verbal instruction and printed sponsor derived instruction manuals(from Medtronic) 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 interventions(s) will be administered by an Endocrinologist(independent of clinical treatment team) together with two research nurses.
Following a run-in period of 21 days running as a sensor augmented pump(SAP) with Predictive low Glucose Monitoring (PLGM) to allow Automode activation, participants will then run non-optimized advanced hybrid closed loop . After these two phases, all participants will enter into the optimisation phase to complete 6 months AHCL study duration total.
Optimization occurs with a mathematical model-based digital-twin tool to personalize and automate user-dependent AHCL .The inputs to this model are carb-insulin ratio, active insulin time, manual mode, basal rates. The tool uses a minimum of 21 consecutive CareLink days of sensor augmented pump therapy to generate the following outcomes:
• 48 segments for Manual Mode basal rates (00:00 - 00:30, 00:30 - 01:00, etc.)
• 1 ISF for Manual Mode to match the Insulin sensitivity factors utilized by the Auto Mode
• 8 segments for Manual Mode and Auto Mode Carbohydrate ratios (00:00-03:00, 03:00 -06:00, etc.)
• active insulin time (AIT) for manual mode and Auto Mode.
Participants will be recommended to electronically upload their insulin pump weekly for the first 6 weeks, to a cloud based server with additional input with the study team, will refine pump settings according to the recommendations.
After 6 weeks, the minimum upload and optimization frequency is every 14 days, but can occur with greater frequency as per discretion of the investigators and subjects. At these upload points the study staff will access pump analytics including time in auto mode and reasons for auto mode exit, as well as amount of insulin used , basal rates, bolus insulin used and blood glucose levels. Therefore these reviews will be used to monitor adherence to the intervention.
The single arm study intervention is: Medtronic AHCL insulin pump running in AHCL mode with associated optimisation protocol
Expected duration of subject participation is 8 months (6 months + 42 days run-in)
The optimisation intervention is a mathematical model-based digital-twin tool, using the previous 21 days data from the AHCL upload on CarelinkTM will generate suggested setting changes (see detail below).
Intervention code [1] 319631 0
Treatment: Devices
Intervention code [2] 319633 0
Lifestyle
Comparator / control treatment
As this is a single arm optimization study there is no control group required.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326395 0
Glycaemic control as measured by Percentage of Time in Range (TIR) (defined as time spent 3.9mmol-10mmol). These levels will be taken from the Medtronic Guardian Continuous Glucose Monitoring system that forms part of the AHCL system.
Timepoint [1] 326395 0
Continuous glucose monitoring data to calculate time in range will be collected from Guardian CGM during the 21 days of the first initiation period and then again in the final 21 days of the optimisation phase as a final point of comparison.
Primary outcome [2] 326396 0
Glycaemic control as measured by average serum glucose data downloaded
Timepoint [2] 326396 0
Continuous glucose monitoring data to calculate an average blood glucose from 288 time points will be collected by the Guardian CGM component during the 21 days of the first initiation period , this result will be compared to average blood glucose from the final 21 days of the optimisation phase
Secondary outcome [1] 391316 0
Glycaemic control as measured by glycated haemaglobin (HbA1C).
Timepoint [1] 391316 0
Baseline-at beginning of optimization phase
Midpoint- at 3 months post beginning of optimisation
Endpoint-at 6 months post beginning of optimisation
Secondary outcome [2] 391317 0
Number of episodes of severe hypoglycemia, defined as coma or convulsion requiring assistance from others, in the 12 months prior to baseline visit, as well as at 3 months and 6 months following the commencement of optimization. These will be identified by patient during face to face reviews as well as through data linkage to electronic medical records with the patients consent.
Timepoint [2] 391317 0
Baseline at beginning of optimization phase
Midpoint - at 3 months post beginning of optimization
Endpoint -at 6 months post beginning of optimization
Secondary outcome [3] 391318 0
Glycaemic outcomes via CGM data for % CGM time <3.0mmol/L
Timepoint [3] 391318 0
Baseline-beginning of optimization phase
Midpoint - at 3 months post beginning of optimisation
Endpoint -at 6 months post beginning of optimisation
Secondary outcome [4] 391319 0

