Julia Ware1, Charlotte K Boughton2, Janet M Allen3, Malgorzata E Wilinska1, Martin Tauschmann1, Louise Denvir4, Ajay Thankamony5, Fiona M Campbell6, R Paul Wadwa7, Bruce A Buckingham8, Nikki Davis9, Linda A DiMeglio10, Nelly Mauras11, Rachel E J Besser12, Atrayee Ghatak13, Stuart A Weinzimer14, Korey K Hood8, D Steven Fox15, Lauren Kanapka16, Craig Kollman16, Judy Sibayan16, Roy W Beck16, Roman Hovorka17. 1. Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK. 2. Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Diabetes & Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 3. Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. 4. Department of Paediatric Diabetes and Endocrinology, Nottingham University Hospitals NHS Trust, Nottingham, UK. 5. Department of Paediatrics, University of Cambridge, Cambridge, UK. 6. Department of Paediatric Diabetes, Leeds Children's Hospital, Leeds, UK. 7. Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 8. Division of Pediatric Endocrinology, Stanford University, Stanford, CA, USA. 9. Department of Paediatric Endocrinology and Diabetes, Southampton Children's Hospital, Southampton General Hospital, Southampton, UK. 10. Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA. 11. Division of Endocrinology, Diabetes & Metabolism, Nemours Children's Health System, Jacksonville, FL, USA. 12. Oxford University Hospitals NHS Foundation Trust, NIHR Oxford Biomedical Research Centre, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK. 13. Alder Hey Children's Hospital, Liverpool, UK. 14. Department of Pediatrics, Yale University, New Haven, CT, USA. 15. Department of Pharmaceutical and Health Economics, School of Pharmacy, University of Southern California, Los Angeles, CA, USA. 16. The Jaeb Center for Health Research, Tampa, FL, USA. 17. Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK. Electronic address: rh347@cam.ac.uk.
Abstract
BACKGROUND: Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population. METHODS: In a multicentre, multinational, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbA1c levels between 53 and 86 mmol/mol (7·0-10·0%). Using block randomisation and central randomisation software, we randomly assigned participants to either closed-loop insulin delivery (closed-loop group) or to usual care with insulin pump therapy (control group) for 6 months. Randomisation was stratified at each centre by local baseline HbA1c. The Cambridge closed-loop algorithm running on a smartphone was used with either (1) a modified Medtronic 640G pump, Medtronic Guardian 3 sensor, and Medtronic prototype phone enclosure (FlorenceM configuration), or (2) a Sooil Dana RS pump and Dexcom G6 sensor (CamAPS FX configuration). The primary endpoint was change in HbA1c at 6 months combining data from both configurations. The primary analysis was done in all randomised patients (intention to treat). Trial registration ClinicalTrials.gov, NCT02925299. FINDINGS: Of 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbA1c was 8·2% (SD 0·7) in the closed-loop group and 8·3% (0·7) in the control group. At 6 months, HbA1c was lower in the closed-loop group than in the control group (between-group difference -3·5 mmol/mol (95% CI -6·5 to -0·5 [-0·32 percentage points, -0·59 to -0·04]; p=0·023). Closed-loop usage was low with FlorenceM due to failing phone enclosures (median 40% [IQR 26-53]), but consistently high with CamAPS FX (93% [88-96]), impacting efficacy. A total of 155 adverse events occurred after randomisation (67 in the closed-loop group, 88 in the control group), including seven severe hypoglycaemia events (four in the closed-loop group, three in the control group), two diabetic ketoacidosis events (both in the closed-loop group), and two non-treatment-related serious adverse events. There were 23 reportable hyperglycaemia events (11 in the closed-loop group, 12 in the control group), which did not meet criteria for diabetic ketoacidosis. INTERPRETATION: The Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.
BACKGROUND: Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population. METHODS: In a multicentre, multinational, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbA1c levels between 53 and 86 mmol/mol (7·0-10·0%). Using block randomisation and central randomisation software, we randomly assigned participants to either closed-loop insulin delivery (closed-loop group) or to usual care with insulin pump therapy (control group) for 6 months. Randomisation was stratified at each centre by local baseline HbA1c. The Cambridge closed-loop algorithm running on a smartphone was used with either (1) a modified Medtronic 640G pump, Medtronic Guardian 3 sensor, and Medtronic prototype phone enclosure (FlorenceM configuration), or (2) a Sooil Dana RS pump and Dexcom G6 sensor (CamAPS FX configuration). The primary endpoint was change in HbA1c at 6 months combining data from both configurations. The primary analysis was done in all randomised patients (intention to treat). Trial registration ClinicalTrials.gov, NCT02925299. FINDINGS: Of 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbA1c was 8·2% (SD 0·7) in the closed-loop group and 8·3% (0·7) in the control group. At 6 months, HbA1c was lower in the closed-loop group than in the control group (between-group difference -3·5 mmol/mol (95% CI -6·5 to -0·5 [-0·32 percentage points, -0·59 to -0·04]; p=0·023). Closed-loop usage was low with FlorenceM due to failing phone enclosures (median 40% [IQR 26-53]), but consistently high with CamAPS FX (93% [88-96]), impacting efficacy. A total of 155 adverse events occurred after randomisation (67 in the closed-loop group, 88 in the control group), including seven severe hypoglycaemia events (four in the closed-loop group, three in the control group), two diabetic ketoacidosis events (both in the closed-loop group), and two non-treatment-related serious adverse events. There were 23 reportable hyperglycaemia events (11 in the closed-loop group, 12 in the control group), which did not meet criteria for diabetic ketoacidosis. INTERPRETATION: The Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.
Authors: Laurel H Messer; Bruce A Buckingham; Fran Cogen; Mark Daniels; Greg Forlenza; Rabab Z Jafri; Nelly Mauras; Andrew Muir; R Paul Wadwa; Perrin C White; Steven J Russell; Edward R Damiano; Firas H El-Khatib; Katrina J Ruedy; Courtney A Balliro; Zoey Li; Martin Chase Marak; Peter Calhoun; Roy W Beck Journal: Diabetes Technol Ther Date: 2022-10 Impact factor: 7.337