A 5-center CRC-based Study of the Accuracy of the GlucoWatch® G2 TM Biographer in Children and Adolescents with Type 1 Diabetes Darrell Wilson 1, Bruce Buckingham 1, Roy Beck 2, Katrina Ruedy 2, Craig Kollman 2, Eva Tsalikian 4, Timothy Wysocki 5, Stuart Weinzimer 3, Peter Chase 6 and the Diabetes Research in Children Network (DirecNet) Study Group 1 Stanford, CA; 2 Tampa, FL; 3 New Haven, CT; 4 Iowa City, IA; 5 Jacksonville, FL; 6 Denver, CO.

Background The Diabetes Research in Children Network (DirecNet) is a NIH-funded collaborative study group. The major objective of DirecNet is to critically evaluate the clinical usefulness of current and future glucose sensor devices in youth with T1DM.

Goals The purpose of this study was to determine the accuracy of the GlucoWatch® G2™ Biographer (GW2B) in children with Type 1 diabetes mellitus (T1DM).

GlucoWatch ® G2 ™ Biographer (GW2B) Measures interstitial glucose extracted by reverse iontophoresis Requires a single calibration value following the 2-hour warm-up period Glucose readings every 10 minutes for 13 hours Values range from 40 to 400 mg/dL

Subject Selection Age 1 to 18 years T1DM for at least 1 year BMI between 5 th and 95 th percentile for age and gender Weight ≥ 12.0 kg if < 7 yrs and ≥ 16.0 kg if ≥ 7 yrs Normal hematocrit No skin or other significant disorders

Study Procedures Admitted to Clinical Research Center Approximately 24 hours Two GW2Bs placed at staggered times Sensor pads were replaced as needed Venous blood sampling Hourly during day (7:00AM to 9:00PM) Twice hourly during night (9:30PM to 6:30AM) Central lab for reference glucoses

Study Procedures Meal induced hyperglycemia high carbohydrate drink 1.75 gm CHO/kg, maximum of 75 grams Samples q 5 minutes for 60 minutes Insulin induced hypoglycemia Subjects older than 7 years only units/kg regular insulin IV bolus After 30 minutes, a second dose if needed Glycemia goal of ≤ 55 mg/dL Samples q 5 minutes for up to 90 minutes

GlucoWatch Function Sensor calibration 1 st attempt 94% 2 nd attempt 2% Failed 4% Sensor lifespan* ≥14.5 hours (Full)81% 10.0 to 14.5 hours 3% 6.0 to 10.0 hours 6% <6.0 hours10% Of 14,232 possible GW2B measurements 17% were skipped * Excludes sensors stopped early for logistical reasons.

Evaluation of Accuracy The appropriate set of accuracy measures to evaluate near continuous glucose monitoring remains to be developed. We used the traditional methods that are utilized to assess the accuracy of blood glucose meters. These methods do not adequately capture the time dimension of glucose sensor data with respect to glucose trend (slope) information or glucose pattern detection across the day.

Measures of Accuracy Pearson’s correlation Difference sensor – reference Relative difference % (sensor – reference)/reference x 100% Absolute difference |sensor – reference| Relative absolute difference (RAD) % |(sensor – reference)/reference| x 100%

Measures of Accuracy ISO criteria (proposed) Reference glucose ≤75 mg/dL Sensor value within ±15 mg/dL Reference glucose value >75 mg/dL Sensor value within ±20% Error grid analysis Clarke Consensus

Subject Characteristics 89 Subjects Gender44 (49%) F 45 (51%) M Age (years) mean ± SD 9.9 ± 4.1 Duration of diabetes (years) mean ± SD 4.6 ± 3.2 Insulin delivery 39 (44%) pump 50 (56%) injections HbA1c mean ± SD 7.8% ± 1.2% BMI percentile mean ± SD 67% ± 23%

A Subject

GW2B Accuracy Summary 3,672 paired values Median difference, 3 mg/dL, Not significantly different than zero Median absolute relative difference 16% Correlation 0.86 Consensus Error Grid 97%, A+B zones

GW2B Accuracy Mean (95% CI) Median (25 th to 75 th %-ile) Difference mg/dL 2.2 (-2.0, 6.1) 3 (-19, 26) Absolute Difference mg/dL 30.9 (28.7, 33.2) 23 (11, 42) Relative Difference 6% (4%, 9%) 2% (-12%, 20%) Relative Absolute Difference 22% (20%, 23%) 16% (7%, 29%)

Factors NOT Impacting Accuracy Age Gender BMI (body mass index) Time (6:30AM -10:30PM vs 11PM – 6AM) Location of GWB placement Upper vs lower arm Inner vs outer arm

Factors Impacting Accuracy Sensor Age Sensor age (hrs) Number of paired values RAD (median) ISO criteria met (%) 0 to <6 hr1,31615%63% 6 to <10 hr1,14215%64% ≥10 hr1,21419%54% p value

Factors Impacting Accuracy Glucose Concentration Glucose (mg/dL) Number of paired values RAD (median) ISO criteria met (%) ≤ %32% %55% %66% %66% > %67% p value<0.001

Clarke Error Grid

Consensus Error Grid

Detection of Hypoglycemia Episode defined as at least two GW2B values ≤ 60 mg/dL without any values > 70 mg/dL. Distinct episodes had to be separated by at least 30 minutes. Episode was considered confirmed if there was at least one reference glucose value ≤ 70 mg/dL. Only 10 of 18 hypoglycemic episodes detected by the GW2B overnight were confirmed.

Alarm=60 Alarm=100 Alarm=80 Alarm=120 Receiver Operator Curve (ROC) for Hypoglycemia ( ≤60 mg/dL) Alarm Setting SensitivityFalse Alarm Rate 6023%51% 8059%67% 10084%80% 12092%85%

Side Effects No serious skin reactions No other problems Moderate Irritation example Mild Irritation example

Summary In summary, our results are very similar to those reported in studies conducted by Cygnus, Inc. We found the GW2B to be more accurate during periods of hyperglycemia than hypoglycemia. The accuracy of this generation of the sensor does not approach the accuracy of current home glucose meters. However, the sensor glucose values are generally within 20% of the serum glucose. This level of accuracy may be sufficient for detecting trends and modifying diabetes management.

Acknowledgements This study would not have been possible without the support of CRC Nurses at the study sites. This research has been supported by the following NIH/NICHD Grants: HD ; HD041915; HD041890; HD ; HD ; and HD Clinical Centers also received funding through the following GCRC Grant Numbers M01 RR00069; RR00059; M01 RR and 5M01RR and Nemours Biomedical Research. University of Minnesota Central Laboratory Michael Steffes, Jean Bucksa, Maren Nowicki