1. Down Alert Function of the GlucoWatch® G2 TM Biographer (GW2B) During Insulin- induced Hypoglycemia in Children Eva Tsalikian 1, Craig Kollman 2, Rosanna Fiallo-Scharer 3, Roy Beck 2, Bruce Buckingham 4, Nelly Mauras 5, Stuart Weinzimer 6, William Tamborlane 6, Katrina Ruedy 2, Dongyuan Xing 2 and the Diabetes Research In Children Network (DirecNet) Study Group. 1 Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, IA; 2 Jaeb Center for Health Research, Tampa, FL; 3 Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO; 4 Division of Pediatric Endocrinology and Diabetes, Stanford University, Stanford, CA; 5 Nemours Children’s Clinic, Jacksonville, FL; 6 Department of Pediatrics, Yale University School of Medicine, New Haven, CT.

2. Abstract Down Alert Function of the GlucoWatch® G2 TM Biographer (GW2B) During Insulin- induced Hypoglycemia in Children The GW2B alarm system for the detection of hypoglycemia has limitations regarding sensitivity and high false alarm rates. We previously reported that the GW2B hypoglycemia alarm would have to be set at 100mg/dL to detect 84% of serum glucose levels <60 mg/dL but at a false alarm rate of 80%. The GW2B also continuously monitors the rate of fall in sensor glucose levels and has a “down-alert” alarm that predicts impending hypoglycemia. In the down-alert algorithm, the slope between two GW2B glucose values at least 10 minutes apart is used to predict the glucose value 20 minutes later. As part of an inpatient protocol to evaluate the accuracy of the GW2B, an insulin-induced hypoglycemia test was performed on 50 children who were wearing 74 GW2Bs. Following IV insulin administration, venous blood was obtained every 5 minutes for up to 90 minutes, for measurement of reference glucose (RG) in a central laboratory. For analysis, the RG values were paired with the GW2B glucose values. This provided an opportunity to evaluate the “down alert” performance of the GW2B. Analysis of these data is in progress. Our preliminary assessment suggests that the down- alert alarm may be considerably more effective in predicting hypoglycemia than the hypoglycemia alarm. Since the GW2B glucose value has a lag time of about 20 minutes, the down alert is actually predicting whether the current glucose level of the individual is hypoglycemic rather than the glucose level 20 minutes earlier as is the case with the hypoglycemia alarm. Therefore, the GW2B down alert alarm may have greater utility than the hypoglycemic alarm.

3. The study was conducted by the Diabetes Research in Children Network (DirecNet) at five academic centers in the United States. The Diabetes Research in Children Network (DirecNet) is a NIH-funded collaborative study group that consists of five clinical centers, a coordinating center, a central laboratory, and representatives from NICHD and NIDDK. The major objective of DirecNet is to critically evaluate the clinical usefulness of current and future glucose sensor devices in youth with T1DM. Continuous glucose sensors have been developed to provide frequent glucose determinations throughout the day and night in individuals with diabetes.

4. Introduction In pediatric patients with type 1 diabetes mellitus (T1DM) hypoglycemia is a major management challenge particularly at night. In very young children with T1DM, there are heightened concerns that hypoglycemia will cause permanent neurologic sequelae. As part of a study to evaluate the accuracy of the GlucoWatch ® G2 TM Biographer compared with venous blood glucose (BG) measurements in children with T1DM, hypoglycemia was induced with intravenous (IV) insulin. This provided the opportunity to study the GlucoWatch ® G2 TM Biographer hypoglycemia alarm and down alert function for reliability (sensitivity) and false positive alarm rates.

5. Objective To evaluate the performance of the hypoglycemia alarm and “down alert” function of the second generation GlucoWatch Automatic Glucose Biographer, the GlucoWatch® G2 TM Biographer ("GW2B“, Cygnus, Inc.) in children with T1DM. Data from the DirecNet Inpatient Accuracy Study were used to evaluate the sensitivity and false alarm rates during insulin induced hypoglycemia and overnight.

6. Methods The sensitivity and false alarm rates during insulin induced hypoglycemia and overnight hypoglycemia were examined Children were admitted to the CRC of each center An indwelling intravenous catheter was inserted into an arm vein for plasma glucose determinations by a central laboratory. In each subject, blood samples were obtained every 60 minutes during the day (7:00 AM to 9:00 PM) and every 30 minutes during the night (9:30 PM to 6:30 AM). One or two GW2Bs were placed on each child according to recommended procedures.

7. Demographic and clinical characteristics of study subjects

8. Statistical Methods 1)The GW2B was considered to have given a hypoglycemia alarm for a glucose reading ≤ 60 mg/dL. 2)A down alert extrapolates the current glucose trend 20 minutes into the future. A linear slope was calculated based on the difference in glucose values from the current and previous readings and a down alert is issued if that slope predicts a reading ≤ 60 mg/dL. 3)Separate analyses were performed for the insulin-induced hypoglycemia test and overnight. Each GW2B glucose reading was retrospectively evaluated at a hypothetical setting of 60 mg/dL regardless of the actual setting for the hypoglycemia alarm and down alert function.

9. GW2B Alarm during Insulin-Induced Hypoglycemia Test *

10. Sensitivity of GW2B Alarms during Overnight (11PM-6AM) Episodes of Hypoglycemia *

11. False Alarm Rates for GW2B Overnight (11PM–6AM)

12. In Summary Only 24% of truly hypoglycemic incidents during the hypoglycemia test and 8% of incidents overnight were detected by the hypoglycemia alarm. Corresponding sensitivity rates of the down alert were 88% and 77%, respectively. Adding the hypoglycemia alarm to the down alert did not improve sensitivity. However, 65% of first overnight down alerts were false positives (reference glucose > 70mg/dL within ±30 min.) compared to only 16% for the hypoglycemia alarm.

13. In Conclusion The down alert can add sensitivity and earlier warnings of hypoglycemia by attempting to anticipate the current trend rather than waiting for a sensor reading below the set hypoglycemia alarm level. This increased sensitivity comes at the cost of a significantly elevated false alarm rate.

14. Barbara Davis Center –H. Peter Chase –Rosanna Fiallo-Scharer –Jennifer Fisher –Barbara Tallant University of Iowa –Eva Tsalikian –Michael Tansey –Linda Larson –Julie Coffey –Amy Sheehan Nemours Children’s Clinic –Tim Wysocki –Nelly Mauras –Keisha Bird –Kelly Lofton Stanford University –Bruce Buckingham –Darrell Wilson –Jennifer Block –Paula Clinton Yale University –William Tamborlane –Stuart Weinzimer –Elizabeth Boland –Kristen Sikes –Amy Steffen Jaeb Center for Health Research –Roy Beck –Katrina Ruedy –Craig Kollman –Dongyuan Xing –Cynthia Silvester