1. Use of the FreeStyle Navigator ™ Continuous Glucose Monitoring System in Children with Type 1 Diabetes Diabetes Research in Children Network L. A. Fox, 1 B. Buckingham, 2 R. Fiallo-Scharer, 3 N. Mauras, 1 W. Tamborlane, 4 E. Tsalikian, 5 S. Weinzimer, 4 T. Wysocki, 1 R. Beck, 6 C. Kollman, 6 K. Ruedy, 6 and the Diabetes Research in Children Network (DirecNet) Study Group. 1 Jacksonville, FL; 2 Stanford, CA; 3 Denver, CO; 4 New Haven, CT; 5 Iowa City, IA; 6 Tampa, FL. Supported by NIH/NICHD Grants HD041919,HD041915,HD041890,HD041918,HD041908, HD041906; GCRC Grants RR00069,RR00059,RR06022,RR00070. The FreeStyle Navigator™ is an investigational device only.

2. Abstract Diabetes Research in Children Network (DirecNet) Pilot Study to Evaluate the Freestyle Navigator Continuous Glucose Monitoring System in the Management of T1D in Children. Larry Fox, 4 Bruce Buckingham, 3 Rosanna Fiallo-Scharer, 1 Nelly Mauras, 4 William Tamborlane, 2 Eva Tsalikian, 5 Stuart Weinzimer, 2 Tim Wysocki, 4 Roy Beck, 6 Craig Kollman, 6 Katrina Ruedy, 6 and the Diabetes Research in Children Network (DirecNet) Study Group 1 Denver, CO ; 2 New Haven, CT; 3 Stanford, CA; 4 Jacksonville, FL; 5 Iowa City, IA; 6 Tampa, FL. Since the more recent real-time glucose sensors (GS) offer the potential to revolutionize treatment of T1D, the current pilot study was undertaken to examine the accuracy, tolerability, and short-term safety of the Freestyle Navigator (Navigator; Abbott Diabetes Care, Alameda, CA) real-time GS in 30 children 4-17yrs with T1D. Following outpatient use of a masked Navigator for 4-7d and a 24hr inpatient admission, subjects were asked to wear an unmasked Navigator daily for 13wks and were contacted frequently (q 1-4wks) to monitor its use. Accuracy of the Navigator was similar during outpatient and inpatient assessments (median relative absolute difference 14% and 12%, respectively) and sensors performed well up to 5d. Subjects averaged 137 hrs/wk of Navigator use at baseline and 131 hrs/wk during wks 11-13. Despite low A1c levels at baseline (7.1 + 0.6%), A1c levels fell to 6.8 + 0.7% after 13 weeks (p=0.02) associated with an increase in the % of sensor values in the target range (71- 180mg/dL) from 52% to 59% (p=0.009). Glycemic variation as measured by the SD and MAGE also decreased during the study period, but this did not achieve statistical significance. Both patients (≥9y) and their parents reported high overall satisfaction with the Navigator on the CGM Satisfaction Scale at 13 weeks with average item scores of 3.6 and 3.9, respectively, on a 5- point Likert scale. The Navigator was well tolerated by children and well received by parents. Only two subjects withdrew and 2 additional subjects had a severe skin reaction. These data provide a compelling rationale for larger scale randomized trials to assess the efficacy of this device in optimizing metabolic control of childhood T1D.

3. Background The need for frequent blood glucose monitoring remains a barrier to achieving excellent diabetes control. An accurate, real-time continuous glucose sensor would provide valuable information in assessing trends in blood sugar patterns. This could allow for more accurate insulin dose adjustments with less risk of hypoglycemia.

4. FreeStyle Navigator ™ Continuous Glucose Monitoring System Measures interstitial glucose. Requires calibration using fingerstick blood glucose at 10, 12, 24 and 72 hours after sensor insertion. After a 10-hr warm-up, provides glucose readings every 60 seconds for up to 120 hours. Values range from 20 to 500 mg/dL. Displays a trend arrow indicating glucose rate of change. Alarms for impending low blood sugar.

5. Study Aims This pilot study was designed to… Assess the accuracy of the FreeStyle Navigator™ Continuous Glucose Monitoring System (Abbott Diabetes Care, Alameda, CA) in inpatient and outpatient settings. Assess whether short-term use of the Navigator impacted glycemic control. Assess satisfaction with outpatient Navigator use.

6. Methods For baseline assessment, 30 children with T1D (4-17 yr old) on CSII wore the Navigator as an outpatient for 1 week but were blinded to sensor data. Subjects were admitted overnight to one of the 5 DirecNet clinical research centers for inpatient accuracy assessment. Subjects then wore the Navigator (unblinded) as an outpatient for 13 weeks. Subjects had the option to continue wearing the Navigator for an additional 13 weeks. Devices were downloaded weekly to their home computers and subjects were contacted frequently (every 1-4 weeks) in order to monitor Navigator use.

7. Methods (cont’d) Inpatient sensor glucose values were compared with reference values performed at the DirecNet central laboratory using a hexokinase enzymatic method. Outpatient sensor data were paired with noncalibration glucose values obtained with the FreeStyle glucose meter built into the Navigator. Glycemic variation was calculated using standard deviation (SD), mean amplitude of glycemic excursions (MAGE) and mean absolute rate of change. Satisfaction with Navigator use was assessed in patients (  9 yr old) and parents using a modified CGM Satisfaction Scale. Due to multiple comparisons, p-values >0.01 were not considered statistically significant.

