Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001400752
Ethics application status
Approved
Date submitted
23/10/2022
Date registered
1/11/2022
Date last updated
27/10/2023
Date data sharing statement initially provided
1/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised controlled trial investigating the safety and efficacy of an open source automated insulin delivery system without manual mealtime boluses, in people with type 1 diabetes
Scientific title
Randomised open label clinical trial examining the safety and efficacy of the Android Artificial Pancreas System (AAPS) with advanced bolus-free features in adults with type 1 diabetes
Secondary ID [1] 308241 0
None
Universal Trial Number (UTN)
U1111-1282-6837
Trial acronym
CLOSE IT (Closed Loop Open SourcE In Type 1 diabetes)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 diabetes mellitus 328013 0
Condition category
Condition code
Metabolic and Endocrine 325072 325072 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This randomised controlled trial will assess the safety and efficacy of the Android Artificial Pancreas System (AAPS) when used without manual mealtime boluses.

AAPS is an automated insulin delivery system, which in this trial will comprise an Ypsomed insulin pump, Dexcom G6 continous glucose monitor (CGM), and an Android phone containing an open-source algorithm. The algorithm uses glucose recordings to calculate required insulin doses and instructs the insulin pump to deliver those doses, in an automated manner.

All participants will be established on AAPS during a three month run-in phase (days 1-84). This will be as a "hybrid" system, whereby participants are still required to give manual insulin boluses around mealtimes, based on carbohydrate counting. This is in keeping with currently established use of the system. Carbohydrate counting will be carried out by the participant, and manual insulin boluses will be delivered using the Ypsomed insulin pump. The study team will advise each individual participant of ratios to be used when calculating insulin boluses (insulin sensitivity factor, carbohydrate ratio). These ratios will likely differ significantly between individuals, resulting in significant variability in bolus size between individuals. The Ypsopump is capable of delivering up to 30 units of insulin in a single bolus.

At the start of the run-in phase participants will attend a face-to-face visit with a member of the study team, at which time they will be provided with the insulin pump and CGM system, and receive training on use of the pump and carbohydrate counting. Insulin pump therapy will only commence once the study team is satisfied that the participant has received adequate training to use the pump safely. Some participants may require multiple site visits before starting pump therapy. Participants will either directly commence the AAPS algorithm or will first use manual pump therapy - this decision will be made by the study team on an individual basis, in consultation with the participant. Once AAPS has started, participants will gradually adjust settings in consultation with the study team, and enable advanced features including supermicroboluses. Supermicroboluses are automated correction boluses delivered by the algorithm in conjunction with numerous safety checks, including temporary suspension of basal insulin delivery. To guide this process, the study team will perform weekly electronic remote review for each participant during the run-in phase, accessing CGM recordings and pump records of insulin delivery, both of which will be uploaded to secure cloud-based systems. The intention is that, by the end of the run-in phase, all participants will be established on AAPS with supermicroboluses enabled and settings optimised.

Participants will then proceed to a three month trial phase (days 85-168), in which they will be randomised on a 1:1 basis to the intervention group or the control group.

In the intervention group participants will be asked to stop delivering manual mealtime insulin boluses. They will be instructed to only give a manual bolus if blood glucose is >15.0 mmol/L for >1 hour, or if they feel unwell due to hyperglycaemia.

Pump insulin delivery and CGM recordings will be uploaded to a secure cloud-based system. These data will be accessed by the study team and, in conjunction with contact with participants where required, will be used to verify participant adherence to the intervention.

