Evening and overnight closed-loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial

Background Automated closed-loop control delivery of insulin, also known as the artificial pancreas, is emerging as a treatment option for type 1 diabetes, which is considered generally superior to sensor-augmented insulin pump therapy. Evening and overnight closed-loop control might account for most of the benefits of 24/7 continuous closedloop control; however, to our knowledge, no direct comparison of these systems has yet been done. In this study, we sought to compare different configurations of a closed-loop control system with activation of automated insulin delivery during the evening and overnight hours compared with continuous 24/7 closed-loop control, and both treatment modalities compared with sensor-augmented insulin pump use. Methods In this randomised crossover trial at the University of Virginia (Charlottesville, VA, USA), we randomly assigned (1:1) participants aged 18 to up to 70 years with a diagnosis of type 1 diabetes for at least 1 year to one of two sequences of four 8-week treatment sessions: sensor-augmented insulin pump therapy, evening and overnight closedloop control, continuous 24/7 closed-loop control, and evening and overnight closed-loop control (group A) or evening and overnight closed-loop control, continuous 24/7 closed-loop control, evening and overnight closed-loop control, and sensor-augmented pump therapy (group B). Randomisation was done by non-clinical study staff using a computer-generated sequence of Bernoulli trials. The primary outcome of the study was the difference in the percentage of time continuous glucose monitored glucose was less than 3.9 mmol/L (70 mg/dL) during sensoraugmented pump therapy compared with evening and overnight closed-loop control. Our overall analysis followed a modified intention-to-treat approach, with all available data for participants who had completed at least two study sessions included in the analysis, regardless of actual use of a closed-loop control device. The trial was registered with ClinicalTrials.gov, NCT02679287. Findings Between April 21, 2016, and June 1, 2018, we assessed 103 patients for eligibility and 93 were randomly assigned to group A (n=47) or group B (n=46). Our final analysis included 80 participants who had completed at least two study phases (40 in group A and 40 in group B). Compared with sensor-augmented pump therapy sessions, evening and overnight closed-loop control sessions reduced the mean overall (day and night) percentage of time blood glucose was less than 70 mg/dL (3.9 mmol/L) from 4.0% (SD 3.3) to 2.2% (1.8), an absolute difference of -1.8% (95% CI 1.2-2.4; p<0.0001). This was accompanied by an overall reduction in HbA 1c from mean 7.4% (SD 1.0) at baseline to 7.1% (0.9) at the end of the study, resulting in an absolute difference of -0.3% (95% CI 0.1-0.4%; p<0.0001). We observed no cases of diabetic ketoacidosis. There were three cases of hyperglycaemia with ketosis that did not meet the criteria for diabetic ketoacidosis, all of which were treated at home with insulin and oral fluid, without known malfunction of the investigational device. There were five cases of severe hypoglycaemia attributed to user-directed boluses without malfunction of the investigational device. Interpretation In type 1 diabetes, evening and overnight closed-loop control was superior to sensor-augmented pump therapy, achieving most of the glycaemic benefits of 24/7 continuous closed-loop control. Our findings could offer people with type 1 diabetes more flexibility in treatment options with use of automated insulin delivery systems at varying times of day. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.