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Trial registered on ANZCTR


Registration number
ACTRN12618000070235
Ethics application status
Approved
Date submitted
24/12/2017
Date registered
17/01/2018
Date last updated
17/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The Impact of Exercise on the Performance of an Artificial Pancreas in Type 1 Diabetes and Impaired Awareness of Hypoglycaemia
Scientific title
Evaluation of the Impact of Exercise and Related Changes in Counter-Regulatory Hormones on the Performance of an Artificial Pancreas in Adults with Type 1 Diabetes and Impaired Awareness of Hypoglycaemia
Secondary ID [1] 293623 0
None
Universal Trial Number (UTN)
U1111-1206-6874
Trial acronym
None
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 305890 0
Hypoglycaemia 305891 0
Condition category
Condition code
Metabolic and Endocrine 305085 305085 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a two-stage randomised crossover study involving adults with type 1 diabetes and impaired awareness of hypoglycaemia who are established on insulin pump therapy and have glucose sensing experience. The study aims to examine the performance of an ‘artificial pancreas’ or hybrid closed-loop (HCL) insulin delivery system challenged by high intensity intermittent exercise (HIIE) and moderate intensity exercise (MIE) in people with type 1 diabetes and impaired awareness of hypoglycaemia.

Previous studies have shown that the HCL system is safe for people with type 1 diabetes undertaking HIIE (anaerobic) and MIE (aerobic). However, this has not been assessed in the group with impaired awareness of hypoglycaemia. Potential participants will be identified using a validated questionnaire (Gold questionnaire) to assess their degree of hypoglycaemia unawareness. A Gold score of 4 or greater implies impaired awareness of hypoglycaemia.

All participants will use the HCL system for the study duration. Education specific to the HCL study system will be provided face-to-face by an experienced study doctor and a diabetes nurse educator, and will be tailored to each participant’s prior knowledge. Participants will also be provided educational material and resources, including a user guide booklet for the investigational HCL system. The HCL system comprises a glucose sensor coupled with an insulin pump containing a computerised automated insulin delivery algorithm. Glucose sensor information is transmitted to the insulin pump, and the dose of insulin is calculated by the algorithm and delivered every 5 minutes to account for basal insulin requirements. Participant initiated bolus insulin doses are still required for meals.

Following clinical assessment, each participant will undergo cardiopulmonary testing to determine their maximal amount of oxygen consumed during exercise (VO2 max as ml/kg/min), maximal exercise capacity (Watts) and anaerobic threshold. All participants will undertake the HIIE and MIE stages in random order. All exercise testing will be closely supervised at all times by both a qualified study doctor and a nurse with dual training in research coordination and diabetes education. Approximately 1 week after activation of the HCL system, participants will undertake their first exercise stage. They will then return ~1 week later to undertake the alternate exercise regimen. All exercise testing will be conducted in the late morning, at least 4 hours after breakfast is consumed.

The MIE protocol will be conducted on a stationary bicycle with 5 minutes of warm-up, followed by 40 minutes of steady-state exercise at 70% of anaerobic threshold. The HIIE protocol is high intensity interval training with 5 minutes of warm-up, then 6 repetitions of 4 minutes of exercise at an intensity halfway between their anaerobic threshold and maximal intensity, followed by 2 minutes of rest (an additional 4 minutes rest will be provided between the 3rd and 4th repetitions).

On the morning of the exercise study days, participants will have an early morning light breakfast (40g of carbohydrate), preceded by an insulin bolus via their own pump to account for the carbohydrate of the meal. The participants will commence their exercise program ~2 hours after arrival at the Clinical Trial Centre, at which time the ‘exercise mode’ of the HCL system will be activated. Venous blood samples will be collected at 15 minute intervals from 1 hour prior to exercise until 2 hours after exercise completion to assess insulin and counter-regulatory hormones.

Participants will return one week following the second exercise stage to return study devices and resume their usual insulin delivery system.
Intervention code [1] 299882 0
Treatment: Devices
Intervention code [2] 299883 0
Treatment: Drugs
Comparator / control treatment
We are comparing the effectiveness of an "Artificial Pancreas" in both aerobic (Moderate intensity exercise [MIE] protocol) and anaerobic exercise (High intensity intermittent exercise [HIIE] protocol).
Control group
Active