At the end of the trial participants will return the study devices, including the Ypsopump and will be supported to resume their usual diabetes therapy prior to discharge from the study. The advanced AAPS algorithm does not currently have regulatory approval, limiting the potential feasibility of ongoing use after trial completion, however participants will be supported if they wish to continue using the algorithm. This would be dependent for each participant on the availability of CGM and an insulin pump compatible with the algorithm. CGM is not currently funded in New Zealand and, in this rapidly evolving landscape, it is difficult to predict if this will be funded at the end of the study. CGM is funded in Australia.
Intervention code [1] 324705 0
Treatment: Devices
Intervention code [2] 324706 0
Treatment: Other
Comparator / control treatment
In the control group participants will continue the hybrid automated insulin delivery that was established during the run-in phase. They will be asked to continue to deliver manual mealtime insulin boluses, based on carbohydrate counting.
Control group
Active

Outcomes
Primary outcome [1] 332894 0
Time in range, defined as the percentage of the time that glucose (measured by the Dexcom G6 continuous glucose monitor) is between 3.9 and 10.0 mmol/L.
Timepoint [1] 332894 0
Days 155-168, representing the final 14 days of the trial phase
Secondary outcome [1] 415009 0
Glycated haemoglobin (HbA1c), as measured on capillary or venous blood sample
Timepoint [1] 415009 0
Baseline, day 84 (completion of run-in phase), day 168 (completion of trial phase)
Secondary outcome [2] 415010 0
Percentage of participants able to maintain time in range (as defined for primary outcome. measured by the Dexcom G6 continuous glucose monitor) >70%
Timepoint [2] 415010 0
Days 155-168, representing the final 14 days of the trial phase
Secondary outcome [3] 415011 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is < 3.0 mmol/L
Timepoint [3] 415011 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [4] 415012 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is < 3.9 mmol/L
Timepoint [4] 415012 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [5] 415014 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is >10.0 mmol/L
Timepoint [5] 415014 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [6] 415015 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is 14.0 mmol/L or higher
Timepoint [6] 415015 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [7] 415016 0
Mean sensor glucose and glucose variability (expressed primarily as coefficient of variation and secondly as a SD), using glucose measured by the Dexcom G6 continuous glucose monitor
Timepoint [7] 415016 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [8] 415018 0
Total daily insulin dose, as assessed by pump insulin delivery records uploaded to secure cloud-based system
Timepoint [8] 415018 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...), expressed as the average daily dose over each 14-day period
Secondary outcome [9] 415019 0
Serious adverse events (SAE), serious adverse device effects (SADE), adverse device effects (ADE), and device deficiencies (DD)

As participants in the study have diabetes and are therefore expected to experience hypoglycaemia and or hyperglycaemia. These normal events are not expected to be reported as an AE as this is not considered an untoward event, but rather an expected occurrence. Any glycaemic excursion that meets the below definitions of severe hypoglycaemia, severe hyperglycaemia or DKA is considered an untoward event and a worsening from the participant’s baseline and would be reported as an AE.

Severe Hypoglycaemia: Is an event requiring assistance of another person due to altered consciousness to actively administer carbohydrate, glucagon, or other resuscitative actions.

Severe Hyperglycaemia: Is defined as hyperglycaemia (blood glucose greater than (>) 16.7 mol/L) with blood glucose ketones greater than (>) 1.5 mmol/L, urine ketones moderate or large, or accompanied by symptoms of nausea, vomiting or abdominal pain.

Hyperglycemic events are classified as DKA if the following are present:
• Symptoms such as polyuria, polydipsia, nausea, or vomiting;
• Serum ketones >1.5 mmol/L or large/moderate urine ketones;
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and
• Treatment provided in a Healthcare facility

A Serious Adverse Event (SAE) is an adverse event that:
• Results in death, or
• Is a life-threatening illness or injury, or
• Causes permanent impairment of a body structure or a body function, or
• Requires in-patient or prolonged hospitalisation, or
• Requires medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function.

An ADE is an adverse event related to the use of the investigational medical device. This definition includes adverse events resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. This also includes any event resulting from use error from intentional misuse of the investigational medical device.

A DD is any inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety, or performance and shall be documented throughout the clinical investigation. NOTE: DD include malfunctions, use errors, and inadequate labelling. However, in clinical management of T1D use errors will not be recorded unless they result in an ADE, because absolute perfect use of the device is not possible in day to day life.

