Multinational study of subcutaneous model-predictive closed-loop control in type 1 diabetes mellitus: summary of the results.
BACKGROUND
In 2008-2009, the first multinational study was completed comparing closed-loop control (artificial pancreas) to state-of-the-art open-loop therapy in adults with type 1 diabetes mellitus (T1DM).


METHODS
The design of the control algorithm was done entirely in silico, i.e., using computer simulation experiments with N=300 synthetic "subjects" with T1DM instead of traditional animal trials. The clinical experiments recruited 20 adults with T1DM at the Universities of Virginia (11); Padova, Italy (6); and Montpellier, France (3). Open-loop and closed-loop admission was scheduled 3-4 weeks apart, continued for 22 h (14.5 h of which were in closed loop), and used a continuous glucose monitor and an insulin pump. The only difference between the two sessions was that insulin dosing was performed by the patient under a physician's supervision during open loop, whereas insulin dosing was performed by a control algorithm during closed loop.


RESULTS
In silico design resulted in rapid (less than 6 months compared to years of animal trials) and cost-effective system development, testing, and regulatory approvals in the United States, Italy, and France. In the clinic, compared to open-loop, closed-loop control reduced nocturnal hypoglycemia (blood glucose below 3.9 mmol/liter) from 23 to 5 episodes (p<.01) and increased the amount of time spent overnight within the target range (3.9 to 7.8 mmol/liter) from 64% to 78% (p=.03).


CONCLUSIONS
In silico experiments can be used as viable alternatives to animal trials for the preclinical testing of insulin treatment strategies. Compared to open-loop treatment under identical conditions, closed-loop control improves the overnight regulation of diabetes.
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia 22908, USA. boris@virginia.edu
Boris
B
Kovatchev
Claudio
C
Cobelli
Eric
E
Renard
Stacey
S
Anderson
Marc
M
Breton
Stephen
S
Patek
William
W
Clarke
Daniela
D
Bruttomesso
Alberto
A
Maran
Silvana
S
Costa
Angelo
A
Avogaro
Chiara
C
Dalla Man
Andrea
A
Facchinetti
Lalo
L
Magni
Giuseppe
G
De Nicolao
Jerome
J
Place
Anne
A
Farret
D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002648:Child; D003198:Computer Simulation; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D054796:Drug Dosage Calculations; D005260:Female; D005602:France; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects; D007332:Insulin Infusion Systems; D007558:Italy; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008991:Monitoring, Physiologic; D019397:Pancreas, Artificial; D010865:Pilot Projects; D013997:Time Factors; D016896:Treatment Outcome; D014768:Virginia; D055815:Young Adult
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; C517652:hemoglobin A1c protein, human