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Secondary Outcome(s)
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(Sub-study 2 Secondary Outcome): Difference in peak counter-regulatory hormone levels measured using serum assays for adrenaline, noradrenaline, dopamine, glucagon, growth hormone and cortisol during HCL vs standard therapy for:
1. High-intensity interval exercise
2. Moderate-intensity exercise
[From time of exercise commencement until 2 hours post-exercise completion
]
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(Sub-study 1): Changes in glycaemic outcome during HCL vs standard therapy, using CGM metrics[Mid-study (11-13 weeks post-randomisation) and end-of-study (23-26 weeks post-randomisation)
]
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(Sub-study 2 Secondary Outcome): Glycaemic outcomes from time of exercise commencement until 2 hours post-exercise completion during HCL vs standard therapy:
1.1. % CGM time 3.9–10mmol/L
1.2. % CGM time <2.8 mmol/L
1.3. % CGM time <3.3 mmol/L
1.4. % CGM time <3.9 mmol/L
1.5. % CGM time 3.9–7.8 mmol/L
1.6. % CGM time >10.0 mmol/L
1.7. % CGM time >13.9 mmol/L
1.8. % CGM time >16.7 mmol/L
1.9 Glycaemia Variability as determined by mean amplitude of glycaemic excursions (MAGE) and standard deviation
1.10 CGM AUC >10.0 mmol/L
1.11 CGM AUC <4.0 mmol/L
[From time of exercise commencement until 2 hours post-exercise completion
]
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Fasting capillary blood glucose during HCL vs standard therapy[During CGM period mid-study (11-13 weeks post-randomisation) and end-of-study (23-26 weeks post-randomisation)]
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Change in total daily dose of insulin, insulin-to-carbohydrate ratio and basal/bolus proportions during HCL vs standard therapy, using participant records in a study logbook and pump uploads.[From 0 to 26 weeks post-randomisation
]
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Psychological function assessing diabetes-specific quality of life during HCL vs standard therapy, using the DAWN impact of diabetes profile questionnaire (7 items - validated) [13 weeks and 26 weeks post-randomisation]
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HbA1c during HCL vs standard therapy measured on whole blood. All samples will be sent to a centralised DCCT-aligned laboratory.
[13 weeks and 26 weeks post-randomisation
]
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(Sub-study 2 Secondary Outcome): Episodes of hypoglycaemia during HCL vs standard therapy confirmed by capillary blood with the study glucose meter
1. Any episode (n) of blood glucose < 3.9 mmol/L for 0-24 hours following exercise commencement.
2. Episodes of major hypoglycaemia i.e. requiring 3rd party assistance (n) for 0-24 hours following exercise commencement.
[0-24 hours post exercise commencement
]
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Psychological function assessing fear of hyperglycaemia during HCL vs standard therapy, using the Hyperglycaemia Avoidance Scale (26 items - validated)
[13 weeks and 26 weeks post-randomisation]
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Glycaemic outcomes during HCL vs standard therapy:
CGM metrics for day [06:00–00:00], night [00:00–06:00] and day+night, measured at mid-study, end-of-study, and mid+end-of-study combined:
1.1. % CGM time 3.9–10mmol/L (excluding the primary endpoint)
1.2. % CGM time <2.8 mmol/L
1.3. % CGM time <3.3 mmol/L
1.4. % CGM time <3.9 mmol/L
1.5. % CGM time 3.9–7.8 mmol/L
1.6. % CGM time >10.0 mmol/L
1.7. % CGM time >13.9 mmol/L
1.8. % CGM time >16.7 mmol/L
1.9. Measures of glycaemic variability including standard deviation and coefficient of variation of CGM values
1.10. Mean CGM glucose[Mid-study (11-13 weeks post-randomisation) and end-of-study (23-26 weeks post-randomisation)]
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HCL system performance using the following measures - % time hybrid closed loop is active; unplanned exits from closed loop (n); sensor performance – mean absolute relative difference (MARD), sensor failures (n); insulin delivery line performance – reported delivery line failures (n); calls to technical help-line (n)[From 0 to 26 weeks post-randomisation]
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(Sub-study 2 Secondary Outcome): Glycaemic outcomes for the night following exercise [0:00-06:00] during HCL vs standard therapy:
1.1. % CGM time 3.9–10mmol/L (excluding the primary endpoint)
1.2. % CGM time <2.8 mmol/L
1.3. % CGM time <3.3 mmol/L
1.4. % CGM time <3.9 mmol/L
1.5. % CGM time 3.9–7.8 mmol/L
1.6. % CGM time >10.0 mmol/L
1.7. % CGM time >13.9 mmol/L
1.8. % CGM time >16.7 mmol/L
1.9 Glycaemia Variability as determined by mean amplitude of glycaemic excursions (MAGE) and standard deviation
1.10 CGM AUC > 10.0 mmol/L
1.11 CGM AUC <4.0 mmol/L[Night following exercise completion [0:00-0:06:00]
]
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Sleep quality during HCL vs standard therapy, using actigraph device, Pittsburgh Sleep Quality Index, Karolinska Sleepiness Scale[Mid-study (11 - 13 weeks post-randomisation) and end-of-study (23 - 26 weeks post-randomisation)]
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Hospitalisations for diabetic ketoacidosis during HCL vs standard therapy, based on self-reporting by participants +/- review of medical records
[From 0 to 26 weeks post-randomisation]
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Biochemical markers of vascular risk (blood and urine samples) during HCL vs standard therapy - including cell adhesion molecules (CAMS); oxidized low density lipoprotein; myeloperoxidase; microRNA signatures for arterial, renal and retinal complications; telomerase; DNA methylation/acetylation; isoprostanes (blood and urine) and proteomics; clotting profile[26 weeks post-randomisation
]
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Human-technology interaction for the HCL study arm using questions designed specifically for the study which were formulated to elicit the individual's perception of the HCL system. Participants will receive two questions per week via short message service (SMS) which have an estimated response time of <30 seconds[From 0 to 26 weeks post-randomisation]
