Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000320257
Ethics application status
Approved
Date submitted
28/02/2018
Date registered
5/03/2018
Date last updated
2/11/2020
Date data sharing statement initially provided
1/05/2019
Date results information initially provided
1/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Managing diabetes in a ‘flash’
Scientific title
A randomised controlled trial investigating flash glucose monitoring targeting glycaemic control among adolescents with sub-optimally controlled type 1 diabetes
Secondary ID [1] 293579 0
None.
Universal Trial Number (UTN)
Universal Trial Number (UTN): U1111-1205-5784
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 diabetes 305818 0
Condition category
Condition code
Metabolic and Endocrine 305035 305035 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The FreeStyle Libre flash glucose monitoring (FGM) system (reader, sensor, software) plus usual care, will be provided to the intervention group for the duration of the trial period (12 months in total: 6-month RCT, followed by a 6-month continuation study).

To use the FGM, a thin sensor is inserted into the back of one arm, which relays the patient's current interstitial glucose levels to a handheld reader when the reader is held next to the sensor. The sensor must be replaced every 14 days during the trial period.

During the baseline study visit, the first FreeStyle Libre sensor will be applied by trained staff (i.e., diabetes nurse or research staff trained by a FreeStyle Libre distributor territory manager) using the manufacturer’s quick start guide. Patients will be instructed to follow the manufacturer's guidelines for using the FGM system and will be given brief education on using the system. As a safety precaution, participants will be advised to perform finger stick blood glucose level measurements to confirm their blood glucose level before therapeutic interventions or corrective action if hypo- or hyperglycaemic glucose levels or symptoms occur.

Fourteen days after the initial visit, participants will return to the clinic for an inspection of the insertion site and be supervised applying a sensor on their own. Participants will be asked to report any adverse events (skin reactions to the sensor and/or adhesive, severe hypoglycaemic events, DKA, hospital admissions) during this visit and will be sent an electronic survey to report adverse events every 14 days thereafter.

At the 6-month visit, all participants will be provided FGM supplies and those who consent to an adhesive sub-study will be randomised to one of two groups. Group 1 will receive a 3-month supply of pre-cut sports tape to place over each sensor. Group 2 will be instructed to use no products to prevent sensor loss. At the 9-month visit participants in the adhesive sub-study will cross over to the other group.

All diabetes care will be as per standard clinic care, with the study only providing support for technical issues with the device. Glucose readings will be downloaded during routine clinic visits to be reviewed by a paediatric endocrinologist and during study visits to download retrospective glucose data for analysis. Data from each participant's FreeStyle Libre glucose monitoring system will also be used to monitor adherence to the intervention (eg, frequency of sensor scanning).
Intervention code [1] 299831 0
Treatment: Devices
Intervention code [2] 299832 0
Behaviour
Comparator / control treatment
Participants allocated to the control group will receive standard diabetes care (as described above) from their usual provider. Participants in this group will continue to self-monitor blood glucose levels using conventional finger stick blood glucose testing with their own glucometer. No additional intervention will be provided during the 6-month primary study period. At 6 months, the group will be offered a 6-month FGM intervention.
Control group
Active

