1. DirecNet Study of the Accuracy of the Navigator Continuous Glucose Monitoring System in Children and Adolescents with Type 1 Diabetes Darrell Wilson 1, Katrina Ruedy 2, Craig Kollman 2, Roy Beck 2, William Tamborlane 3, Larry Fox 4, Stuart Weinzimer 3, Barb Tallant 5 and the Diabetes Research in Children Network (DirecNet) Study Group 1 Stanford, CA; 2 Tampa, FL; 3 N ew Haven, CT; 4 Jacksonville, FL; 5 Denver, CO.

4. Background The Diabetes Research in Children Network (DirecNet) is an 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.

5. Goals One of the goals of this study was to determine the accuracy of the FreeStyle Navigator™ Continuous Glucose Monitoring System, an investigational device, (Abbott Diabetes Care, Alameda, CA) in children with Type 1 diabetes mellitus (T1DM) in both the inpatient (CRC) and outpatient environment.

6. FreeStyle Navigator™ Continuous Glucose Monitoring System Measures interstitial glucose Requires calibration at 10, 12, 24 and 72 hours after sensor insertion Provides glucose readings every 60 seconds for up to 120 hours Values range from 20 to 500 mg/dL Also displays trend arrow for glucose rate of change

7. Subject Selection Type 1 diabetes for at least 1 year Age 3 to <18 years Using a downloadable insulin infusion pump for a least 6 months Home computer with email access

9. Study Procedures Inpatient Admitted to Clinical Research Center Approximately 24 hours Two Navigators: one inserted at home prior to admission and second placed at time of admission Venous blood sampling Every 30 minutes Every 10 minutes for 1 hour after breakfast Insulin bolus delayed until after 1 hour of blood draws complete (correction dose given at start if BG >250) Central lab for reference glucoses Exercise session for those older than 7 yrs Four 15-min sessions walking on a treadmill at a target heart rate 140 bpm interspersed with three 5-min rest breaks

10. Study Procedures Outpatient Subjects instructed to wear Navigator on a daily basis FreeStyle meter used for outpatient reference glucoses Meter values used to calibrate the Navigator were excluded for the accuracy evaluation

11. Navigator Function Outpatient Sensor successfully calibrated96% Hours per Sensor WornData < 24 hours 6%18% 24 - < 48 hours13% 11% 48 - < 72 hours 13% 13% 72 - < 96 hours 15% 15% ≥ 96 hours 53%42% mean ± SD (hours)89 ± 35 71 ± 38

12. Evaluation of Accuracy Point to Point Analysis 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 capture the time dimension of glucose sensor data with respect to glucose trend (slope) information or glucose pattern detection across the day.

13. Measures of Accuracy Point to Point Difference sensor – reference Absolute difference |sensor – reference| Relative absolute difference (RAD) % |(sensor – reference)/reference| x 100% ISO criteria Reference glucose ≤75 mg/dL Sensor value within ±15 mg/dL Reference glucose value >75 mg/dL Sensor value within ±20%

14. Subject Characteristics 30 Subjects Gender n (%)12 (40%) F 18 (60%) M Age (years) mean ± SD 11.2 ± 4.1 Duration of diabetes (years) mean ± SD 5.8 ± 3.0 Baseline HbA1c mean ± SD 7.1% ± 0.6%

15. Sample Inpatient Navigator Data

16. Navigator Inpatient Point Accuracy (excludes exercise and post-breakfast challenge) Number of pairs: 1,811 Median difference, -2 mg/dL, Not significantly different than zero Hypoglycemia (reference ≤70 mg/dL) Median absolute difference = 14 mg/dL (25 th -75 th %-iles: 8, 22 mg/dL) Target Range (reference 71-180 mg/dL) Median RAD = 13% (25 th -75 th %-iles: 6%, 22%) Hyperglycemia (reference >180 mg/dL) Median RAD = 10% (25 th -75 th %-iles: 5%, 18%)

