Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000034932
Ethics application status
Approved
Date submitted
19/11/2019
Date registered
20/01/2020
Date last updated
17/05/2022
Date data sharing statement initially provided
20/01/2020
Date results information initially provided
28/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing efficacy and safety of Automated Insulin Delivery utilizing open source technology in children and adults with Type 1 Diabetes
Scientific title
Randomised parallel arm open label clinical trial comparing automated insulin delivery using an open-source algorithm (AnyDANA-loop), with sensor augmented pump therapy in type 1 diabetes.
Secondary ID [1] 299770 0
CREATE-0001
Universal Trial Number (UTN)
U1111-1243-2843
Trial acronym
CREATE (Community deRivEd AutomaTEd insulin delivery) trial
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 315133 0
Condition category
Condition code
Metabolic and Endocrine 313454 313454 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants in the intervention arm used AnyDANA-Loop during the 6month RCT. AnyDANA-Loop is an AID system consisting of an the Dana-iTM insulin pump, Dexcom G6® CGM, and a locked-down version of the AndroidAPS algorithm (as an application installed on a smartphone provided to all participants). The AnyDANA-Loop app communicates with the Dana-iTM pump to obtain details of all recent insulin dosing (basal and boluses) and with the CGM to obtain current and recent sensor glucose levels, and issues commands to the pump to adjust insulin dosing to optimise glucose levels.

Approximately three months into the study with around two thirds of the cohort having had been recruited, a universal issue with the Dana-iTM insulin pump battery draining quickly (within hours to days) emerged. As a result, the Dana-iTM pumps underwent a rigorous process of refurbishment, and further recruitment was delayed until refurbished pumps had been deployed to active participants. AID users were able to be supported to safely continue AID with the Dana-iTM pump and they were given priority for a refurbished pump.

During the 6month continuation phase, participants in the intervention arm had the option to continue using the Dana-i insulin pump with automation, or switch to the YpsoPump with automation. The insulin pump was the only a change, and the AID algorithm was unchanged.
Intervention code [1] 316024 0
Treatment: Devices
Comparator / control treatment
Participants in the SAPT arm used the Dexcom G6® CGM with either a refurbished Dana-iTM insulin pump or their personal pump during the RCT Phase (personal pumps were made an option due to the Dana-i pump battery issue). Those using a Tandem t:Slim X2 pump were asked to ensure the Basal IQ software was inactive. An application, called Monitor, was installed on the study mobile phone of SAPT participants which ran in the background to receive insulin pump and CGM data and upload these in real-time to Nightscout. Like participants in the intervention arm, those randomised to SAPT could choose to have high/ low glucose alerts set in the Dexcom app, but they did not have access to automation of insulin delivery. SAPT participants were managed clinically by the investigative team at each site who reviewed glucose data in Nightscout and recommended changes to insulin pump settings at the 3 monthly study visits. At the conclusion of the RCT Phase, SAPT participants underwent AID training prior to progressing into the Continuation Phase. All participants originally randomised to SAPT used the YpsoPump with automation during the 6month continuation phase.
Control group
Active

Outcomes
Primary outcome [1] 321924 0
The primary outcome, mean percentage of time spent in target glucose range (3.9 to 10.0 mmol/L) will be collected from days 155 – 168 (last 2 weeks 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.
Timepoint [1] 321924 0
The randomised clinical trial phase is 6-months duration, with the primary outcome measured at the end of this phase (day 155-168)
Secondary outcome [1] 376717 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to: Glycaemic Control by measuring HbA1c 3 monthly (in clinics) during the RCT and continuation phase and assessment of standard CGM metrics including:
% CGM time 3.0 - 3.9 mmol/L (level 1 hypoglycaemia)
% CGM time less than 3.0 mmol/L (level 2 hypoglycaemia)
% CGM time less than or equal to 2.5 mmol/L
% CGM time 10.1 - 13.9 mmol/L (level 1 hyperglycaemia)
% CGM time more than or equal to 14.0 mmol/L (level 2 hyperglycaemia)
Timepoint [1] 376717 0
Glycaemic control based upon CGM data will be calculated for each participant for each adjacent 14 day block throughout the study (for example, day 1 to day 14, day 15 to day 28, …, day 155 to day 168). This data will be summarised as medians and quantiles by treatment group and time, and presented in figures.
Secondary outcome [2] 376718 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to experience of fear related to hypoglycemia using the Hypoglycaemia Fear Survey II, short form. Participants aged 7-17 years inclusive and their parent/ guardian will complete child and parent versions of the Hypoglycaemia Fear Survey (HFS II) respectively. Participants 18 years and older will complete the adult version.