Outcomes
Primary outcome [1] 304226 0
Glycaemic control (as measured by HbA1c)
Timepoint [1] 304226 0
baseline, 3-, 6- (primary time point), 9-, and 12 months post-baseline.
Secondary outcome [1] 341299 0
Mean number of sensor scans/blood glucose level tests over the preceding 14 days. This objective data will be captured by the glucose monitoring devices (i.e., FreeStyle Libre glucose monitoring system, glucose meter, respectively).
Timepoint [1] 341299 0
baseline, 3-, 6-, 9-, and 12 months post-baseline.
Secondary outcome [2] 341300 0
Diabetes treatment satisfaction as measured by the Diabetes Treatment Satisfaction Questionnaire (status and change versions).
Timepoint [2] 341300 0
baseline, 3-, 6-, and 12 months post-baseline.
Secondary outcome [3] 341301 0
Quality of life as measured by the Euro Quality of Life (EQ-5D-3L).
Timepoint [3] 341301 0
baseline, 3-, 6-, and 12 months post-baseline.
Secondary outcome [4] 341302 0
Flash glucose monitoring acceptability (i.e., acceptability of sensor application, wear/use of the device and comparison to finger stick self-monitoring blood glucose) will be measured by a non-validated questionnaire designed specifically for this study.
Timepoint [4] 341302 0
3-, 6-, and 12 months post-baseline.
Secondary outcome [5] 341303 0
Self-reported days off from school or work because of diabetes will be captured via an unvalidated online questionnaire asking "In the previous 14 days, did you miss school or work?" "If yes, how many days of school or work did you miss?" "If yes, why did you miss school or work?". "In the previous 14 days, did a parent/caregiver miss work to take care of you?" "If yes, how many days?" "If yes, why did a parent/caregiver miss work to take care of you?"
Timepoint [5] 341303 0
2-, 4-, 6-, 8-, 10-, 12-, 14-, 16-, 18-, 20-, 22-, 24-, 26-, 28-, 30-, 32-, 34-, 36-, 38-, 40-, 42-, 44-, 46-, 48-, 50-, 52-weeks post-baseline.
Secondary outcome [6] 343737 0
Self-reported health care professional visits (eg., general practitioner, nurse, endocrinologist)
Timepoint [6] 343737 0
2-, 4-, 6-, 8-, 10-, 12-, 14-, 16-, 18-, 20-, 22-, 24-, 26-, 28-, 30-, 32-, 34-, 36-, 38-, 40-, 42-, 44-, 46-, 48-, 50-, 52-weeks post-baseline.
Secondary outcome [7] 343738 0
For safety purposes, we will monitor adverse events associated with flash glucose monitoring use (eg, severe hypoglycaemia, diabetic ketoacidosis, skin irritations and reactions, and sensor failures). Participants will self-report such adverse events via an online questionnaire emailed and sent by text message.
Timepoint [7] 343738 0
2-, 4-, 6-, 8-, 10-, 12-, 14-, 16-, 18-, 20-, 22-, 24-, 26-, 28-, 30-, 32-, 34-, 36-, 38-, 40-, 42-, 44-, 46-, 48-, 50-, 52-weeks post-baseline.
Secondary outcome [8] 343821 0
Self-reported emergency department visits
Timepoint [8] 343821 0
2-, 4-, 6-, 8-, 10-, 12-, 14-, 16-, 18-, 20-, 22-, 24-, 26-, 28-, 30-, 32-, 34-, 36-, 38-, 40-, 42-, 44-, 46-, 48-, 50-, 52-weeks post-baseline.
Secondary outcome [9] 343822 0
Self-reported hospital admissions
Timepoint [9] 343822 0
2-, 4-, 6-, 8-, 10-, 12-, 14-, 16-, 18-, 20-, 22-, 24-, 26-, 28-, 30-, 32-, 34-, 36-, 38-, 40-, 42-, 44-, 46-, 48-, 50-, 52-weeks post-baseline.
Secondary outcome [10] 375372 0
Self-reported sensor loss (a sensor falling off prematurely, before the end of the 14-day session).
Timepoint [10] 375372 0
-28, -30, -32, -34, -36, -38, -40, -42, -44, -46, -48, -50, -52 weeks from baseline.

Eligibility
Key inclusion criteria
1) aged 13 to 20 years, inclusive;
2) diagnosed with T1D for at least 12 months;
3) mean HbA1c of >= 75 mmol/mol over the past 6 months;
4) >0.5 units of insulin/kg/day (with no restrictions based on insulin regimen);
5) plans to continue with routine clinical care during the 6-month study;
6) currently residing in and expecting to remain in regions served by the Canterbury, Capital and Coast, South Canterbury, and Southern District Health Boards for the following year;
7) the ability to understand study procedures and to comply with them for the entire length of the study.
Minimum age
13 Years
Maximum age
20 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Any severe diabetes related complications (nephropathy on treatment, retinopathy with associated visual loss – milder degrees will not be excluded);
2) Other severe uncontrolled medical or psychiatric co-morbidity/severe mental illness;
3) currently using a CGM device or has used one continuously (other than for intermittent hospital use) within the previous 4 months;
4) participation in another device or drug study that could affect glucose measurements during the study period;
5) pregnancy, lactation, or plans to become pregnant;
6) inability of individual or legal guardian to give written informed consent.

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)
Allocation is concealed. Patients who give consent for participation and fulfil the eligibility criteria will be enrolled in the study and randomly allocated by an offsite biostatistician in batches using a 1:1 ratio to either the waitlist control (SMBG) group or the intervention (FGM) group. The statistician will be blinded to allocation arm and will use non-informative group codes until all planned analyses are completed. The study group will be revealed to the participant at the baseline visit after all assessments have been completed.