All adverse device effects (ADE), serious adverse events (SAE), serious adverse device effects (SADE) and device deficiencies (DD) will be documented in a timely manner throughout the clinical investigation. The following information will be captured via the electronic clinical record form:
• Start and stop date of the event;
• A description of the event including any associated symptoms;
• Assessment of seriousness;
• Assessment of intensity;
• Assessment of relationship to the investigational device;
• Intervention/ troubleshooting;
• Outcome.
Timepoint [9] 415019 0
As reported throughout trial duration (day 1-168). Participants will receive contact details of study staff and asked to make contact if any adverse events occur. Study staff will be available 24 hours to respond to participant contact.
Secondary outcome [10] 415020 0
INSPIRE questionnaire, designed to evaluate quality of life metrics specific to automated insulin delivery systems
Timepoint [10] 415020 0
Baseline (pre-intervention INSPIRE questionnaire), day 84 (end of run-in phase, post-intervention INSPIRE questionnaire), day 168 (end of trial phase, post-intervention INSPIRE questionnaire)
Secondary outcome [11] 415021 0
EuroQol 5-dimensional questionnaire (EQ-5D), designed to measure overall health status
Timepoint [11] 415021 0
Baseline, day 84 (end of run-in phase), day 168 (end of trial phase)
Secondary outcome [12] 415022 0
System usability scale questionnaire
Timepoint [12] 415022 0
Day 168 (end of trial phase)
Secondary outcome [13] 415023 0
Up to 15 participants from the intervention group will be invited to a qualitative interview at study completion, exploring experiences using the study system. Interviews will be individual semi-structured interviews, conducted either face-to-face or via videoconference.

Participants will be selected by study staff from the first to volunteer for the interview, aiming to include a diverse range of participants, factoring in:
- Age
- Gender
- Baseline diabetes control
- Baseline use of diabetes technology
Timepoint [13] 415023 0
Day 168 (end of trial phase)
Secondary outcome [14] 415024 0
Percentage of time that study insulin pump is running in automated insulin delivery mode. This will be uploaded by the study phone to a secure cloud-based system.
Timepoint [14] 415024 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [15] 415025 0
Frequency of manual insulin boluses, further categorised in the intervention arm as boluses delivered in accordance with protocol and boluses delivered outside of protocol. This will be uploaded by the study phone to a secure cloud-based system, and corroborated with contact with participants where necessary.
Timepoint [15] 415025 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [16] 415026 0
Total insulin dose delivered by manual boluses, expressed as a percentage of overall total insulin dose, further categorised in the fully-automated arm as boluses delivered in accordance with protocol and boluses delivered outside of protocol. This will be uploaded by the study phone to a secure cloud-based system, and corroborated with contact with participants where necessary.
Timepoint [16] 415026 0
14-day increments throughout run-in and trial phases (i.e. days 1-14, days 15-28, etc...)
Secondary outcome [17] 415028 0
Daily carbohydrate intake, as self-reported by participants (with dietitian assistance), assessed during face-to-face study visit with the assistance of provided dietary diary forms.
Timepoint [17] 415028 0
Baseline, day 84 (end of run-in phase), day 168 (end of trial phase)
Secondary outcome [18] 428261 0
Percentage of participants for whom TIR (as defined for the primary outcome) decreases by >5%
Timepoint [18] 428261 0
Secondary outcome [19] 428262 0
Percentage of participants for whom TIR (as defined for the primary outcome) decreases by >5%
Timepoint [19] 428262 0
Days 155-168 (final 14 days of trial phase), compared to days 71-84 (final 14 days of run-in phase)
Secondary outcome [20] 428263 0
The tertiary objective of this study is to analyse biomarkers associated with complication risk, including but not limited to:

A. Measures related to glycaemia such as 1,5 anhydroglucitol.
B. Measures of systemic and vascular inflammation such as CRP (C-reactive protein) and vascular cell adhesion molecules like sVCAM-1, s-ICAM, sE-selectin.
C. Oxidative stress biomarkers, such as myeloperoxidase and mitochondrial DNA copy number.
D. MicroRNAs that are associated with vascular damage.