Timepoint [2] 376718 0
This questionnaire will be completed at the baseline visit, at the end of the RCT phase and again at the end of the Continuation Phase.
Secondary outcome [3] 376719 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to: Platform Performance. This will be assessed by measuring the percentage of time participants randomised to the AID arm are using AID mode. This data will be available and pulled from the cloud based sever- Nightscout. Platform performance will also be gauged by documenting any software and/ or hardware technical issues which participants can flag to study staff at any time during the entire study duration. Such issues will also be asked at clinic visits (at least 6 scheduled during the study), raised in the individual interviews (to occur after the RCT phase) for those who consent to participate in these and may also become apparent from analysis of the online peer-peer discussions.
Timepoint [3] 376719 0
Continuous throughout the RCT and Continuation Phase.
Secondary outcome [4] 376720 0
A secondary (composite) objective of this study is to evaluate the effectiveness of the Human-Technology Interaction for both participants using AID mode as well as healthcare professionals (HCPs).
This will be assessed by:
- ongoing content/ thematic analysis of online, peer-to-peer learning of participants to assess topics posted (i.e., basic functioning of AID, troubleshooting AID problems, Advanced AID use, tips and tricks for using AID, impact of AID, celebration of successes and sharing of difficulties), frequency of posts, study ID initiating posts and responding to posts (in order to establish a profile superusers including their glycaemic control and demographic characteristics).
- ongoing content analysis of online, peer-to-peer learning of HCPs ( (Slack Technologies Ltd, 2018) will assess frequency of posts by channel over time by HCP and Investigators, frequency of specific words in posts over time and conversation length. Analysis will focus on the topics being discussed and changes in frequency of topic, and frequency with which NI’s Crocket and Lewis provide answers vs other Healthcare Professionals providing answers over the duration of the trial.
- interviews with participants to assess their processes of learning and explore usability and acceptability of the intervention
- a focus group examining processes of learning amongst HCPs will focus on their experiences of supporting trial participants to use the AID system and the training materials provided.
- interviews with a selection of HCPs may be conducted at each site as the all participants randomised to AID complete the RCT phase to assess their experiences of supporting trial participants to use the AID system and the training materials provided.
- interviews with participants who discontinue the treatment (to occur within one month of the participant discontinuing the study) to assess usability and acceptability of the intervention.
Timepoint [4] 376720 0
Participant interviews will occur within 6 weeks of completing the RCT phase for those randomised to the AID arm. Thematic analysis will be undertaken on interview data.
HCP interviews to occur within one month of the site’s last subject completing the RCT phase.
There will be ongoing content and thematic analysis of online, peer-to-peer learning of participants and HCPs throughout the study duration.
HCP focus groups to occur within one month of all sites having 5 participants complete the first three months of the RCT phase
Interviews with participants who discontinue the treatment to occur within one month of the participant discontinuing the study.
Secondary outcome [5] 378035 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to:
Mean sensor glucose and glucose variability (expressed primarily as coefficient of variation and secondly as a SD)
Timepoint [5] 378035 0
This secondary outcome based upon CGM data will be calculated for each participant for each adjacent 14 day block throughout the study (for example, day 1 to day 14, day 15 to day 28, …, day 155 to day 168). This data will be summarised as medians and quantiles by treatment group and time, and presented in figures.
Secondary outcome [6] 378037 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to:
Glycaemic outcomes differentiated as 24 hours, day (0600-2159 hours) and night (2200-0559 hours)
Timepoint [6] 378037 0
This secondary outcome based upon CGM data will be calculated for each participant for each adjacent 14 day block throughout the study (for example, day 1 to day 14, day 15 to day 28, …, day 155 to day 168). This data will be summarised as medians and quantiles by treatment group and time, and presented in figures.
Secondary outcome [7] 378038 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to: Severe Adverse Event (SAE) and Severe Adverse Device Effect (SADE) rates including diabetic ketoacidosis and severe hypoglycaemia and; Adverse Device Effect (ADE) rate.
Timepoint [7] 378038 0
AE collection will occur continuously. Participants will have clear instructions to contact study staff for issues such as ketones or severe hypoglycaemia. Participants will specifically be asked about any potential AEs at each study visit (at least 6 visits are scheduled).
Secondary outcome [8] 378620 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to sleep quality using the Pittsburgh Sleep Quality Index in participants 13 years inclusive and older.
Timepoint [8] 378620 0
The PSQI will be completed at the baseline visit, at the end of the RCT phase and again at the end of the Continuation Phase.
Secondary outcome [9] 378621 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to participants current treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire status (DTSQs). A Parent version of the DTSQs will be completed for participants 7-12 years inclusive, participants 13-17 years inclusive will complete a teen version (parents can also do this) and the adult version is to be completed by participants 18 years inclusive and older.
Timepoint [9] 378621 0
The DTSQs will be completed at the baseline visit, at the end of the RCT phase and again at the end of the Continuation Phase.
Secondary outcome [10] 378622 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to health state (physical and mental) using the EuroQol 5-dimensional Questionnaire (EQ-5D). The EQ-5D-Y will be completed by participants 8-15 years inclusive. The EQ-5D-5L will be completed by participants 16 years inclusive and older. This questionnaire will not be completed by participants 7 years of age.
Timepoint [10] 378622 0
The EQ-5D will be completed at the baseline visit, at the end of the RCT phase and again at the end of the Continuation Phase.
Secondary outcome [11] 378623 0
A secondary objective of this study is to evaluate the effectiveness of the AnyDANA-loop platform relative to SAPT therapy, with regards to eating behaviors using the Research Food Diary app on four non-consecutive days (three weekdays and one weekend day).
Timepoint [11] 378623 0
Participants will be asked to complete the 4 day food diary during the 4 week run in period as well as in the last week of the RCT Phase.