At the 6-month visit, participants who consent to the adhesive sub-study will be randomised to using pre-cut sports tape "patches" over each sensor for 3 months or to no use of any products to prevent premature sensor loss. The randomization sequence will be generated by one of the investigators (AG) using Stata software (version 11.2 for MAC; StataCorp, College Station, TX) and entered into a spreadsheet of group allocation (Rockadex patch or control) with sequence numbers and codes. The spreadsheet will be printed and cut so that individual slips of paper with the sequence number and group allocation will be put into an opaque envelope labelled with the sequence number. Once a participant consents to the adhesive study, the next envelope will be opened and the group assignment will be added to the 6-month study visit details in REDCap and the randomization process is completed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
As gender and pre-study HbA1c may significantly affect the primary outcomes, minimisation will be used (based on gender [male, female; HbA1c [75 to less than 100 mmol/mol, greater than or equal to 100 mmol/mol ]) and with a small random component (20%) along with randomly ordering the participants in each batch used to preserve allocation concealment.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
At 6-months, only the waitlist control group will crossover and receive a 6-month FGM intervention.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Means and standard deviations (SDs) will be reported for continuous variables (i.e., age, diabetes duration, HbA1c, glucose monitoring behaviour, questionnaire scores) that are approximately normally distributed, geometric means and SDs for those that are approximately log-normally distributed, and medians and IQRs otherwise. Categorical variables will be described as the number and percent of participants in each category (i.e., gender, ethnic group, insulin regimen). Adverse events will be categorised by the type of event (e.g., severe hypoglycaemia, DKA, sensor insertion issues, sensor wear issues). The frequency of events will be reported by event category.

A mixed linear model will be used to test the difference in HbA1c, with the primary outcome being at 6-months, between the intervention and control groups, using data from all time points with a random participant effect used to accommodate the repeated measures and a group-time interaction to model differences in longitudinal changes. Changes in number of glucose measurements performed and patient-reported outcome measures (i.e., PedsQL generic core scale, PedsQL diabetes module, HFS, and DTSQs scores) from baseline through to 6 months will be calculated by comparing scores from control and intervention group participants using Poisson (or negative binomial regression if there is evidence of over-dispersion) for count outcomes and linear mixed models for continuous outcomes with all collected data included. Model residuals will be examined along with the distribution of random effects. If residuals are positively skewed, natural logarithmic transformations will be investigated and retained if these improve the satisfaction of model assumptions. Mixed quantile regression will be investigated for continuous outcomes if issues with model residuals remain following such transformations. If HbA1c values of 130 are observed, mixed Tobit models with right censoring at 130 will be used for this outcome instead. All mixed models will use restricted maximum likelihood (REML) estimation for the variance components.

Some secondary analyses, such as those involving the wait-list control after they cross over, will only include participants from one group and so group (and group-time interaction) terms will not be included in these models.

The main analyses will follow a modified intention-to-treat principle with all participants analysed in the group to which they were randomised, regardless of actual sensor wear. Per protocol analyses will be also be investigated by including only those from the FGM group who scanned at least 12 out of 14 days in the two weeks prior to the 6-month study visit and excluding any participants from the SMBG group who used FGM at any time during the study. All models will include variables used in minimization.

Any missing HbA1c values will be imputed using multiple imputation with chained equations (100 imputations after at least 100 burn-ins) and with the imputation model including: gender, HbA1c status at baseline as well as values of that variable from other time points, insulin regimen, frequency of self-monitored glucose (capillary or interstitial) and socioeconomic status. If missing data exceeds 10%, plausible scenarios involving informative missing data will be investigated to explore the robustness of findings.

To investigate the effect of using pre-cut sports tape (Rockadex) to prevent sensor loss, statistical analyses will be performed using Cox's proportional hazards regression with robust clustered standard errors at the participant level to accommodate the repeated measures and with a time effect to adjust for systematic changes in survival during the six month period.

Statistical analyses will be performed using R 3.5.2 or Stata 15.1 software (or later versions) with two-sided p < 0.05 considered significant. To maintain the integrity of the study, statistical analyses will be performed by the biostatistician blinded to group allocation.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
12/03/2018
Actual
12/04/2018
Date of last participant enrolment
Anticipated
31/12/2018
Actual
21/11/2018
Date of last data collection
Anticipated
31/12/2019
Actual
15/10/2019
Sample size
Target
64
Accrual to date
Final
64
Recruitment outside Australia
Country [1] 9430 0
New Zealand
State/province [1] 9430 0
Otago
Country [2] 9431 0
New Zealand
State/province [2] 9431 0
Canterbury
Country [3] 9634 0
New Zealand
State/province [3] 9634 0
Southland
Country [4] 9635 0
New Zealand
State/province [4] 9635 0
Wellingon

