Randomized cross over trial comparing advanced hybrid closed loop mode with sensor augmented pump therapy in type 1 diabetes.

Randomised, open label, two sequence cross-over study. Comparing MiniMed 670G insulin pump running in advanced hybrid closed loop (AHCL) mode with sensor augmented pump (SAP) therapy with predictive low-glucose management (PLGM) MINIMED™ 670G INSULIN PUMP The MiniMed™ 670G is an automated insulin delivery device approved in the United States for use in T1DM in individuals aged above 7 years. The pump is worn and delivers insulin continuously as at a 'basal rate' with additional bolus doses to cover food consumed. Insulin is administered from the pump via tubing into the subcutaneous tissue. A non-controlled pivotal safety study in patients aged 14 – 75 years (n = 124) for 3 months demonstrated safety; in addition, diabetes control was improved and participants HbA1c reduced from 7.4% to 6.9% (1). Adolescent participants used the automated insulin delivery feature (“automode”) 75.8% of the time, with an observed change in HbA1c from 7.7%± 0.8% to 7.1%± 0.6% (2). The algorithm that governs automated insulin delivery, and the parameters within it can operate have further been refined, designed to further improve glycaemic outcomes and the user experience. This is defined as advanced hybrid closed loop mode hereinafter. This cross-over trial will utilise the MiniMed™ 670G, coupled with a CONTOUR NEXT LINK wireless blood glucose meter, 4th generation glucose sensor and GST3C transmitter. The glucose sensor is worn continuously on the skin and the subcutaneous tissue is sampled. The transmitter sends sensor glucose data wirelessly every 5 min to the pump, providing real-time glucose measurements and trends. Calibration of the glucose sensor is required with the CONTOUR NEXT LINK blood glucose meter at least once every 12 h. Blood glucose meters require patients to use a lancet to obtain a drop of capillary blood. The pump is uploaded to transfer information to Medtronic CareLink therapy Management Software through the use of CONTOUR NEXT LINK glucose meter, which is also the uploading device. ADVANCED HYBRID CLOSED LOOP MODE One arm of the study will assess the MiniMed™ 670G running in advanced hybrid closed loop (AHCL) mode. The closed loop algorithm is contained in the MiniMed™ 670G, using a modified proportional integrative derivative (PID) model, with insulin feedback and additional safety features. The algorithm receives continuous glucose monitoring (CGM) data every 5 minutes, and a “basal rate” insulin delivery is computed and adjusted every five minutes. Therefore, standard “basal” insulin that is pre-programmed in regular insulin pump therapy is replaced by the algorithm derived insulin delivery (given as a micro-bolus every 5 minutes). Meals will be announced, and an insulin bolus delivered according to the individualised patient carbohydrate ratio and insulin sensitivity factor (should a correction bolus be required in addition to the insulin for carbohydrate). SENSOR AUGMENTED PUMP THERAPY WITH PREDICTIVE LOW GLUCOSE MANAGEMENT For the remainder of the study, the MiniMed™ 670G will run in Sensor Augmented Pump (SAP) Therapy Mode with Predictive Low Glucose Management (PLGM). The ‘Suspend before low’ SmartGuard function suspends basal insulin infusion when sensor glucose is predicted to fall below the set low limit in 30 min. The pump suspends basal insulin infusion when two criteria are met: 1. Sensor glucose is at or within 3.9 mmol/L above the set low limit, and; 2. Sensor glucose is predicted to be 1.1 mmol/L above the set low limit in 30 min. In the current study the low limit is set at 3.2 mmol/L. The pump will thus suspend insulin infusion when the sensor glucose is less than 7.1 mmol/L (3.9 + 3.2) and predicted to be 4.3 mmol/L (3.2 + 1.1) in 30 min. If the ‘alert before low’ function is selected, the patient will receive an alert when insulin delivery is suspended. In the absence of any participant interaction, the insulin infusion will resume after a maximum suspend period of 2 h or according to the auto-resumption parameters. Basal insulin will automatically resume if sensor glucose is above the low limit and trending upward, and insulin has been suspended for at least 30 min. However, the infusion may be resumed earlier if the patient intervenes during the suspend time and overrides the suspend function. STUDY DESIGN This is a randomised, open-label, two-sequence cross-over study. Participants will be allocated to one of two treatment sequences (AB or BA) on a 1:1 basis. Treatments are as follows: A. MiniMed™ 670G insulin pump running in AHCL mode B. MiniMed™ 670G insulin pump running as SAP with PLGM Each treatment period is of 4 weeks duration, with a two-week washout between treatments. Study duration is expected to be 12 weeks. Five visits to the study centre are planned: Day 1: Screening / baseline Day 14: Randomization and start of Treatment Period 1 Day 42: End of Treatment Period 1 Day 56: Start of Treatment Period 2 Day 84: End of Study During the study participants will be required to upload their insulin pumps on a weekly basis. On initiation of auto-mode, participants will be required to upload daily for the first seven days. Up to approximately 60 subjects will be enrolled into the study. Additional subjects may be enrolled at the Investigator’s discretion to replace individual subjects who withdraw from the study prematurely or who do not complete required assessments. References 1. Hovorka R, Elleri D, Thabit H, Allen JM, Leelarathna L, El-Khairi R, et al. Overnight closed-loop insulin delivery in young people with type 1 diabetes: a free-living, randomized clinical trial. Diabetes Care. 2014; 37:1204-11. 2. de Bock MI, Roy A, Cooper MN, Dart JA, Berthold CL, Retterath AJ, et al. Feasibility of Outpatient 24-Hour Closed-Loop Insulin Delivery. Diabetes care. 2015; 38:e186-e7