Manual Closed-loop Insulin Delivery in Children and Adolescents with Type 1 Diabetes: a Phase 2 Randomised Crossover Trial

Background: Closed-loop systems link continuous glucose measurements to insulin delivery. We aimed to establish whether closed-loop insulin delivery could control overnight blood glucose in young people.

Methods: We undertook three randomised crossover studies in 19 patients aged 5-18 years with type 1 diabetes of duration 6.4 years (SD 4.0). We compared standard continuous subcutaneous insulin infusion and closed-loop delivery (n=13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n=7; APCam02); and closed-loop delivery and standard treatment after exercise (n=10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were masked to plasma glucose. During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump. During control nights, patients' standard pump settings were applied. Primary outcomes were time for which plasma glucose concentration was 3.91-8.00 mmol/L or 3.90 mmol/L or lower. Analysis was per protocol. This trial is registered, number ISRCTN18155883.

Findings: 17 patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not differ significantly between treatment groups in APCam01 (12 analysed; target range, median 52% [IQR 43-83] closed loop vs 39% [15-51] standard treatment, p=0.06; <or=3.90 mmol/L, 1% [0-7] vs 2% [0-41], p=0.13), APCam02 (six analysed; target range, rapidly 53% [48-57] vs slowly absorbed meal 55% [37-64], p=0.97; <or=3.90 mmol/L, 0% [0-4] vs 0% [0-0], p=0.16]), and APCam03 (nine analysed; target range 78% [60-92] closed loop vs 43% [25-65] control, p=0.0245, not significant at corrected level; <or=3.90 mmol/L, 10% [2-15] vs 6% [0-44], p=0.27). A secondary analysis of pooled data documented increased time in the target range (60% [51-88] vs 40% [18-61]; p=0.0022) and reduced time for which glucose concentrations were 3.90 mmol/L or lower (2.1% (0.0-10.0) vs 4.1% (0.0-42.0); p=0.0304). No events with plasma glucose concentration lower than 3.0 mmol/L were recorded during closed-loop delivery, compared with nine events during standard treatment.

Interpretation: Closed-loop systems could reduce risk of nocturnal hypoglycaemia in children and adolescents with type 1 diabetes.

Funding: Juvenile Diabetes Research Foundation; European Foundation for Study of Diabetes; Medical Research Council Centre for Obesity and Related Metabolic Diseases; National Institute for Health Research Cambridge Biomedical Research Centre.