These markers will be measured on blood samples already obtained for HbA1c. This will be applicable to participants in Australia only, who provide consent for storage of blood samples.
Timepoint [20] 428263 0
Days 155-168 (final 14 days of trial phase), compared to days 71-84 (final 14 days of run-in phase)
Secondary outcome [21] 428264 0
The tertiary objective of this study is to analyse biomarkers associated with complication risk, including but not limited to:

A. Measures related to glycaemia such as 1,5 anhydroglucitol.
B. Measures of systemic and vascular inflammation such as CRP (C-reactive protein) and vascular cell adhesion molecules like sVCAM-1, s-ICAM, sE-selectin.
C. Oxidative stress biomarkers, such as myeloperoxidase and mitochondrial DNA copy number.
D. MicroRNAs that are associated with vascular damage.

These markers will be measured on blood samples already obtained for HbA1c. This will be applicable to participants in Australia only, who provide consent for storage of blood samples.
Timepoint [21] 428264 0
Baseline, day 84 (completion of run-in phase), day 168 (completion of intervention phase)

Eligibility
Key inclusion criteria
1. Type 1 diabetes as per the American Diabetes Association classification for > 12 months prior to the screening visit
2. Aged 18 – 70 years inclusive
3. Willing and able to adhere to the study protocol
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. If female, is pregnant or plans to become pregnant while participating in the study. A positive pregnancy test at screening is exclusionary.
2. Use of non-insulin glucose lowering therapy within 3 months of study commencement.
3. Severe renal impairment (eGFR < 30 mL/min/1.73m2).
4. Any documented active or suspected malignancy, except appropriately treated basal cell or squamous cell carcinoma of the skin or any “in situ” carcinoma.
5. Acute cardiovascular event (myocardial infarction, unstable angina, stroke) in the 3 months prior to study commencement.
6. Severe hypoglycaemia or diabetic ketoacidosis in the 3 months prior to study commencement.
7. Consumption of a very low carbohydrate diet, defined as carbohydrate intake <40g per day.
8. Inability to use insulin pump and mobile phone.
9. Any comorbid medical or psychological factors that would, on assessment by the investigators, make the person unsuitable for the study.
10. A lack of English literacy that would, on assessment by the investigators, make the person unsuitable for the study.
11. Allergy to insulin NovoRapid®

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)
The randomisation list will be loaded into the REDCap (Research Data Capture) database by the study statistician immediately prior to moving the project to production status. Once the project is moved to production, the randomisation list is locked and becomes unmodifiable and inaccessible to the study team.

Participants may only be randomised once they have completed the run-in phase of the trial. At commencement of the RCT phase, research staff with authorisation to randomise participants may click the ‘randomise’ button, which will assign the treatment to the study number and lock the fields containing the treatment group and stratification variables. This process will ensure allocation is kept concealed from researcher staff and participants until after the run-in phase has been completed.
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 study site.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Participants will be analysed as-randomised (intention-to-treat) and multiple imputation methods used if missing data exceeds 10%. Two-sided P values will be reported and an alpha of 0.05 considered statistically significant. No interim analysis will be undertaken. Analysis will be performed using up-to-date version of specialist statistical software (R, SAS, or Stata). The primary endpoint, mean percentage of time spent in target glucose range (3.9 to 10.0 mmol/L) (TIR) will be collected from days 155 – 168 of the RCT phase, and will be calculated for each participant by dividing the number of CGM measures within range by the total number of CGM measures recorded. Pre-intervention TIR will be calculated in a similar manner, using CGM obtained at days 71-84. Baseline TIR will be assessed from blinded CGM obtained prior to the run-in phase, however will be used to provide descriptive data about the cohort and will not be factored into analysis of the primary outcome.. Group means and differences in group means will be estimated with 95% confidence intervals.

This study has a non-inferiority study design. Based on a mean TIR of 70% (SD 10%) and a largest clinically acceptable difference of 7% TIR, 70 participants (35 in each group) are required to provide 90% power at a = 0.05. The overall sample size of 75 participants accounts for a small dropout rate of 5 participants.

Continuous secondary endpoints will be calculated and compared in a similar manner. Where possible (for example for HbA1c and psychosocial factors), analysis of covariance (ANCOVA) models will be used to also adjust for participants’ levels at baseline.
Harms, for example SAE, SADE, ADE and DD rates, will be grouped, tallied and reported.

Glycaemic outcomes will additionally be divided into daytime (0600-2159 hours) and night (2200-0559 hours)

Generic qualitative descriptive research will be used to explore participant experiences with the fully-automated closed loop system. Up to 15 participants from the fully-automated closed loop arm will be invited to a qualitative interview at study completion. Verbatim transcripts will be prepared and a descriptive qualitative thematic analysis used.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2023
Actual
27/04/2023
Date of last participant enrolment
Anticipated
30/06/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
75
Accrual to date
18
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23432 0
Baker Heart and Diabetes Institute - Melbourne
Recruitment postcode(s) [1] 38834 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 25077 0
New Zealand
State/province [1] 25077 0
Canterbury

Funding & Sponsors
Funding source category [1] 312499 0
Charities/Societies/Foundations
Name [1] 312499 0
JDRF Diabetes Research Fund
Country [1] 312499 0
United States of America
Primary sponsor type
Other
Name
Baker Heart and Diabetes Institute
Address
75 Commercial Road, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 314087 0
University
Name [1] 314087 0
University of Otago, Christchurch
Address [1] 314087 0
2 Riccarton Ave, Christchurch Central, Christchurch 8011
Country [1] 314087 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311833 0
The Alfred Health Research Ethics Committee
Ethics committee address [1] 311833 0
Ethics committee country [1] 311833 0
Australia
Date submitted for ethics approval [1] 311833 0
24/10/2022
Approval date [1] 311833 0
05/12/2022
Ethics approval number [1] 311833 0
615/22
Ethics committee name [2] 311834 0
Health and Disability Ethics Committees
Ethics committee address [2] 311834 0
Ethics committee country [2] 311834 0
New Zealand
Date submitted for ethics approval [2] 311834 0
31/10/2022
Approval date [2] 311834 0
15/12/2022
Ethics approval number [2] 311834 0
2022 FULL 13832

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

Contacts
Principal investigator
Name 122534 0
A/Prof Neale Cohen
Address 122534 0
Baker Heart and Diabetes Institute
75 Commercial Road
Melbourne VIC 3004
Country 122534 0
Australia
Phone 122534 0
+61 385321800
Fax 122534 0
Email 122534 0
[email protected]
Contact person for public queries
Name 122535 0
Neale Cohen
Address 122535 0
Baker Heart and Diabetes Institute
75 Commercial Road
Melbourne VIC 3004
Country 122535 0
Australia
Phone 122535 0
+61 385321800
Fax 122535 0
Email 122535 0
[email protected]
Contact person for scientific queries
Name 122536 0
Neale Cohen
Address 122536 0
Baker Heart and Diabetes Institute
75 Commercial Road
Melbourne VIC 3004
Country 122536 0
Australia
Phone 122536 0
+61 385321800
Fax 122536 0
Email 122536 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
Privacy laws in Australia and New Zealand


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
SourceTitleYear of PublicationDOI
Dimensions AIStudy protocol for a randomised open-label clinical trial examining the safety and efficacy of the Android Artificial Pancreas System (AAPS) with advanced bolus-free features in adults with type 1 diabetes: the ‘CLOSE IT’ (Closed Loop Open SourcE In Type 1 diabetes) trial2024https://doi.org/10.1136/bmjopen-2023-078171
N.B. These documents automatically identified may not have been verified by the study sponsor.