Outcomes
Primary outcome [1] 304263 0
Continuous glucose monitoring (CGM) % time spent in target glucose range (3.9–10mmol/L) for each exercise stage.
Timepoint [1] 304263 0
From exercise commencement to 24 hours post-exercise completion for each exercise stage.
Secondary outcome [1] 341538 0
Glycaemic outcomes 24 hours post exercise commencement
1.1. % CGM time 3.9–10mmol/L (excluding the primary endpoint)
1.2. % CGM time 3.9–8.0mmol/L
1.3. % CGM time <3.9 mmol/L
1.4. % CGM time <3.5 mmol/L
1.5. % CGM time <3.0 mmol/L
1.6. % CGM time <2.8 mmol/L
1.7. % CGM time >10.0 mmol/L
1.8 Glycaemia Variability as determined by mean amplitude of glycaemic excursions (MAGE) and standard deviation
1.9 CGM AUC > 10.0 mmol/L
1.10 CGM AUC <3.9 mmol/L
Timepoint [1] 341538 0
From exercise commencement to 24 hours post-exercise completion for each exercise stage.
Secondary outcome [2] 341539 0
Glycaemic outcomes for the night following exercise [0:00-08:00]
1.1 % CGM time 3.9–10mmol/L (excluding the primary endpoint)
1.2 % CGM time 3.9–8.0mmol/L
1.3 % CGM time <3.9 mmol/L
1.4 % CGM time <3.5 mmol/L
1.5 % CGM time <3.0 mmol/L
1.6 % CGM time <2.8 mmol/L
1.7 % CGM time >10.0 mmol/L
1.8 Glycaemia Variability as determined by mean amplitude of glycaemic excursions (MAGE) and standard deviation
1.9 CGM AUC > 10.0 mmol/L
1.10 CGM AUC <3.9 mmol/L
Timepoint [2] 341539 0
Night following exercise [00:00 - 08:00] for each exercise stage
Secondary outcome [3] 341540 0
Glycaemic outcomes from time of exercise commencement until 2 hours post-exercise completion
1.1 % CGM time 3.9–10mmol/L (excluding the primary endpoint)
1.2 % CGM time 3.9–8.0mmol/L
1.3 % CGM time <3.9 mmol/L
1.4 % CGM time <3.5 mmol/L
1.5 % CGM time <3.0 mmol/L
1.6 % CGM time <2.8 mmol/L
1.7 % CGM time >10.0 mmol/L
1.8 Glycaemia Variability as determined by mean amplitude of glycaemic excursions (MAGE) and standard deviation
1.9 CGM AUC > 10.0 mmol/L
1.10 CGM AUC <3.9 mmol/L
Timepoint [3] 341540 0
From exercise commencement to 2 hours post-exercise completion for each exercise stage.
Secondary outcome [4] 341541 0
Differences in peak counter-regulatory hormone levels measured using serum assays for catecholamines, glucagon, growth hormone, cortisol, lactate, ketones during hybrid closed-loop therapy for:
1. High-intensity intermittent exercise
2. Moderate-intensity exercise
Timepoint [4] 341541 0
Monitored at 15 minute intervals from 1 hour prior to exercise commencement until 2 hours post-exercise completion (ie. specific timepoints in relation to exercise commencement: -60, -45, -30, -15, 0, +15, +30, +45, +60, +75, +90, +105, +120, +135, +150, +165 minutes)
Secondary outcome [5] 341542 0
Number of episodes of hypoglycaemia (glucose levels < 3.9mmol/L) using CGM data uploaded from the HCL study pump
Timepoint [5] 341542 0
From exercise commencement to 2 hours post-exercise completion for each exercise stage.
Secondary outcome [6] 341543 0
Number of episodes of hypoglycaemia (glucose levels < 3.9mmol/L) using CGM data uploaded from the HCL study pump
Timepoint [6] 341543 0
From exercise commencement to 24 hours post-exercise completion for each exercise stage.
Secondary outcome [7] 341544 0
Number of episodes of hypoglycaemia (glucose levels < 3.9mmol/L) using CGM data uploaded from the HCL study pump
Timepoint [7] 341544 0
From exercise commencement to 48 hours post-exercise completion for each exercise stage.
Secondary outcome [8] 341545 0
Total number of episodes of hypoglycaemia (glucose levels <3.9mmol/L) whilst using the hybrid closed-loop system
Timepoint [8] 341545 0
Commencement of study to end-of-study.
Secondary outcome [9] 341546 0
Episodes of symptomatic hypoglycaemia (the presence of typical symptoms of hypoglycaemia accompanied by a measured finger-prick glucose level <3.9mmol/l) as reported by the participant
Timepoint [9] 341546 0
From exercise commencement to 24 hours post-exercise completion for each exercise stage.
Secondary outcome [10] 341547 0
Episodes of major hypoglycaemia (defined as any low glucose level requiring the assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions) as reported by the participant
Timepoint [10] 341547 0
From exercise commencement to 24 hours post-exercise completion for each exercise stage.
Secondary outcome [11] 341548 0
Episodes of hyperglycaemia (>10.0mmol/L) and blood ketones >0.6 mmol/L as reported by the participant (composite secondary outcome)
Timepoint [11] 341548 0
From exercise commencement to 24 hours post-exercise completion for each exercise stage.
Secondary outcome [12] 341549 0
Number of unscheduled exits from closed-loop system using CGM data uploaded from the HCL study pump.
Timepoint [12] 341549 0
Commencement of study to end-of-study.

