1. Background: DirecNet Diabetes Research in Children Network NIH funded collaborative study group 5 clinical centers, central laboratory, coordinating center, and representatives form NICHD and NIDDK Objective: to critically evaluate the clinical usefulness of current and future glucose sensors in youth with TIDM

2. Background: CGMS Accuracy Study CGMS was first FDA approved sensor Has been used to characterize glucose profiles in children by many investigators Most CGMS validation studies were performed with adults and used comparisons to meter instead of reference laboratory serum glucose levels Recent reports have questioned accuracy and reproducibility of CGMS readings

3. Objective To assess the accuracy of the CGMS inc children and adolescents with type 1 diabetes when compared with reference serum glucose levels Examined accuracy under three conditions:  Spontaneous fluctuations in 24 hour period  Acute hyperglycemia (1.75gm/kg CHO liquid meal)  Acute hypoglycemia (0.05-0.10 u Regular insulin intravenous bolus)

4. Methods: Overall Subjects were admitted to the CRC for 24-26 hrs IV catheter was inserted to obtain serum glucose levels to be measured by central lab Blood samples were obtained every 60 min during the day, and every 30 min during the night (930p- 630a) Blood samples were also obtained with symptomatic hypoglycemia (if FS < 65 mg/dL) Skin assessment at time of discharge and in 3-5 days following discharge

5. Methods: CGMS CGMS were inserted by study staff either on day of admission or 1-2 days prior to admission to assess full 72 hour life of sensor Four fingerstick blood sugars done with a One Touch Ultra meter were entered into the CGMS for calibration Sensors were replaced if they failed Simultaneous use of a second CGMS was offered as an option. Sensors were inserted into abdomen or buttucks

6. Statistical Methods: CGMS Measurements CGMS glucose measurements were matched to reference measurements from blood samples drawn within 2.5 min of each other CGMS time was adjusted by 2.5 min to account for averaging of glucose levels made over the previous 5 min When comparing CGMS monitors simultaneously, sensor values were matched within 2.5 min of each other

7. Statistical Methods: Modified Sensors During the course of the study, Medtronic MiniMed changed the manufacturing process of the sensor that had been in place since 1999 Sensor fabrication process was modified Accuracy analyses were conducted separately with the “original” and “modified” sensors

8. Subjects ( N= 91) Mean age: 9.9 + 4.1 yrs Gender: 45 M, 46 F Race: 85% White Duration T1DM: 4.7 + 3.2 yr Mean HbA1c = 7.8 + 1.2% Injections (57%) Pump (43%) Diabetes Therapy

9. Sensor Function Day of sensor insertion Percent (%) ** 6% of all possible readings were skipped (N/A)

10. CGMS Accuracy Summary Statistics (N = 6,778 sensor reference pairs) Mean (95% confidence interval) Median (25 th, 75 th percentiles) Difference mg/dL -2.9 (-8.0, 2.1)2 (-27, 28) Absolute difference mg/dL 38.0 (34.7, 41.7)28 (12,50) Relative difference4% (1%, 8%)2% (-16%, 20%) Relative absolute difference 25% (23%, 27%)18% (8%, 34%)

11. Original vs Modified Sensors Comparison of Accuracy Relative Absolute Difference (median) (25 th, 75 th percentiles) 19% (9%, 36%) 11% (5%, 23%) <0.001 Modified Clarke Error Grid Zone A (percentage) 58%78%<0.001 Modified Clarke Error Grid Zone A+B (percentage) 93%98%<0.001 Original Sensors Modified Sensors P-Value N=5,658 Paired Values N=1,120 Paired Values

12. Original vs Modified Sensors Comparison of Accuracy ISO Criteria † Met According to Reference Glucose Level Percent (%)  70 mg/dL 71-120 mg/dL 121-180 mg/dL 181-240 mg/dL >240 mg/dL All Values Original Sensors N=5,658 Paired Values Modified Sensors N=1,120 Paired Values * P<.05 ** P<.001 ISO for Ultra Meter = 94% † ISO criteria: for reference BG ≤75 mg/dL, SG within ±15 mg/dL for reference BG >75 mg/dL, SG value within ±20% * * * **

13. Original vs Modified Sensors Comparison of Accuracy – Variation Among Sensors Original Sensors Modified Sensors P-Value N=112 Sensors* N=25 Sensors* Sensors with Median RAD<10% Sensors with Median RAD<20% Sensors with Median RAD<30% Sensors with  80% of Values Meeting ISO Criteria Sensors with  60% of Values Meeting ISO Criteria 9% 54% 80% 9% 35% 36% 88% 100% 24% 80% 0.01 <0.001 0.07 <0.001 * Sensors were included if they had at least 10 paired readings

14. Original vs Modified Sensors: Precision of 2 Simultaneous CGMS Original SensorsModified Sensors # Paired Data Points13,6695,021 Absolute Difference median mg/dL (25 th, 75 th percentiles) 28 (12,55) 17 (7,34) Relative Absolute Difference median (25 th, 75 th percentiles) 17% (7%, 33%) 10% (4%, 20%) Values within 10% percentage32%50% Values within 20% percentage55%76% Pearson Correlation0.770.92

15. Conclusions Sensors were tolerated well by children aged 3-17, and there were no adverse events Most sensors functioned for full three days Overall percentage of skipped readings was low

16. Conclusions: Original Sensors Original sensors were frequently inaccurate in detecting glucose excursions and detecting hypoglycemia  Accuracy was better during hyperglycemia than during hypoglycemia Precision (comparing two CGMS worn simultaneously) was poor (r =.77)

17. Conclusions: Modified Sensors Modified sensors were more accurate on all measures Modified sensors had better precision (r =.92) Further research is necessary to determine if detection of hypoglycemia will be better with the modified sensors

18. Barbara Davis Center –H. Peter Chase –Rosanna Fiallo-Scharer –Jennifer Fisher University of Iowa –Eva Tsalikian –Michael Tansey –Linda Larson Nemours Children’s Clinic –Tim Wysocki –Nelly Mauras –Kristen Gagnon University of Minnesota Central Lab –Michael Steffes –Jean Bucksa –Maren Nowicki Stanford University –Bruce Buckingham –Darrell Wilson –Jennifer Block Yale University –William Tamborlane –Stuart Weinzimer –Elizabeth Boland Jaeb Center for Health Research –Roy Beck –Katrina Ruedy –Craig Kollman –Andrea Booth –Gladys Bernett