Ware J, Boughton CK, Allen JM, Wilinska ME, Tauschmann M, Denvir L, Thankamony A, Campbell FM, Wadwa RP, Buckingham BA, Davis N, DiMeglio LA, Mauras N, Besser REJ, Ghatak A, Weinzimer SA, Hood KK, Fox DS, Kanapka L, Kollman C, Sibayan J, Beck RW, and Hovorka R
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 HbA 1c 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 HbA 1c . 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 HbA 1c 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 HbA 1c was 8·2% (SD 0·7) in the closed-loop group and 8·3% (0·7) in the control group. At 6 months, HbA 1c 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., Competing Interests: Declaration of interests MT reports receiving speaker honoraria from Novo Nordisk. RPW reports receiving grants and contract support from Tandem Diabetes Care and Dexcom, consulting fees from Beta Bionics, and honoraria and travel support from Tandem Diabetes. BAB declares grant support from JDRF and National Institutes of Health (NIH), honoraria from Lilly, reports receiving grant support and advisory board fees from ConvaTec, grant support and honoraria from Insulet, advisory board fees from Medtronic MiniMed, grant support from Tandem Diabetes Care, Data Safety Monitoring Board role for ConvaTec, NovoNordisk, and Medtronic, advisory board fees from Arecor, advisory board role for ConvaTec, Medtronic and NovoNordisk, and patents (US 6,572,545 B2, PCT/US 2020/017997, US 2010/0174228 A1). LADM reports grants from Medtronic, leadership/fiduciary role regarding ISPAD Guidelines and Editorial Board, and receipt of equipment from Dexcom. NM reports receiving grants, contracts and payment, and honoraria from Novo Nordisk. SAW reports receiving consulting fees from Zealand Pharma, speaker honoraria from Dexcom, Insulet, Medtronic, Tandem Diabetes Care, and Abbott, and is a Data and Safety Monitoring Board member for two AID studies (NCT04492566, NCT04510506), and study supply receipt from Medtronic. RWB reports receiving grant support from NIH, Tandem Diabetes Care, Beta Bionics, and Dexcom; donated supplies from Tandem Diabetes Care, Beta Bionics, Dexcom, Medtronic, Ascencia, Roche, Eli Lilly, and Novo Nordisk; and consulting fees from Novo Nordisk, Bigfoot Biomedical, Eli Lilly, and Insulet. RH reports receiving speaker honoraria from Eli Lilly, Dexcom, and Novo Nordisk, receiving license fees from B Braun and Medtronic, declares consulting fees from Abbott Diabetes Care; patent issued in closed-loop field (Glucose monitoring and control using multi-model approach, patent number CA2702345C) with University of Cambridge and patent issued in closed-loop field (methods for reducing false hypoglycaemia alarm occurrence during closed-loop, patent number US9579456B2) with University of Cambridge and Abbott Diabetes Care, being director and stockholder at CamDiab, and leadership/fiduciary role for ATTD. MEW reports patents related to closed-loop (US9402953B2, US9579456B2) and being a consultant at CamDiab. REJB declares a leadership and fiduciary role for NovoNordisk. JW declares support for attending meetings from the YDEF Lilly Scholarship. KKH declares consulting fees for Cecelia Health, Insulet, and Lifescan Diabetes Institute. LK, CKo, CKB, JMA, AT, JS, LD, FMC, ND, AG, and DSF declare no competing financial interests exist., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)