Eligibility
Key inclusion criteria
1. Type 1 diabetes
2. Established on insulin pump therapy for at least 6 months
3. Sensor experience
4. HbA1c < 10.0%
5. GOLD score >=4
6. Ability to perform exercise as per protocol
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Chronic kidney disease (eGFR <45mL/min/1.73m2)
2. Requiring > 150 units of insulin/day
3. Diabetic ketoacidosis within the past 4 weeks
4. Use of non-insulin glucose-lowering agent in the past 3 months
5. Steroid use (oral or injected) within past 3 months
6. Pregnancy
7. Ischaemic heart disease or peripheral vascular disease precluding exercise

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised random allocation (i.e. equal numbers in both groups)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
N/A
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is an exploratory study. There is an absence of available data allowing the calculation of statistical power. The data generated by this study will enable power calculations for future research.

Descriptive statistics will be used to describe safety and efficacy parameters. A formal statistical comparison by ANOVA will be used to compare time spent within target glucose range for each of the two exercise modalities. A quantitative analysis will be performed examining changes in circulating free insulin and counter-regulatory hormones in response to the two different forms of exercise.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9575 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 18331 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 298236 0
Hospital
Name [1] 298236 0
St Vincent's Hospital
Address [1] 298236 0
41 Victoria Pde
Fitzroy
VIC 3065
Country [1] 298236 0
Australia
Funding source category [2] 298240 0
Commercial sector/Industry
Name [2] 298240 0
Medtronic Diabetes
Address [2] 298240 0
18000 Devonshire Street
Northridge CA 91325
Country [2] 298240 0
United States of America
Funding source category [3] 298241 0
Charities/Societies/Foundations
Name [3] 298241 0
Diabetes Australia
Address [3] 298241 0
Level 1
101 Northbourne Ave
Turner ACT 2612
Country [3] 298241 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital
Address
41 Victoria Pde
Fitzroy
VIC 3065
Country
Australia
Secondary sponsor category [1] 297354 0
University
Name [1] 297354 0
The University of Melbourne
Address [1] 297354 0
Grattan Street
Parkville
VIC 3010
Country [1] 297354 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299246 0
St Vincent's Hospital Melbourne
Ethics committee address [1] 299246 0
41 Victoria Pde
Fitzroy
VIC 3065
Ethics committee country [1] 299246 0
Australia
Date submitted for ethics approval [1] 299246 0
Approval date [1] 299246 0
14/11/2017
Ethics approval number [1] 299246 0
HREC 167/17

Summary
Brief summary
A hybrid closed-loop (HCL) system or ‘artificial pancreas’ provides automated control of basal insulin delivery, with ongoing requirements for manual boluses of insulin for meals. These systems offer the potential to reduce significant glucose excursions outside of a healthy glucose range compared with current available therapies. Some people with type 1 diabetes have difficulty recognising when they are having a hypoglycaemic episode, which is called hypoglycaemic unawareness. This often leads to fear of exercise due to the unpredictable changes in glucose levels that can occur with exercise. It is known that short intense bursts of exercise (anaerobic exercise) may initially increase glucose levels, whilst less intense exercise (aerobic exercise) tends to reduce glucose levels.

This study aims to collect information on how well the HCL system controls glucose levels in people with type 1 diabetes and hypoglycaemia unawareness when they undertake anaerobic and aerobic exercise. Outcomes of interest will include time spent in healthy glucose range, and time spent in hypoglycaemic range. Insulin and counter-regulatory hormones will also be measured providing insights into changes in glucose levels with exercise in this group of people.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79782 0
Prof David O'Neal
Address 79782 0
St Vincent's Hospital Melbourne
41 Victoria Parade
Fitzroy
VIC 3065
Country 79782 0
Australia
Phone 79782 0
+61 3 9231 2211
Fax 79782 0
Email 79782 0
dno@unimelb.edu.au
Contact person for public queries
Name 79783 0
Dr Melissa Lee
Address 79783 0
St Vincent's Hospital Melbourne
41 Victoria Parade
Fitzroy
VIC 3065
Country 79783 0
Australia
Phone 79783 0
+61 3 9231 2211
Fax 79783 0
Email 79783 0
melissa.lee@svha.org.au
Contact person for scientific queries
Name 79784 0
Dr Melissa Lee
Address 79784 0
St Vincent's Hospital Melbourne
41 Victoria Parade
Fitzroy
VIC 3065
Country 79784 0
Australia
Phone 79784 0
+61 3 9231 2211
Fax 79784 0
Email 79784 0
melissa.lee@svha.org.au

No data has been provided for results reporting
Summary results
Not applicable