Funding & Sponsors
Funding source category [1] 298193 0
University
Name [1] 298193 0
University of Otago
Country [1] 298193 0
New Zealand
Funding source category [2] 298816 0
Charities/Societies/Foundations
Name [2] 298816 0
Cure Kids
Country [2] 298816 0
New Zealand
Primary sponsor type
University
Name
Department of Women's and Children's Health, DSM
Address
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 297319 0
None
Name [1] 297319 0
Address [1] 297319 0
Country [1] 297319 0
Other collaborator category [1] 279863 0
Government body
Name [1] 279863 0
Southern District Health Board
Address [1] 279863 0
Dunedin Hospital
201 Great King St, Dunedin, 9016
Country [1] 279863 0
New Zealand
Other collaborator category [2] 279968 0
Government body
Name [2] 279968 0
Capital and Coast District Health Board
Address [2] 279968 0
Riddiford St, Newtown, Wellington 6021
Country [2] 279968 0
New Zealand
Other collaborator category [3] 279969 0
Government body
Name [3] 279969 0
Canterbury District Health Board
Address [3] 279969 0
The Princess Margaret Hospital
PO Box 800
Christchurch 8140
Country [3] 279969 0
New Zealand
Other collaborator category [4] 279974 0
Government body
Name [4] 279974 0
South Canterbury District Health Board
Address [4] 279974 0
High St, Parkside, Timaru 7910
Country [4] 279974 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299205 0
Health and Disability Ethics Committee
Ethics committee address [1] 299205 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 299205 0
New Zealand
Date submitted for ethics approval [1] 299205 0
23/11/2017
Approval date [1] 299205 0
13/03/2018
Ethics approval number [1] 299205 0
Ethics reference 17/STH/240

Summary
Brief summary
Managing diabetes in a ‘flash’ is a mixed-methods study exploring a novel flash glucose monitoring (FGM) system among adolescents with poorly controlled type 1 diabetes (T1D). 64 paediatric participants with T1D will be recruited from Canterbury, Capital and Coast, South Canterbury, and Southern District Health Board diabetes clinics.
Participants in the FGM group (n=32) will be given a FreeStyle Libre reader, a 12-month supply of sensors, and access to FreeStyle Libre software. The waitlist control group (n=32) will continue usual standard care for the first six months of the study. At six months, the waitlist control group will crossover and be provided a FreeStyle Libre reader, a six-month supply of sensors, and access to FreeStyle Libre software. All participants in the FGM group, and their caregivers, will be invited to one-to-one interviews to explore their experiences with the FGM.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2267 2267 0 0
/AnzctrAttachments/374147-Info sheet for Teens.docx

Contacts
Principal investigator
Name 79646 0
Dr Ben Wheeler
Address 79646 0
Department of Women’s and Children’s Health
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 79646 0
New Zealand
Phone 79646 0
+64 3 470 9167
Fax 79646 0
Email 79646 0
[email protected]
Contact person for public queries
Name 79647 0
Dr Sara Boucher
Address 79647 0
Department of Women’s and Children’s Health
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 79647 0
New Zealand
Phone 79647 0
+63 3 470 9167
Fax 79647 0
Email 79647 0
[email protected]
Contact person for scientific queries
Name 79648 0
Dr Ben Wheeler
Address 79648 0
Department of Women’s and Children’s Health
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 79648 0
New Zealand
Phone 79648 0
+64 3 470 9167
Fax 79648 0
Email 79648 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
Participant information sheets that were approved by the Ethics committee and since used in the study did not seek consent to share participant data with individuals who are not a named investigator. Requests for data can be sent to the primary investigator and consideration for amendments to the original ethics application can be made as required.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Boucher SE, Gray AR, Wiltshire EJ, de Bock MI, Gal... [More Details]
Plain language summaryNo For youth with high-risk glycemic control, flash g... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe 'flash' adhesive study: a randomized crossover trial using an additional adhesive patch to prolong freestyle libre sensor life among youth with type 1 diabetes mellitus.2020https://dx.doi.org/10.1007/s00592-020-01556-y
EmbaseImpact of 6 months' Use of Intermittently Scanned Continuous Glucose Monitoring on Habitual Sleep Patterns and Sleep Quality in Adolescents and Young Adults with Type 1 Diabetes and High-Risk HbA1c.2023https://dx.doi.org/10.1155/2023/1842008
EmbaseUse of intermittently scanned continuous glucose monitoring in young people with high-risk type 1 diabetes-Extension phase outcomes following a 6-month randomized control trial.2022https://dx.doi.org/10.1111/dme.14756
EmbaseExploring parental perspectives after commencement of flash glucose monitoring for type 1 diabetes in adolescents and young adults not meeting glycaemic targets: a qualitative study.2020https://dx.doi.org/10.1111/dme.14188
EmbaseInitial experiences of adolescents and young adults with type 1 diabetes and high-risk glycemic control after starting flash glucose monitoring - a qualitative study.2020https://dx.doi.org/10.1007/s40200-019-00472-5
EmbaseCutaneous adverse events in a randomized controlled trial of flash glucose monitoring among youth with type 1 diabetes mellitus.2020https://dx.doi.org/10.1111/pedi.13121
EmbaseEffect of 6 months of flash glucose monitoring in youth with type 1 diabetes and high-risk glycemic control: A randomized controlled trial.2020https://dx.doi.org/10.2337/dc20-0613
N.B. These documents automatically identified may not have been verified by the study sponsor.