Use of the Hybrid Closed Loop therapy in hypoglycaemia awareness in people with Type 1 diabetes

This study will follow a randomised controlled parallel design. Potential participants will be identified using an in clinic screening tool for hypoglycaemic unawareness (Gold questionnaire) to assess if they are hypoglycaemia unaware. A Gold score greater than or equal to 4 implies impaired hypoglycaemia awareness. Following a two weeks period of blinded continuous glucose monitoring (CGM) to assess baseline hypoglycaemia exposure, eligible participants will undergo a hyperinsulinaemic, hypoglycaemic clamp study at the beginning and at the end of a 6 weeks study period. After the initial clamp study participants will be randomised to either hybrid closed-loop (intervention), or to continue on their conventional pump therapy (control). After 6 weeks, participants will undergo a second hypoglycaemic clamp, with analysis of their physiological and symptom response to hypoglycaemia compared to baseline. The hypoglycaemic clamp procedure and the hybrid closed loop system are detailed below. Hyperinsulinemic hypoglycaemic clamp study: The clamp studies will be performed before randomisation and 6 weeks post randomisation, irrespective of whether the participant is in the control or intervention group. The participant will present after an overnight fast for the clamp study in the morning. The clamp procedure will involve infusing insulin intravenously at a constant rate of 80mU/m2 per minute and plasma glucose targets will be achieved by adjusting the rate of infusion of a solution of 20% glucose in water. Prior to induction of hypoglycaemia, plasma glucose will be maintained in euglycaemia (5-6mmol/l) for 30 to 60 minutes followed by gradual reduction over 30 minutes to a nadir of 2.8mmol/l. This controlled decline will be guided by plasma blood glucose measurements taken at 5-minute intervals. The blood glucose concentration of 2.8mmol/l will be maintained for 40 minutes before euglycaemia will be restored. For the duration of the clamp procedure, blood glucose will be measured using glucose oxidase technique with a bedside YSI analyser. Venous blood will be sampled during the euglycaemic and hypoglycaemic phase to determine plasma insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone concentrations during both study days. Symptoms of hypoglycaemia will also be assessed with a questionnaire in which the participants will rate the symptoms on a scale of 1 (no symptoms) to 7 (extreme). The scores of the symptoms will be added up to give the total symptom score. Hybrid Closed Loop System: This system consists on an insulin pump (MiniMed (Trademark) Medtronic 670G, a continuous glucose monitoring system (3rd generation Enlite sensor), and an algorithm within the insulin pump that calculates background (basal) insulin delivery according to changes in the sensor glucose value. The insulin pump and continuous glucose monitor communicate wirelessly. The pump is small enough to fit in the palm of a hand, and is usually carried clipped to a belt. The pump is water resistant and is built to last 4 years. The hybrid closed-loop control algorithm is inbuilt into the insulin pump hardware. The glucose sensor is the size of a 20 cent coin and clips on to the subcutaneously inserted glucose sensor. The sensor has an "inserter" and participants will be trained to insert the sensors themselves by a diabetes educator. The insulin pump and glucose sensor transmitter communicate wirelessly, with a range of approximately 6 meters. During the run-in phase all participants will receive individual education sessions on continuous glucose monitoring provided by a diabetes educator or a study doctor. Those randomised to the hybrid closed loop system will have additional training provided by a diabetes nurse educator before entering the 6 weeks study period. The following is an outline of the visit history during the run-in phase which also describes the duration and frequency of sessions, and also the post randomisation training required for those participants who go on to the intervention. Visit 1: Screening and consent, blinded CGM and baseline glycaemic data collection (4 hours) 1. Confirm participant is able to take part in the study and sign a consent form. 2. Collect baseline data including height, weight and current diabetes treatment. 3. Ask the participant to complete some questionnaires about diabetes. 4. We will teach the participant how to insert a sensor and give them a Contour Next glucometer (to use in addition to their usual glucometer) to record BGLs at least 4 times a day 5. We will also give a logbook and ask participants to record signs and treatment of hypoglycaemia 6. Start with blinded continuous glucose monitoring, Visit 2: Sensor Download and Sensor Change (30 mins) This visit will occur 7 days after visit 1 to: 1. Download the sensor and glucometer data 2. Change the sensor and transmitter 3. Check that the log book is up to date Visit 2 may be able to happen at the participant location. Visit 3: Sensor download, hyperinsulinaemic, hypoglycaemic clamp and randomisation (6 hours) This visit will occur 7 days after visit 2 to: 1. Download the sensor data and collect logbook data. 2. Particpants will then undergo a hyperinsulinaemic, hypoglyaceamic clamp as outlined above. 3. Participants will then be randomized to either stay on usual treatment (control), or to the hybrid closed loop system (intervention). Visit 4: Entry into Study Arm (1 hour) The schedule for this visit will depend on randomisation: (i) Control Group Those randomised to control will have visit 4 in combination with visit 3. 1. Participants will be issued with a new logbook. 2. Participants will be asked not to use other continuous glucose monitoring systems for the duration of the study. (ii) Intervention Group We will ask the participant to come in to the clinic for the following visits to teach them how to operate the pump, insert sensors and use the closed loop function: Participants will require general pump education, followed by CGM and HCL operation. Visit 4A: (1 – 4 hours) This visit will occur within 7 days of visit 3 (clamp) but not on the clamp day. This session is to provide sensor and Minimed 670G pump training, including training on how to change a sensor and linking the sensor to the pump. We will provide them with a sensor user guide and enough sensors for the duration of the study. Visit 4B: (1 – 2 hours) Once CGM data has been established for a minimum of 3 days, and maximum 7 days, participant returns for face to face instruction on HCL use and initiation. During the intervention period the sensor needs to be changed every 7 days. The overall intervention period is 8-10 weeks (two to three weeks run in, and 6 weeks post randomisation). Adherence will be monitored by downloading the CGM data and examining the hybrid closed loop system pump download data - which includes an adherence report. All data is intention to treat analysis, so participants will be under no pressure to continue the intervention if they wish to withdraw.