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Type 1 diabetes as per the American Diabetes Association classification for > 1 years prior to the Baseline Visit
2. Aged 7 - 70 years inclusive stratified into two groups (7 - 15 years inclusive and 16 - 70 years years inclusive) at Baseline
3. Currently on insulin pump therapy for > 6 months prior to the Baseline Visit
4. Mean HbA1c < 10.5% (91 mmol/mol) within 6 months prior to the Baseline Visit (minimum of one test)
5. Willing and able to adhere to the study protocol
6. Have daily access to a Wi-Fi network
Minimum age
7 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. If female, is pregnant or plans to become pregnant while participating in the study. A positive urine pregnancy test at Screening is exclusionary
2. Alcohol or drug dependence
3. Severe visual impairment that would impair use of the device
4. Any comorbid medical or psychological factors that would, on assessment by the investigators, make the person unsuitable for the study
5. A lack of English literacy that would, on assessment by the investigators, make the person unsuitable for the study
6. Allergic or intolerant to NovoRapid® insulin

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 obtainment of consent has been verified and stratification variables entered into REDCap. Then 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 participant has been enrolled.
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 participants’ age, baseline HbA1c (<8.1%/64mmol/mol and >8.0%/64mmol/mol), and study site to ensure these prognostic factors are balanced between groups.
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
Determination of Sample Size
Data from recent studies in a similar patient demographic show percentage of time spent in target range using SAPT was 57 ± 11% for children and 54 ± 12% for adults. Assuming a standard deviation of 12.5%, a total sample size of 68 (17 per group per strata) will provide 90% power at a two-sided significance level of 0.05 to detect a treatment effect if the absolute improvement in time in target glycaemic range of children and adults is at least 10% or more (effect size = 0.8). The sample size in each strata (children and adults) will be inflated to 50 (a total study sample size of 100) to allow for the absolute improvement in one of the strata to be as low as 5% and to include up to 15% lost-to-follow-up. A sample size of 100 will also provide up to 69 person-years of intervention follow up giving 90% power to detect event rates as low as 3.4 per 100 person-years, capturing clinically
meaningful data with respect to safety endpoints and time spent in significant hypoglycaemia (<2.5mmol/L).