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(Sub-study 2 Primary Outcome) Percent CGM time spent in target glycaemia (3.9–10 mmol/L) for twenty-four hours following exercise commencement during HCL vs standard therapy
[0-24 hours post exercise commencement
]
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(Sub-study 2 Secondary Outcome): Sensor MARD during exercise, compared with reference YSI venous blood glucose measurements[During 45 min of exercise
]
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Psychological function assessing hypoglycaemia awareness during HCL vs standard therapy, using the Gold Score and Hypoglycaemia Awareness Scale of the HypoA-Q (validated)[13 weeks and 26 weeks post-randomisation]
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Psychological function assessing fear of hypoglycaemia during HCL vs standard therapy, using the Hypoglycaemia Fear Survey-II short form (11 items – validated)
[13 weeks and 26 weeks post-randomisation
]
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Psychological function assessing treatment satisfaction during HCL vs standard therapy, using The Diabetes Treatment Satisfaction Questionnaire (8 items - validated)
[13 weeks and 26 weeks post-randomisation]
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(Sub-study 1): Change in counter-regulatory hormone responses during HCL vs standard therapy, using serum assays[End-of-study (26 weeks post-randomisation)
]
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(Sub-study 2 Secondary Outcome): Glycaemic outcomes 24 hours post exercise commencement, during HCL vs standard therapy:
1.1. % CGM time 3.9–10mmol/L (excluding the primary endpoint)
1.2. % CGM time <2.8 mmol/L
1.3. % CGM time <3.3 mmol/L
1.4. % CGM time <3.9 mmol/L
1.5. % CGM time 3.9–7.8 mmol/L
1.6. % CGM time >10.0 mmol/L
1.7. % CGM time >13.9 mmol/L
1.8. % CGM time >16.7 mmol/L
1.9 Glycaemia Variability as determined by mean amplitude of glycaemic excursions (MAGE) and standard deviation
1.10 CGM AUC > 10.0 mmol/L
1.11 CGM AUC <4.0 mmol/L[0-24 hours post exercise commencement
]
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Change in body weight, assessed using digital scales, during HCL vs standard therapy
[From 0 to 26 weeks post-randomisation
]
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Cognitive function during HCL vs standard therapy, using the Prospective-Retrospective Memory Questionnaire (16 items) and psychomotor vigilance task
[Prospective-Retrospective Memory Questionnaire - 13 weeks and 26 weeks post-randomisation.
Psychomotor vigilance task - mid-study (11-12 weeks post-randomisation) and end-of-study (23-24 weeks post-randomisation)
]
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Psychological function assessing diabetes distress during HCL vs standard therapy, using the Problem Areas in Diabetes Questionnaire (20 items - validated)
[13 weeks and 26 weeks post-randomisation]
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Electrocardiograph profiles using Holter Monitors during HCL vs standard therapy, using corrected QT interval (QTc); heart rate; cardiac arrhythmias as a composite outcome[Mid-study (11-12 weeks post-randomisation) and end-of-study (23-24 weeks post-randomisation)]
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Health-economic impact of HCL vs standard therapy using data derived from:
QALYs; hypoglycaemic events and HbA1c; participant and family reporting on work interruption; reported time spent on training, education and support, by the type of health professional resource used; diabetes management consumables; administrative linked data from the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) to track resource utilisation
[From 0 to 26 weeks post-randomisation
]
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1,5-anhydroglucitol on serum[26 weeks post-randomisation
]
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Psychological function assessing diabetes-specific positive well-being during HCL vs standard therapy, using the W-B Q28 subscale: DPosWB (4 items – validated)
[13 weeks and 26 weeks post-randomisation]
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Psychological function assessing participants' expectations and experiences with the technology for the HCL study arm, using semi-structured psychological interviews [1 week, 13 weeks, 26 weeks and 39 weeks post-randomisation]
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Symptomatic hypoglycaemia requiring carbohydrate rescue (with finger-prick glucose < 3.5 mmol/L) during HCL vs standard therapy[From 0 to 26 weeks post-randomisation]
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(Sub-study 1): Changes in hypoglycaemia awareness during HCL vs standard therapy, using the Clarke and Edmonton Hypoglycaemia Questionnaire
[Mid-study (11-13 weeks post-randomisation) and end-of-study (26 weeks post-randomisation)
]
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(Sub-study 2 Secondary Outcome): Episodes of hyperglycaemia (>10.0 mmol/L) and blood ketones >0.4 mmol/L (n) following exercise commencement during HCL vs standard therapy, using CGM data and finger prick blood ketone testing
[0-24 hours post exercise commencement
]
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Driving performance during HCL vs standard therapy, using a vehicle driving logger device
[Mid-study (11 - 13 weeks post-randomisation) and end-of-study (23 - 26 weeks post-randomisation)]
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Psychological function assessing satisfaction with technology during HCL vs standard therapy, using the Diabetes Management Experiences Questionnaire (validated)
[13 weeks and 26 weeks post-randomisation
]
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Severe hypoglycaemia (defined as any low glucose level requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) during HCL vs standard therapy
[From 0 to 26 weeks post-randomisation]
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