Type 1 diabetes is one of the most common chronic conditions of childhood and is characterised by a deficiency of insulin caused by immune-mediated destruction of pancreatic beta cells in genetically predisposed individuals. Despite increasing technology use to manage type 1 diabetes, most children struggle to meet treatment guidelines for target glycated haemoglobin levels.

Closed-loop insulin delivery systems, consisting of glucose sensor, insulin pump and an algorithm automatically adjusting insulin delivery in response to real-time glucose levels, have the potential to transform diabetes management. Longer-term unsupervised studies had been lacking across the paediatric age span, hampering reimbursement and clinical adoption of this novel therapy.

The aim of my thesis is to evaluate hybrid closed-loop insulin delivery in children and young people with type 1 diabetes over the longer-term in real-life conditions. It incorporates clinical studies conducted in the unsupervised home setting lasting four months or longer. The thesis will also assess the feasibility of using novel ultra-rapid acting insulin with hybrid closed-loop insulin delivery in the paediatric setting, and evaluate the safety of a novel personalisable feature of the hybrid closed-loop system.

In an open-label, multicentre, multinational, randomised, parallel design study, the longer-term safety and efficacy of hybrid closed-loop insulin delivery over a six-month period compared to standard insulin pump therapy in children and young people with suboptimal glycaemic control was investigated. Compared to standard insulin pump therapy with or without glucose sensor, hybrid closed-loop therapy was safe and improved glycaemic control over this six-month period. Post-hoc outcomes highlighted that closed-loop efficacy relies on consistently high closed-loop usage, as demonstrated by a marked difference in treatment effect between two hardware configurations (FlorenceM vs CamAPS FX) used with the same closed-loop algorithm in this study.

An open-label, multicentre, multinational, randomised crossover study evaluated the safety and efficacy of hybrid closed-loop insulin delivery in very young children with type 1 diabetes over a four-month period compared with gold standard sensor-augmented pump therapy. Results showed that closed-loop therapy was safe, with clinically significant improvements in glycaemic control without any increase in hypoglycaemia. Closed-loop usage was consistently high, suggesting good acceptability of a novel therapy in this vulnerable age group.

A second, shorter eight-week double-blind randomised crossover study compared use of hybrid closed-loop insulin delivery with novel ultra-rapid acting insulin with hybrid closed-loop insulin delivery using standard rapid-acting insulin in very young children with type 1 diabetes. There was no significant difference in glycaemic control compared to standard insulin aspart after eight weeks, suggesting that use of faster insulin aspart with closed-loop therapy does not offer any additional clinical benefit over using standard insulin aspart.

Finally, the safety of a unique user-initiated mode of insulin intensification during hybrid closed-loop therapy was assessed by evaluating time spent in hypoglycaemia across all age groups (2-80 years) in four randomised controlled studies. Use of this intensification mode in hybrid closed-loop therapy appeared safe across all age groups with type 1 diabetes, with no increase in time spent in hypoglycaemia on days the intensification mode was in use.

In conclusion, the studies included in my thesis demonstrate that hybrid closed-loop therapy is safe and effective longer-term across the paediatric age span. Additionally, my thesis addresses the question of whether additional clinical benefits can be conferred with use of approved ultra-rapid insulins in conjunction with hybrid closed-loop therapy in very young children. My work supports widespread clinical adoption and integration of hybrid closed-loop therapy into routine clinical care.