Statistical Methods

The primary endpoint; mean percentage of time spent in target glucose range (3.9 to 10.0 mmol/L) between days 155 - 168 (RCT phase), will be calculated for each participant by dividing the number of CGM measures within range by the total number of CGM measures recorded. The overall treatment effect (primary outcome) shall be determined by using a global F-test (ANOVA) to compare a linear model containing age strata and treatment group and their interaction, versus the ‘null’ model containing age strata only. Simulation shows that this approach preserves the overall type 1 error rate, whilst allowing for investigation of treatment effects at a subgroup level. Group means and differences in group means will be estimated with 95% confidence intervals using ordinary least squares linear regression models with adjustment for stratification factors.
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. The stability of outcomes achieved by participants at day 168 (end of RCT phase) will be assessed by entering data collected during the continuation phase into likelihood-based linear mixed-effect models. The mean change and standard deviation of change in outcomes over time between days 168 - 336 (continuation phase) will be estimated with 95% confidence intervals, stratified by treatment group. Harms, for example adverse event (AE) and severe adverse event rates, will be grouped, tallied and reported.

Content (quantitative) and thematic (qualitative) analysis will be undertaken of interactions on both Healthcare Professionals (HCPs) and patients’ online platforms. Content analysis will be separately undertaken for HCPs’ and patients’ data sets as follows.
HCP’s use of a shared Slack Workspace (Slack Technologies Ltd, 2018) will be tracked using Excel (Microsoft Corporation Ltd, 2019). Data recorded will include: topic of questions being asked (i.e., basic functioning of AID, trouble-shooting AID problems, tips and tricks for using AID, impact of AID, psycho-social aspects), frequency of questions being asked, and whether answers are provided by other HCPs or by investigators with expertise in AnyDana-Loop (NI’s Crocket and Lewis). Analysis will focus on the topics being discussed and changes in frequency of topic, and ability of HCPs to answer questions over the duration of the trial.
Patient’s use of a shared, private online platform (Tribe Technologies Ltd, 2019) for peer-to-peer learning and support will be recorded using Excel (Microsoft Corporation Ltd, 2019). Data recorded will include: Study ID of patient initiating a post, topic of the post (i.e., basic functioning of AID, trouble-shooting AID problems, tips and tricks for using AID, impact of AID, psycho-social aspects), frequency of posts and frequency of responses to posts. Analysis will focus on the frequency of topics being posted in relation to the length of time the initial poster and responders have been participating in the trial.
Data for qualitative analysis from individual interviews (verbatim transcripts) and online platforms (screenshots of posts) will be imported into qualitative data management software Nvivo (QRS International Pty Ltd, 2014) for management, retrieval and interrogation by two researchers, including NI Crocket. Thematic analysis, as described by Braun and Clark, will be used. Coding will be undertaken inductively. Generation of themes from these codes will be informed by social-ecological theory and prior literature relating to human factors in AID use.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/03/2020
Actual
7/09/2020
Date of last participant enrolment
Anticipated
1/12/2020
Actual
28/05/2021
Date of last data collection
Anticipated
1/02/2022
Actual
6/05/2022
Sample size
Target
100
Accrual to date
Final
100
Recruitment outside Australia
Country [1] 22035 0
New Zealand
State/province [1] 22035 0
Christchurch, Canterbury
Country [2] 22036 0
New Zealand
State/province [2] 22036 0
Dunedin, Otago
Country [3] 22037 0
New Zealand
State/province [3] 22037 0
Auckland
Country [4] 22038 0
New Zealand
State/province [4] 22038 0
Hamilton, Waikato

Funding & Sponsors
Funding source category [1] 304236 0
Government body
Name [1] 304236 0
Health Research Council of New Zealand
Country [1] 304236 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
University of Otago
362 Leith Street, North Dunedin, Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 304475 0
None
Name [1] 304475 0
Address [1] 304475 0
Country [1] 304475 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304696 0
Health and Disability Ethics Committees (HDEC)
Ethics committee address [1] 304696 0
Postal address:
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Street address:
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 304696 0
New Zealand
Date submitted for ethics approval [1] 304696 0
20/12/2019
Approval date [1] 304696 0
14/04/2020
Ethics approval number [1] 304696 0
20/STH/1/AM01