8. Results 57% of subjects (17/30) wore the sensor for an average of  6 days per week for the first 13 weeks of unblinded use Navigator use decreased throughout the study (Figure 1). The frequency of fingerstick BG checks also decreased during the study (Table 2). Frequency of Navigator use did not vary significantly by A1c, age, gender, or education level. The A1c improved after 13 weeks of Navigator use, despite low levels at baseline, but increased again by 26 weeks (Figure 2). The percent of sensor values in target range increased during the study period for the subjects as a group (Table 2; Figure 3).

9. Results (cont’d) There was a trend for glycemic variation to decrease during the study (Table 2). Accuracy of the Navigator was similar during outpatient and inpatient use. No meaningful effect of sensor age (up to 5 th day of use) on accuracy. Sensor accuracy was better at night than during the day, and was better for adolescents. Outpatient and inpatient accuracy measures improved using a 10-minute sensor lag. No effect of gender, BMI or sensor location on accuracy.

10. Results (cont’d) Both patients (≥9 yr) and their parents reported high overall satisfaction with the Navigator, with average CGM Satisfaction item scores of 3.6 and 3.9, respectively, on a 5-point Likert scale. Two subjects had a severe skin reaction related to sensor adhesive. There were no episodes of severe hypoglycemia.

11. Table 1. Demographics of study subjects a N30 b Age11.2 ± 4.1 yr Female12 (40%) Caucasian28 (93%) HbA1c7.1 ± 0.6% T1D duration5.8 ± 3.0 yr a Age, HbA1c and T1D duration are mean ± S.D. b 2 subjects dropped out after the 7-week visit, one because of difficulty wearing the sensor, the other because of perceived insufficient accuracy.

12. Table 2. Frequency of Freestyle testing, mean glucose, percent of values in target range, and glucose lability. a BL = baseline. Subjects were blinded to sensor data at this time. b Did not include calibration values c Only subjects with at least 24 hours of Navigator glucose data for the given period are included in the calculation of mean glucose and glucose lability d Rate of change calculated using consecutive Navigator readings 10 minutes apart (mg/dL/min).

13. Navigator use (hours/week) 0 40 80 120 160 200 BaselineWks 1-4 Wks 5-8 Wks 9-13 Wks 14-17 Wks 18-21 Wks 22-26 Figure 1. Navigator use during the study.* Hours of wear Hours of glucose readings Zero wear: 0% 0% 0% 0% 4% 20% 12% N=25 N=28 N=30 N=28 N=25 * Black dots denote mean values and boxes denote median, 25 th and 75 th percentiles. Comparisons for hours of wear and hours of glucose readings were made at 9-13 wk vs. 1-4 wk (p=0.003 and p=0.002, respectively), 22-26 wk vs. 9-13 wk (p<0.001 for both), and 22-26 wk vs. BL (p=0.004 and p=0.009, respectively).

14. Figure 2. HbA1c throughout the study.* HbA1c (%) 5.5 6.0 6.5 7.0 7.5 8.0 8.5 Baseline Week 7Week 13Week 26 Baseline A1c  7.0% Baseline A1c >7.0% N=15 N=13 N=15 N=13 N=12 * Black dots denote mean values and boxes denote median, 25 th and 75 th percentiles. Comparisons for each group were made only at 13 wk vs. BL and 26 wk vs. 13 wk. For A1c >7 group, wk 13 vs. baseline was significant at p=0.004; for A1c  7 group, 26 wk vs. 13 wk was significant at p=0.002.

15. Figure 3. Percentage of Navigator glucose values in target during the study.* 30% 40% 50% 60% 70% 80% 90% BaselineWks 1-4 Wks 5-8 Wks 9-13 Wks 14-17 Wks 18-21 Wks 22-26 Percent in target range (71-180) Baseline A1c  7.0% Baseline A1c >7.0% N=14 N=15 N=11 N=9 N=11 N=13 N=15 N=13 * Black dots denote mean values and boxes denote median, 25 th and 75 th percentiles.

16. Figure 4. Percentage of Navigator glucose values below 70 mg/dL.* Percent below 70 mg/dL 0% 2% 4% 6% 8% 10% 12% 14% BaselineWks 1-4 Wks 5-8 Wks 9-13 Wks 14-17 Wks 18-21 Wks 22-26 Baseline A1c  7.0% Baseline A1c >7.0% N=11 N=13 N=15 N=13 N=14 N=15 N=11 N=9 N=11 * Black dots denote mean values and boxes denote median, 25 th and 75 th percentiles.

17. Conclusion Navigator sensor accuracy is sustained for up to 5 days. Diabetes control improved after short term use (13 weeks) of the Navigator. –A1c increased again by 26 weeks, though it remained significantly below baseline in the group whose initial A1c was >7%. The Navigator is well-tolerated by children and well- received by parents. Larger, randomized controlled studies are needed to evaluate the clinical usefulness of this promising device in the management of children with T1DM.

18. 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 Yale University –William Tamborlane –Stuart Weinzimer –Elizabeth Doyle –Heather Mokotoff –Melody Martin –Amy Steffen Stanford University –Bruce Buckingham –Darrell Wilson –Kimberly Caswell –Paula Clinton Nemours Children’s Clinic –Tim Wysocki –Nelly Mauras –Larry A. Fox –Keisha Bird –Kim Englert Jaeb Center for Health Research –Roy Beck –Katrina Ruedy –Craig Kollman –Dongyuan Xing –Cynthia Stockdale