Investigation of an artificial pancreas for adults with type 1 diabetes

The intervention is a hybrid closed-loop (HCL) automated insulin delivery system.  This randomised, controlled study compares the efficacy of insulin delivered via the HCL system versus standard insulin therapy for 26 weeks. 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 min to account for basal insulin requirements. Participant initiated bolus insulin doses are still required for meals.  Participants recruited from seven clinical sites in Australia will undertake a 5-9 week run-in period, during which time they will receive carbohydrate-counting education provided by a dietician and will be taught how to adjust their rapid-acting insulin administered with meals accordingly. This will be an individualised one-on-one education program, tailored to each participant’s prior knowledge. Each education session will take approximately 30–60 min, and up to 4 sessions will be scheduled over the subsequent 2-3 weeks until the participant’s carbohydrate-counting ability is deemed proficient by a study dietician. Other study data collected includes masked continuous glucose monitoring (CGM), psychological and cognitive measures, sleep quality, cardiac rhythm, and biochemical markers of vascular risk.  Following run-in, participants will be randomised 1:1 to intervention or control. Participants in the intervention group will transition from their usual insulin delivery regimen to HCL, with close supervision by study doctors and nurses. These participants will use the HCL system until 26 weeks post-randomisation, following which they will transfer back to their usual diabetes management. The participants randomised to intervention will receive detailed individualised education and training regarding use of the HCL system over a 2–5 week period following randomisation. This will include programming and operation of the HCL system, basal and bolus insulin delivery, set up of the reservoir and infusion set, insulin delivery line insertion and change, sensor insertion and change, and sick day management. This education specific to the HCL system will be provided face-to-face by a diabetes nurse educator over 2-4 individual educational sessions, each 1–4 hours in duration, 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, and will receive regular phone contact between study visits from a diabetes nurse educator to support their transition to the HCL system. Participants will upload their pump weekly for review. Two sub-studies will be performed within the main study. The first sub-study will involve a sub-group of participants with refractory hypoglycaemia and impaired hypoglycaemia awareness. Changes in counter-regulatory hormonal responses assessed via hypoglycaemic clamp studies, and changes in hypoglycaemia awareness and glycaemic control, will be compared during HCL vs. standard therapy. A total of 10 participants will be enrolled in this sub-study to be conducted at two sites that specialise in islet cell transplantation. These participants need to meet the additional criteria of refractory hypoglycaemia and impaired hypoglycaemia awareness. The hypoglycaemic clamp studies will be conducted in hospital clinical trial centres, under direct supervision of study doctors, at two additional time points during the study (mid-study at ~11-13 weeks post-randomisation, and end-of-study at 26 weeks post-randomisation). An insulin infusion will be started at 1.0 mU/kg/min for 270 min. Subsequently, a variable rate of 25% glucose intravenous infusion will be initiated to achieve 45 min of plasma glucose plateaus at 4.4 mmol/L, 3.6 mmol/L and 2.5 mmol/L, sequentially. Venous glucose measurements will be taken every 5 min to adjust the glucose infusion rate. Additional venous samples will be collected every 30 min for analyses.  The second sub-study will compare metabolic control with two different types of exercise on a stationary bicycle in the intervention vs control groups. Each participant will undertake both exercise protocols (moderate-intensity and high-intensity interval exercise) in random order. The washout period between exercise sessions will be ~7 days. The high-intensity interval exercise protocol involves high-intensity interval training to simulate strenuous team sport activities: 5 min warm-up at 25% VO2max, then six repetitions each of 4 min cycling at an intensity halfway between anaerobic threshold (calculated for each participant) and maximal intensity (100% VO2max) which corresponds to approximately 70% VO2max, followed by 2 min complete rest. An additional 4 min rest will be provided between the third and fourth repetitions. The moderate-intensity exercise protocol involves steady-state exercise to simulate undertaking a run or bicycle ride: 5 min warm-up at 25% VO2max, followed by 40 min steady-state cycling up to 70% of anaerobic threshold which corresponds to approximately 45% VO2max. For the exercise sub-study, we aim to recruit 20 participants (10 in each study arm).