Summary
Brief summary
The CREATE (Community deRivEd AutomaTEd insulin delivery) trial is the first randomised controlled trial assessing an open-source algorithm for automated insulin delivery. The system studied was a version of AndroidAPS (using the OpenAPS algorithm) paired with the DANA-i™ insulin pump and Dexcom G6® CGM. The user interface was an Android smartphone application: termed AnyDANA-Loop for convenience in the study. Participants used the AnyDANA-Loop application for mealtime insulin dosing and AnyDANA-Loop then automated insulin delivery in response to the glucose target. The study included 100 participants 7-70 years from four diabetes centres in New Zealand. The 6 month RCT assessed efficacy and safety of open-source AID compared to sensor augmented pump therapy (SAPT). A 6 month continuation phase followed to assess long-term efficacy and safety, with the majority of participants undergoing a hardware switch to use an YpsoPump in place of the Dana pump.
Trial website
https://www.otago.ac.nz/christchurch/departments/paediatrics/research/otago717634.html
Trial related presentations / publications
Public notes
Protocol paper published in May JDMD 2020:
Burnside M, Lewis D, Crocket H, Wilson R, Williman J, Jefferies C et al. CREATE (Community deRivEd AutomaTEd insulin delivery) trial, Randomised parallel arm open label clinical trial comparing automated insulin delivery using a mobile controller (AnyDANA-loop) with an open-source algorithm with sensor augmented pump therapy in type 1 diabetes. Journal of Diabetes and Metabolic Disorders. Published online 2 June 2020.

Crocket, H, Lewis, DM, Burnside, M, et al. Learning challenges of healthcare professionals supporting open-source automated insulin delivery. Diabet Med. 2021; 00:e14750. doi:10.1111/dme.14750

100 participants recruited. 3 participants with drew during the Run in phase, so 97 entered in to the RCT.

Contacts
Principal investigator
Name 97902 0
Dr Martin de Bock
Address 97902 0
Department of Paediatrics
University of Otago, Christchurch
2 Riccarton Avenue
Christchurch 8011
Country 97902 0
New Zealand
Phone 97902 0
+64 211 956 579
Fax 97902 0
Email 97902 0
Martin.debock@otago.ac.nz
Contact person for public queries
Name 97903 0
Dr Martin de Bock
Address 97903 0
Department of Paediatrics
University of Otago, Christchurch
2 Riccarton Avenue
Christchurch 8011
Country 97903 0
New Zealand
Phone 97903 0
+64 211 956 579
Fax 97903 0
Email 97903 0
Martin.debock@otago.ac.nz
Contact person for scientific queries
Name 97904 0
Dr Martin de Bock
Address 97904 0
Department of Paediatrics
University of Otago, Christchurch
2 Riccarton Avenue
Christchurch 8011
Country 97904 0
New Zealand
Phone 97904 0
+64 211 956 579
Fax 97904 0
Email 97904 0
Martin.debock@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Participant data will not be shared outside of the CREATE Trial.


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
EmbaseCurrent advances of artificial pancreas systems: A comprehensive review of the clinical evidence.2021https://dx.doi.org/10.4093/dmj.2021.0177
EmbaseExtended Use of an Open-Source Automated Insulin Delivery System in Children and Adults with Type 1 Diabetes: The 24-Week Continuation Phase Following the CREATE Randomized Controlled Trial.2023https://dx.doi.org/10.1089/dia.2022.0484
EmbaseInterviews with Indigenous Maori with type 1 diabetes using open-source automated insulin delivery in the CREATE randomised trial.2023https://dx.doi.org/10.1007/s40200-023-01215-3
EmbaseCREATE (Community deRivEd AutomaTEd insulin delivery) trial. Randomised parallel arm open label clinical trial comparing automated insulin delivery using a mobile controller (AnyDANA-loop) with an open-source algorithm with sensor augmented pump therapy in type 1 diabetes.2020https://dx.doi.org/10.1007/s40200-020-00547-8
N.B. These documents automatically identified may not have been verified by the study sponsor.