Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial.
BACKGROUND
Closed-loop systems link continuous glucose measurements to insulin delivery. We aimed to establish whether closed-loop insulin delivery could control overnight blood glucose in young people.


METHODS
We undertook three randomised crossover studies in 19 patients aged 5-18 years with type 1 diabetes of duration 6.4 years (SD 4.0). We compared standard continuous subcutaneous insulin infusion and closed-loop delivery (n=13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n=7; APCam02); and closed-loop delivery and standard treatment after exercise (n=10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were masked to plasma glucose. During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump. During control nights, patients' standard pump settings were applied. Primary outcomes were time for which plasma glucose concentration was 3.91-8.00 mmol/L or 3.90 mmol/L or lower. Analysis was per protocol. This trial is registered, number ISRCTN18155883.


RESULTS
17 patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not differ significantly between treatment groups in APCam01 (12 analysed; target range, median 52% [IQR 43-83] closed loop vs 39% [15-51] standard treatment, p=0.06; <or=3.90 mmol/L, 1% [0-7] vs 2% [0-41], p=0.13), APCam02 (six analysed; target range, rapidly 53% [48-57] vs slowly absorbed meal 55% [37-64], p=0.97; <or=3.90 mmol/L, 0% [0-4] vs 0% [0-0], p=0.16]), and APCam03 (nine analysed; target range 78% [60-92] closed loop vs 43% [25-65] control, p=0.0245, not significant at corrected level; <or=3.90 mmol/L, 10% [2-15] vs 6% [0-44], p=0.27). A secondary analysis of pooled data documented increased time in the target range (60% [51-88] vs 40% [18-61]; p=0.0022) and reduced time for which glucose concentrations were 3.90 mmol/L or lower (2.1% (0.0-10.0) vs 4.1% (0.0-42.0); p=0.0304). No events with plasma glucose concentration lower than 3.0 mmol/L were recorded during closed-loop delivery, compared with nine events during standard treatment.


CONCLUSIONS
Closed-loop systems could reduce risk of nocturnal hypoglycaemia in children and adolescents with type 1 diabetes.


BACKGROUND
Juvenile Diabetes Research Foundation; European Foundation for Study of Diabetes; Medical Research Council Centre for Obesity and Related Metabolic Diseases; National Institute for Health Research Cambridge Biomedical Research Centre.
Hovorka
Roman
R
Department of Paediatrics, University of Cambridge, Cambridge, UK. rh347@cam.ac.uk
Allen
Janet M
JM
Elleri
Daniela
D
Chassin
Ludovic J
LJ
Harris
Julie
J
Xing
Dongyuan
D
Kollman
Craig
C
Hovorka
Tomas
T
Larsen
Anne Mette F
AM
Nodale
Marianna
M
De Palma
Alessandra
A
Wilinska
Malgorzata E
ME
Acerini
Carlo L
CL
Dunger
David B
DB
D000293:Adolescent; D000465:Algorithms; D015374:Biosensing Techniques; D001786:Blood Glucose / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D055104:Infusions, Subcutaneous; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood; D007332:Insulin Infusion Systems; D008297:Male; D016896:Treatment Outcome
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin