title: Safety of outpatient closed-loop control: first randomized crossover trials of a wearable artificial pancreas.
abstract: OBJECTIVE
  We estimate the effect size of hypoglycemia risk reduction on closed-loop control (CLC) versus open-loop (OL) sensor-augmented insulin pump therapy in supervised outpatient setting.
  
  
  METHODS
  Twenty patients with type 1 diabetes initiated the study at the Universities of Virginia, Padova, and Montpellier and Sansum Diabetes Research Institute; 18 completed the entire protocol. Each patient participated in two 40-h outpatient sessions, CLC versus OL, in randomized order. Sensor (Dexcom G4) and insulin pump (Tandem t:slim) were connected to Diabetes Assistant (DiAs)-a smartphone artificial pancreas platform. The patient operated the system through the DiAs user interface during both CLC and OL; study personnel supervised on site and monitored DiAs remotely. There were no dietary restrictions; 45-min walks in town and restaurant dinners were included in both CLC and OL; alcohol was permitted.
  
  
  RESULTS
  The primary outcome-reduction in risk for hypoglycemia as measured by the low blood glucose (BG) index (LGBI)-resulted in an effect size of 0.64, P = 0.003, with a twofold reduction of hypoglycemia requiring carbohydrate treatment: 1.2 vs. 2.4 episodes/session on CLC versus OL (P = 0.02). This was accompanied by a slight decrease in percentage of time in the target range of 3.9-10 mmol/L (66.1 vs. 70.7%) and increase in mean BG (8.9 vs. 8.4 mmol/L; P = 0.04) on CLC versus OL.
  
  
  CONCLUSIONS
  CLC running on a smartphone (DiAs) in outpatient conditions reduced hypoglycemia and hypoglycemia treatments when compared with sensor-augmented pump therapy. This was accompanied by marginal increase in average glycemia resulting from a possible overemphasis on hypoglycemia safety.
authors.affiliation: Center for Diabetes Technology and Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA boris@virginia.edu.
authors.forename: Boris P
authors.initials: BP
authors.lastname: Kovatchev
authors.affiliation: Department of Endocrinology, Diabetes, and Nutrition, Montpellier University Hospital, INSERM Clinical Investigation Center 1001, Institute of Functional Genomics, CNRS UMR 5203, INSERM U661, University of Montpellier 1, Montpellier, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Renard
authors.affiliation: Department of Information Engineering and Department of Internal Medicine, Unit of Metabolic Disease, University of Padova, Padova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.affiliation: Sansum Diabetes Research Institute, Santa Barbara, CA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Zisser
authors.affiliation: Center for Diabetes Technology and Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Keith-Hynes
authors.affiliation: Center for Diabetes Technology and Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Anderson
authors.affiliation: Center for Diabetes Technology and Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA.
authors.forename: Sue A
authors.initials: SA
authors.lastname: Brown
authors.affiliation: Center for Diabetes Technology and Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Chernavvsky
authors.affiliation: Center for Diabetes Technology and Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Breton
authors.affiliation: Center for Diabetes Technology and Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA.
authors.forename: Lloyd B
authors.initials: LB
authors.lastname: Mize
authors.affiliation: Department of Endocrinology, Diabetes, and Nutrition, Montpellier University Hospital, INSERM Clinical Investigation Center 1001, Institute of Functional Genomics, CNRS UMR 5203, INSERM U661, University of Montpellier 1, Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Farret
authors.affiliation: Department of Endocrinology, Diabetes, and Nutrition, Montpellier University Hospital, INSERM Clinical Investigation Center 1001, Institute of Functional Genomics, CNRS UMR 5203, INSERM U661, University of Montpellier 1, Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Place
authors.affiliation: Department of Information Engineering and Department of Internal Medicine, Unit of Metabolic Disease, University of Padova, Padova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bruttomesso
authors.affiliation: Department of Information Engineering and Department of Internal Medicine, Unit of Metabolic Disease, University of Padova, Padova, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Del Favero
authors.affiliation: Department of Information Engineering and Department of Internal Medicine, Unit of Metabolic Disease, University of Padova, Padova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Boscari
authors.affiliation: Department of Information Engineering and Department of Internal Medicine, Unit of Metabolic Disease, University of Padova, Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Galasso
authors.affiliation: Department of Information Engineering and Department of Internal Medicine, Unit of Metabolic Disease, University of Padova, Padova, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
authors.affiliation: Department of Systems Engineering, University of Pavia, Pavia, Italy.
authors.forename: Lalo
authors.initials: L
authors.lastname: Magni
authors.affiliation: Department of Systems Engineering, University of Pavia, Pavia, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Di Palma
authors.affiliation: Department of Systems Engineering, University of Pavia, Pavia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Toffanin
authors.affiliation: Department of Systems Engineering, University of Pavia, Pavia, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Messori
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, CA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Dassau
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, CA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Doyle
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D015190:Blood Glucose Self-Monitoring; D040421:Cell Phone; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007332:Insulin Infusion Systems; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D019397:Pancreas, Artificial / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin