ANZCTR - Registration

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

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]

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

Poor Glycaemic Control

Condition category

Condition code

Metabolic and Endocrine

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]

Treatment: Devices

Intervention code [2]

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]

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]

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]

Glycaemic control as measured by average serum glucose data downloaded

Timepoint [2]

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]

Glycaemic control as measured by glycated haemaglobin (HbA1C).

Timepoint [1]

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]

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]

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]

Glycaemic outcomes via CGM data for % CGM time <3.0mmol/L

Timepoint [3]

Baseline-beginning of optimization phase
Midpoint - at 3 months post beginning of optimisation
Endpoint -at 6 months post beginning of optimisation

Secondary outcome [4]

Glycaemic outcomes via CGM data for Percentage of CGM time <3.9 mmol/L

Timepoint [4]

Baseline -at the beginning of optimisation phase
Midpoint - 3 months following optimisation
Endpoint - 6 months following optimisation

Secondary outcome [5]

Glycaemic outcomes via CGM data for Percentage of CGM time>10.0 mmol

Timepoint [5]

Baseline -at the beginning of optimisation phase
Midpoint - 3 months following optimisation
Endpoint - 6 months following optimisation

Secondary outcome [6]

Glycaemic outcomes via CGM data for Percentage of CGM time>13.9 mmol

Timepoint [6]

Baseline -at the beginning of the optimisation
Midpoint - 3 months following optimisation
Endpoint - 6 months following optimisation

Secondary outcome [7]

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]

Baseline- at the beginning of optimization phase
Midpoint-3 months
Endpoint-6 months

Secondary outcome [8]

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]

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]

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]

Baseline- at the beginning of the optimization phase
Midpoint- at 3 months
Endpoint- at 6 months

Secondary outcome [10]

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]

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]

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]

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]

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]

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?

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

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Otago, Canterbury

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Otago Medical Research Foundation

Address [1]

PO Box 5726
Dunedin 9054
New Zealand

Country [1]

New Zealand

Funding source category [2]

Commercial sector/Industry

Name [2]

Medtronic Diabetes

Address [2]

18000 Devonshire Street
Northridge
California 91326
United States of America

Country [2]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Southern Health and disability ethics committee

Ethics committee address [1]

Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

24/11/2020

Approval date [1]

20/01/2021

Ethics approval number [1]

20/STH/214

Summary

Brief summary

65 volunteers aged 2-80 years with type 1 diabetes will take part in this open label extension study. After baseline assessments and two run-in periods of increased automation (where the pump increasingly controls your child’s blood glucose levels), the participants will then undergo a 6-month period of using the insulin pump in its trial settings (fully automated with optimisation of settings every 21 days). The new insulin delivery method being tested in all patients in this study is the Medtronic AHCL system running in the fully automated AHCL mode.
The primary outcomes are to compare the proportion of time spent in target glycaemic range (sensor glucose level 3.9 - 10 mmol/l)
- The Medtronic insulin pump running in advanced hybrid closed loop (AHCL) mode
- The Medtronic insulin pump running as sensor augmented pump therapy (SAP) with predictive low-glucose management (PLGM).
Our secondary outcomes will include
-longer term glycaemic control while using AHCL as measured by glycated haemoglobin (HbA1c) at 3 and 6 months compared to pre-study baseline.
- longer term safety (as defined by severe hypoglycaemia, Diabetic ketoacidosis, adverse device events (expected and unexpected).
We will also analyze Sleep Quality by conducting the PSQI questionnaire and evaluate the lived experience of patients using AHCL by conducting a qualitative questionnaire.During the lead in phases participants will be required to upload their insulin pumps on a weekly basis. On initiation of auto-mode, participants will be required to upload daily for the first seven days. The study will be conducted in Canterbury and Otago.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Martin De Bock

Address

Department of Paediatrics
University of Otago, Christchurch
2 Riccarton Avenue, P.O. Box 4345
Christchurch 8140

Country

New Zealand

Phone

+64 3 372 6763

Fax

+64 3 365 9133

[email protected]

Contact person for public queries

Name

Dr Shekhar Sehgal

Address

University of Otago
201 Great King Street
Dunedin Central
Dunedin 9016

Country

New Zealand

Phone

+64 211718514

Fax

[email protected]

Contact person for scientific queries

Name

Dr Martin De Bock

Address

Department of Paediatrics
University of Otago, Christchurch
2 Riccarton Avenue, P.O Box 4345
Christchurch 8140

Country

New Zealand

Phone

+64 3 372 6763

Fax

+64 3 365 9133

[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

Current Study Results

No documents have been uploaded by study researchers.

Update to Study Results

Doc. No.	Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
3887	Basic results	No			381340-(Uploaded-09-08-2023-08-08-59)-Basic results summary.docx
4159	Plain language summary	No		The use of decision support tools in Advanced Hybr... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	User experiences during the transition to calibration-free sensors with remote monitoring while using automated insulin delivery - a qualitative study.	2023	https://dx.doi.org/10.3389/fendo.2023.1214975

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically