Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001401741
Ethics application status
Approved
Date submitted
23/10/2022
Date registered
1/11/2022
Date last updated
30/10/2023
Date data sharing statement initially provided
1/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Trial investigating the safety and efficacy of an ultra-fast acting insulin in 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: extension trial using ultra-fast acting insulin
Secondary ID [1] 308243 0
None
Universal Trial Number (UTN)
U1111-1282-6837
Trial acronym
CLOSE IT (Closed Loop Open SourcE In Type 1 diabetes) - extension trial
Linked study record
Extension study of the CLOSE IT trial ACTRN12622001400752 (same UTN: U1111-1282-6837), separately submitted to ANZCTR

Health condition
Health condition(s) or problem(s) studied:
Type 1 diabetes mellitus 328014 0
Condition category
Condition code
Metabolic and Endocrine 325073 325073 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This extension of the CLOSE IT trial will investigate the efficacy and safety of an ultra-fast acting insulin (Fiasp), when used in a fully-automated insulin delivery system.

AAPS (Android Artificial Pancreas System) is an automated insulin delivery system, which in this trial will comprise an Ypsomed insulin pump, Dexcom G6 continous glucose monitor, 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.

Participants in this extension trial will be recruited from the intervention arm of CLOSE IT. At the time of recruitment they will have used AAPS for six months, including three months with no manual mealtime boluses. Participants will continue this system, however the insulin delivered will change from fast acting NovoRapid (aspart) to ultra-fast acting Fiasp (aspart with niacinamide).

Participants will attend a face-to-face study visit, where they will be supplied with Fiasp and receive instruction on its use.

The extension study will last 4 weeks, with participants using Fiasp throughout this time, delivered subcutaneously by insulin pump. The specific dose delivered will be that selected by AAPS and likely to significantly vary between participants. We anticipate a typical total daily insulin dose in the range of 0.3-0.5 units per kg body weight.

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 ongoing participant adherence to instructed use of the AAPS system, including specifically not to give manual insulin boluses at mealtimes unless glucose is > 15.0 mmol/L for > 1 hour or symptoms of hyperglycaemia develop.

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.

If participants in Australia wish to continue using Fiasp this will be communicated to their usual clinical team. As Fiasp is an unapproved medication in New Zealand, participants in New Zealand will not be able to continue using Fiasp after the trial has concluded.
Intervention code [1] 324707 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332895 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] 332895 0
Days 183-196 of the overall CLOSE IT trial (days 15-28 of this extension trial), compared to days 155-168 (final 14 days of the main CLOSE IT trial)
Secondary outcome [1] 415029 0
Glycated haemoglobin (HbA1c), as measured on capillary or venous blood sample
Timepoint [1] 415029 0
Day 196 (completion of extension trial), compared to day 168 (end of main CLOSE IT trial)
Secondary outcome [2] 415030 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] 415030 0
Days 183-196 of the overall CLOSE IT trial (days 15-28 of this extension trial), compared to days 155-168 (final 14 days of the main CLOSE IT trial)
Secondary outcome [3] 415032 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is < 3.0 mmol/L
Timepoint [3] 415032 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [4] 415033 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is < 3.9 mmol/L
Timepoint [4] 415033 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [5] 415034 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is > 10.0 mmol/L
Timepoint [5] 415034 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [6] 415035 0
Percentage of time that glucose (measured by the Dexcom G6 continuous glucose monitor) is 14.0 mmol/L or higher
Timepoint [6] 415035 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [7] 415036 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] 415036 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [8] 415038 0
Total daily insulin dose, as assessed by pump insulin delivery records uploaded to secure cloud-based system
Timepoint [8] 415038 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [9] 415039 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 [9] 415039 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [10] 415040 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 [10] 415040 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [11] 415041 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 [11] 415041 0
Days 169-182 and days 183-196 of the overall CLOSE IT trial (days 1-14 and 15-28 of this extension trial), compared to the same outcome at 14-day increments throughout the main CLOSE IT trial
Secondary outcome [12] 415042 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 [12] 415042 0
As reported throughout trial duration (day 169-196 of overall CLOSE IT trial, representing days 1-28 of this extension trial). 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 [13] 415044 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 [13] 415044 0
Day 196 (completion of extension trial), compared to day 168 (end of main CLOSE IT trial)
Secondary outcome [14] 428377 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.
Biomarkers will be measured from blood samples already obtained for measurement of HbA1c. This will be applicable to participants in Australia only, who provide consent for storage of blood samples.
Timepoint [14] 428377 0
Secondary outcome [15] 428378 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.
Biomarkers will be measured from blood samples already obtained for measurement of HbA1c. This will be applicable to participants in Australia only, who provide consent for storage of blood samples.
Timepoint [15] 428378 0
Day 196 (completion of extension trial), compared to day 168 (end of main CLOSE IT trial).

Eligibility
Key inclusion criteria
Participants will be drawn from those randomised to the intervention arm of the main CLOSE IT trial.

Inclusion criteria for CLOSE IT are:
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
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
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) will be collected from days 183 – 196, and will be calculated for each participant by dividing the number of CGM measures within range by the total number of CGM measures recorded. This will be compared with time in range between days 155 - 168.

This trial is exploratory, with the sample size (n = 20) determined by resource limitations.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
26/10/2023
Actual
23/10/2023
Date of last participant enrolment
Anticipated
30/06/2024
Actual
Date of last data collection
Anticipated
31/07/2024
Actual
Sample size
Target
20
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23433 0
Baker Heart and Diabetes Institute - Melbourne
Recruitment postcode(s) [1] 38835 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 25078 0
New Zealand
State/province [1] 25078 0
Canterbury

Funding & Sponsors
Funding source category [1] 312500 0
Charities/Societies/Foundations
Name [1] 312500 0
JDRF Diabetes Research Fund
Country [1] 312500 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] 314088 0
University
Name [1] 314088 0
University of Otago, Christchurch
Address [1] 314088 0
2 Riccarton Ave, Christchurch Central, Christchurch 8011
Country [1] 314088 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311835 0
The Alfred Health Research Ethics Committee
Ethics committee address [1] 311835 0
Ethics committee country [1] 311835 0
Australia
Date submitted for ethics approval [1] 311835 0
24/10/2022
Approval date [1] 311835 0
05/12/2022
Ethics approval number [1] 311835 0
615/22
Ethics committee name [2] 311836 0
Health and Disability Ethics Committees
Ethics committee address [2] 311836 0
Ethics committee country [2] 311836 0
New Zealand
Date submitted for ethics approval [2] 311836 0
31/10/2022
Approval date [2] 311836 0
15/12/2022
Ethics approval number [2] 311836 0
2022 FULL 13832

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

Contacts
Principal investigator
Name 122538 0
A/Prof Neale Cohen
Address 122538 0
Baker Heart and Diabetes Institute
75 Commercial Road
Melbourne VIC 3004
Country 122538 0
Australia
Phone 122538 0
+61 385321800
Fax 122538 0
Email 122538 0
neale.cohen@baker.edu.au
Contact person for public queries
Name 122539 0
Neale Cohen
Address 122539 0
Baker Heart and Diabetes Institute
75 Commercial Road
Melbourne VIC 3004
Country 122539 0
Australia
Phone 122539 0
+61 385321800
Fax 122539 0
Email 122539 0
neale.cohen@baker.edu.au
Contact person for scientific queries
Name 122540 0
Neale Cohen
Address 122540 0
Baker Heart and Diabetes Institute
75 Commercial Road
Melbourne VIC 3004
Country 122540 0
Australia
Phone 122540 0
+61 385321800
Fax 122540 0
Email 122540 0
neale.cohen@baker.edu.au

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.