17. Navigator Outpatient Point Accuracy Number of pairs: 8,639 Median difference = -1 mg/dL, Hypoglycemia (reference ≤70 mg/dL) Median absolute difference = 15 mg/dL (25 th -75 th %-iles: 7, 26 mg/dL) Target Range (reference 71-180 mg/dL) Median RAD = 15% (25 th -75 th %-iles: 7%, 27%) Hyperglycemia (reference >180 mg/dL) Median RAD = 12% (25 th -75 th %-iles: 6%, 21%)

18. Accuracy (Outpatient)* did not Deteriorate with Age of Sensor * Inpatient results were similar (data not shown) Sensor Age (hours) Number of paired values RAD (median) ISO criteria met (%) <24 hrs1,50315%62% 24-<48 hrs2,41314%67% 48-<96 hrs3,60115%66% >96 hrs1,12214%67%

19. Effect of Glucose Concentration

20. Lead/Lag Analysis Inpatient Data (excludes exercise and post-breakfast challenge) Median Median % DifferenceRADISO 30 min lead+118%55% 20 min lead016%61% 10 min lead-114%67% No lag/lead-212%74% 10 min lag-311%78% 20 min lag-411%77% 30 min lag-413%71%

21. Event Analysis Glycemic Excursions during Exercise N=20 subjects participated in exercise test median (25 th -75 th percentiles) NavigatorLabDifference Abs. Diff. Baseline170177-10 (-24, +21) 23 (15, 29) Glucose Drop a 8589-5 (-21, +6) 11 (5, 22) Minutes to Nadir8577+3 (-7, +14) 8 (4, 14) Rate of Change b 1.01.2-0.1 (-0.3, +0.1) 0.1 (0.1, 0.3) a-baseline minus nadir; b-mg/dL/minute (timed from baseline to nadir)

22. Event Analysis Glycemic Excursions during Exercise Fall in Glucose from Baseline to Nadir (mg/dL)

23. Event Analysis Detection of Hypoglycemia (Glucose values <70 mg/dL within ± 30 min treated as a single event) False positive rate: % Navigator events for which the reference is >70 mg/dL and >10 mg/dL higher than the concurrent Navigator value*: 13/35 = 37% (inpatient) 179/642 = 28% (outpatient) Sensitivity rate: % Reference events for which there is a Navigator value <70 mg/dL within ±30 min of the first low reference*: 23/47 = 49% (inpatient) 568/911 = 62% (outpatient) * If all Navigator values within 10 mg/dL of a concurrent reference, but on the other side of the 70 mg/dL threshold (e.g., Navigator=68/reference=72), then the event is not counted as a failure or a success (excluded from calculation).

24. Side Effects There were 2 cases of severe skin reactions thought to be allergic reactions to the sensor adhesive No other problems

25. Summary & Conclusions In summary, accuracy of the Navigator in the home environment is similar to accuracy in an inpatient setting. The sensor continues to perform well even during the 5th day of wear and functions as well during the night as during the day. The sensor glucose values are generally within 5-20% of the serum glucose. This level of accuracy is sufficient for detecting trends and modifying diabetes management.

26. 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: HD041919; HD041915; HD041890; HD041918; HD041908; and HD041906. Clinical Centers also received funding through the following GCRC Grant Numbers M01 RR00069; RR00059; M01 RR 06022 and 5M01RR00070 and Nemours Biomedical Research. DirecNet Central Laboratory: University of Minnesota Central Laboratory Michael Steffes, Jean Bucksa, Maren Nowicki

27. Barbara Davis Center H. Peter Chase Rosanna Fiallo-Scharer Laurel Messer Barbara Tallant University of Iowa Eva Tsalikian Michael Tansey Linda Larson Julie Coffey Joanne Cabbage Nemours Children’s Clinic Tim Wysocki Nelly Mauras Larry Fox Keisha Bird Kim Englert Stanford University Bruce Buckingham Darrell Wilson Jennifer Block Paula Clinton Yale University William Tamborlane Stuart Weinzimer Elizabeth Doyle Melody Martin Amy Steffen Jaeb Center for Health Research Roy Beck Katrina Ruedy Craig Kollman Dongyuan Xing Cynthia Stockdale