Glycaemic outcomes via CGM data for Percentage of CGM time <3.9 mmol/L
Timepoint [4] 391319 0
Baseline -at the beginning of optimisation phase
Midpoint - 3 months following optimisation
Endpoint - 6 months following optimisation
Secondary outcome [5] 391320 0
Glycaemic outcomes via CGM data for Percentage of CGM time>10.0 mmol
Timepoint [5] 391320 0
Baseline -at the beginning of optimisation phase
Midpoint - 3 months following optimisation
Endpoint - 6 months following optimisation
Secondary outcome [6] 391321 0
Glycaemic outcomes via CGM data for Percentage of CGM time>13.9 mmol
Timepoint [6] 391321 0
Baseline -at the beginning of the optimisation
Midpoint - 3 months following optimisation
Endpoint - 6 months following optimisation
Secondary outcome [7] 391343 0
Episodes of Diabetic Ketoacidosis defined by serum ketones>0.6, PH<7.35 requiring hospital admission. These will be identified by patient during face to face reviews as well as through data linkage to electronic medical records with the patients consent.
Timepoint [7] 391343 0
Baseline- at the beginning of optimization phase
Midpoint-3 months
Endpoint-6 months
Secondary outcome [8] 391348 0
Sleep quality assessed using Pittsburgh sleep quality index(PSQI) with the Medtronic advanced hybrid closed loop insulin pump running in AHCL mode versus SAP+PLGM.
Pittsburgh sleep quality index:
- 4 questions requiring 1 sentence answer
- 4 questions requiring frequency of sleep behaviours in last month
Timepoint [8] 391348 0
Baseline- at beginning of the optimization phase
Midpoint- at 3 months
Endpoint- at 6 months
with questionnaire covering last 28 days at each timepoint
Secondary outcome [9] 391352 0
Sleep duration will be assessed by participants completing a sleep diary for 8 consecutive nights prior to the baseline and 3- and 6-month follow-up visits.
Timepoint [9] 391352 0
Baseline- at the beginning of the optimization phase
Midpoint- at 3 months
Endpoint- at 6 months
Secondary outcome [10] 392463 0
Actigraphy(using a motion sensor worn like a wrist watch) in order to assess the participants’ usual level of moderate-vigorous physical activity in waking hours .
Timepoint [10] 392463 0
Baseline - at the beginning of the optimization phase for 7 days and 8 nights prior to review.
At 6 months visit post optimization for 7 days and 8 nights prior to review.
Secondary outcome [11] 392464 0
ActiGraphy (using a a motion sensor worn like a wrist-watch) to collect duration of sleep in hrs for 7 days and 8 nights prior to each review.
Timepoint [11] 392464 0
Baseline - at the beginning of the optimization phase -for 7 days and 8 nights prior to review.
At 6 months visit post optimization.-for 7 days and 8 nights prior to review.
Secondary outcome [12] 392465 0
ActiGraphy (using a a motion sensor worn like a wrist-watch) to collect number of discrete events , lasting 15s or more of night time wakening.
Timepoint [12] 392465 0
Baseline - at the beginning of the optimization phase -for 7 days and 8 nights prior to review.
At 6 months visit post optimization.-for 7 days and 8 nights prior to review.

Eligibility
Key inclusion criteria
1. Male or female aged 2 – 80 years inclusive.
2. Type I diabetes as per the American Diabetes Association Classification, diagnosed at least 1 year prior to Study Day 1.
3. On insulin pump therapy for at least 6 months prior to trial.
4. Minimum daily insulin requirement (Total Daily Dose) of greater than or equal to 8 units.
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
2 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Mean HbA1c more than 10.0% (86 mmol/mol) within 6 months prior to Study Day 1 (minimum of one test).
2. Use of a medication indicative of diabetes complications (ACE inhibitors and statins are permitted).
3. Use of systemic glucocorticoids within 2 weeks prior to the Baseline visit.
4. Current use of SGLT-2 or GLP-1 medications.
5. History or current evidence of significant seizure disorder, renal impairment or cardiovascular disease (including uncontrolled hypertension), in the opinion of the Investigator.
6. History of severe visual impairment, in the opinion of the Investigator.
7. If female, is pregnant or plans to become pregnant while participating in the study. A positive urine pregnancy test at Screening is exclusionary.
8. 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
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This trial is an open label extension of a prior randomized controlled trial, allocation concealment is not required.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features

Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
This study has a primary endpoint comparing Time in Range (TIR) and average sensor glucose from 21 days baseline CGM data to the final two weeks of the intervention. Data will be presented as mean changes and standard deviations.
A sample size of 60 will provide 95% power at a two-sided alpha of 0.05 to detect an effect size (Dz) of 0.47. Assuming that participants’ change in time in range (TIR) has a standard deviation of 8.5, this represents an absolute improvement of 4.0 percentage points (ie. from 70% to 74% TIR). The sample has been expanded to 65 to allow for new investigational use in children <7 years.
MISSING DATA
All ITT analyses will incorporate all available data, the full analysis set, and there will be on imputation of missing data. For the general linear mixed models participants are not required to have both interventions to be included in the analyses.
DEVIATION FROM PLANNED STATISTICAL ANALYSIS
Any deviation from the planned statistical analysis will be describe in the final study report.
ANALYSIS POPULATIONS
SAFETY ANALYSIS POPULATION
All subjects who have used the study device, whether prematurely withdrawn from the study or not, will be included in the safety analysis population.
INTENT-TO-TREAT POPULATION
All subjects who complete the screening process and are enrolled into the study (i.e. assigned to a treatment sequence) are included in the Intent-to-Treat (ITT) population. This population is the primary analysis population for all non-safety related analyses.
PER-PROTOCOL POPULATION
Subset of the ITT population who meet all inclusion and exclusion criteria and have complete CGM data will be included in the Per-Protocol (PP) population. All decisions on subject exclusions from the PP population will be made prior to database closure and will be justified in the clinical study report.
SAFETY DATA ANALYSIS
All safety analyses will be based on the safety analysis population.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/05/2021
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
65
Accrual to date
Final
Recruitment outside Australia
Country [1] 23424 0
New Zealand
State/province [1] 23424 0
Otago, Canterbury

Funding & Sponsors
Funding source category [1] 307740 0
Charities/Societies/Foundations
Name [1] 307740 0
Otago Medical Research Foundation
Country [1] 307740 0
New Zealand
Funding source category [2] 307747 0
Commercial sector/Industry
Name [2] 307747 0
Medtronic Diabetes
Country [2] 307747 0
United States of America
Primary sponsor type
University
Name
University of Otago
Address
University of Otago Dunedin School of Medicine
201 Great King Street
Dunedin Central
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 308450 0
None
Name [1] 308450 0
Address [1] 308450 0
Country [1] 308450 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307766 0
Southern Health and disability ethics committee
Ethics committee address [1] 307766 0
Ethics committee country [1] 307766 0
New Zealand
Date submitted for ethics approval [1] 307766 0
24/11/2020
Approval date [1] 307766 0
20/01/2021
Ethics approval number [1] 307766 0
20/STH/214

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108418 0
Dr Martin De Bock
Address 108418 0

Department of Paediatrics
University of Otago, Christchurch
2 Riccarton Avenue, P.O. Box 4345
Christchurch 8140
Country 108418 0
New Zealand
Phone 108418 0
+64 3 372 6763
Fax 108418 0
+64 3 365 9133
Email 108418 0
[email protected]
Contact person for public queries
Name 108419 0
Shekhar Sehgal
Address 108419 0
University of Otago
201 Great King Street
Dunedin Central
Dunedin 9016
Country 108419 0
New Zealand
Phone 108419 0
+64 211718514
Fax 108419 0
Email 108419 0
[email protected]
Contact person for scientific queries
Name 108420 0
Martin De Bock
Address 108420 0

Department of Paediatrics
University of Otago, Christchurch
2 Riccarton Avenue, P.O Box 4345
Christchurch 8140
Country 108420 0
New Zealand
Phone 108420 0
+64 3 372 6763
Fax 108420 0
+64 3 365 9133
Email 108420 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
Current Study Results
No documents have been uploaded by study researchers.

Update to Study Results
Doc. No.TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
3887Basic resultsNo 381340-(Uploaded-09-08-2023-08-08-59)-Basic results summary.docx
4159Plain language summaryNo The use of decision support tools in Advanced Hybr... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseUser experiences during the transition to calibration-free sensors with remote monitoring while using automated insulin delivery - a qualitative study.2023https://dx.doi.org/10.3389/fendo.2023.1214975
N.B. These documents automatically identified may not have been verified by the study sponsor.