title: Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study.
abstract: Tight control of blood glucose concentration in people with type 1 diabetes predisposes to hypoglycaemia. We aimed to investigate whether day-and-night hybrid closed-loop insulin delivery can improve glucose control while alleviating the risk of hypoglycaemia in adults with HbA1cbelow 7·5% (58 mmol/mol).
  
  
  
  In this open-label, randomised, crossover study, we recruited adults (aged ≥18 years) with type 1 diabetes and HbA1cbelow 7·5% from Addenbrooke's Hospital (Cambridge, UK) and Medical University of Graz (Graz, Austria). After a 2-4 week run-in period, participants were randomly assigned (1:1), using web-based randomly permuted blocks of four, to receive insulin via the day-and-night hybrid closed-loop system or usual pump therapy for 4 weeks, followed by a 2-4 week washout period and then the other intervention for 4 weeks. Treatment interventions were unsupervised and done under free-living conditions. During the closed-loop period, a model-predictive control algorithm directed insulin delivery, and prandial insulin delivery was calculated with a standard bolus wizard. The primary outcome was the proportion of time when sensor glucose concentration was in target range (3·9-10·0 mmol/L) over the 4 week study period. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02727231, and is completed.
  
  
  
  Between March 21 and June 24, 2016, we recruited 31 participants, of whom 29 were randomised. One participant withdrew during the first closed-loop period because of dissatisfaction with study devices and glucose control. The proportion of time when sensor glucose concentration was in target range was 10·5 percentage points higher (95% CI 7·6-13·4; p<0·0001) during closed-loop delivery compared with usual pump therapy (65·6% [SD 8·1] when participants used usual pump therapy vs 76·2% [6·4] when they used closed-loop). Compared with usual pump therapy, closed-loop delivery also reduced the proportion of time spent in hypoglycaemia: the proportion of time with glucose concentration below 3·5 mmol/L was reduced by 65% (53-74, p<0·0001) and below 2·8 mmol/L by 76% (59-86, p<0·0001). No episodes of serious hypoglycaemia or other serious adverse events occurred.
  
  
  
  Use of day-and-night hybrid closed-loop insulin delivery under unsupervised, free-living conditions for 4 weeks in adults with type 1 diabetes and HbA1cbelow 7·5% is safe and well tolerated, improves glucose control, and reduces hypoglycaemia burden. Larger and longer studies are warranted.
  
  
  
  Swiss National Science Foundation (P1BEP3_165297), JDRF, UK National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z).
authors.affiliation: Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Diabetes & Endocrinology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK; Department of Diabetes, Endocrinology, Clinical Nutrition & Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Lia
authors.initials: L
authors.lastname: Bally
authors.affiliation: Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Diabetes & Endocrinology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.
authors.forename: Hood
authors.initials: H
authors.lastname: Thabit
authors.affiliation: Department of Internal Medicine, Division of Endocrinology & Diabetology, Medical University of Graz, Graz, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Kojzar
authors.affiliation: Department of Internal Medicine, Division of Endocrinology & Diabetology, Medical University of Graz, Graz, Austria.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Mader
authors.affiliation: Department of Internal Medicine, Division of Endocrinology & Diabetology, Medical University of Graz, Graz, Austria.
authors.forename: Jehona
authors.initials: J
authors.lastname: Qerimi-Hyseni
authors.affiliation: Department of Diabetes & Endocrinology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Hartnell
authors.affiliation: Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Tauschmann
authors.affiliation: Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Allen
authors.affiliation: Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK.
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Wilinska
authors.affiliation: Department of Internal Medicine, Division of Endocrinology & Diabetology, Medical University of Graz, Graz, Austria.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.affiliation: Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Diabetes & Endocrinology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Evans
authors.affiliation: Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK. Electronic address: rh347@cam.ac.uk.
authors.forename: Roman
authors.initials: R
authors.lastname: Hovorka
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D015918:Infusion Pumps, Implantable; D007328:Insulin / Q000008:administration & dosage*; D007332:Insulin Infusion Systems; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin