1 GLUCOWATCH ® G2™ BIOGRAPHER H. PETER CHASE, MD I)INTRODUCTION II)ACCURACY DATA III) HOME PILOT TRIAL IV) DIRECNET STUDY GROUP V) SUMMARY

2 GlucoWatch ® G2™ Biographer

3 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

4 GlucoWatch G2 Biographer INTRODUCTION i) Second generation model (G2B) ii) Warm-up 2 hours  enter BG value iii) Reverse iontophoresis: AAA battery iv) Pulls interstitial fluid (including glucose) into gel discs in Auto Sensor v) Readings as often as every 10 min for up to 13 hrs (max = 76 readings; Ave = 55) v) Readings as often as every 10 min for up to 13 hrs (max = 76 readings; Ave = 55)

5 INTRO: G2B vi) Numerous data integrity checks are performed that monitor environmental factors (temperature, sweating), sensor function, and performance. If the reading fails the data integrity checks, it is skipped because the value may be incorrect. vii) The G2 Biographer averages the reading obtained in the most recent cycle with the reading obtained in the previous 10 minute cycle.

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7 INTRO: G2B vii) Alarms for: Hypo/hyper-glycemia (level set by user) Hypo/hyper-glycemia (level set by user) Pending low in next minutes Pending low in next minutes Low or drop 30 minutes prior to detection of sweat Low or drop 30 minutes prior to detection of sweat viii) Up or down arrows with change of 9mg/dl

8 INTRO: G2B: Major uses: i) Nocturnal hypoglycemia ii) Postprandial hyperglycemia iii) Hypoglycemic unawareness iv) Gestational diabetes v) Type 2 diabetes vi) Other (e.g. Glycogen Storage Dis.)

9 G2B: Positives: i)Detection of lows – particularly during the night ii) Making aware of post-prandial highs iii) “Watchdog” effect iv) Detecting “patterns” v) ing data to MD or RN

10 INTRO: G2B:Negatives: i)Skipped readings with sweating ii)Not always awakening for alarm iii) Not waterproof iv) Skin itching, blisters, (remove sensor with Unisolve®) (adults > youth) v)Won’t take first calibration (6%) due to sweat, rapid BG change, weak signal vi) Other skipped readings

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

12 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. DirecNet Data

13 Analyzer Features Analyzer alert settings may differ from Biographer settings Biographer DOWN alerts Trend arrows not shown on Analyzer screen 220 mg/dL 160 mg/dL

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16 Part II: ACCURACY STUDIES IN CHILDREN 1)Eastman RC, Chase HP, Buckingham B, et al. Pediatric Diabetes 3:127, 2002 i)Clinic setting ii)3 First GW Biographers/subject iii) Multiple wear sites iv) Compared to HemoCue® meter

17 ACCURACY STUDIES IN CHILDREN ACCURACY STUDIES IN CHILDREN 2)DirecNet Study Group i)Inpatient ii) 2 – 4 G2Bs/subject iii) Upper and lower arm sites iv) Compared to hospital lab BG

18 ACCURACY STUDIES IN CHILDREN GWB G2B GWB G2B (Pediatric Diabetes)(DirecNet) SettingsClinic (14 Hr)Inpatient (26 Hr) No. Youth 66 (11.9 yrs) 89 (9.9 yrs) Sensors Comparisons ,659 Skipped Readings: 14% 17%

19 ACCURACY STUDIES IN CHILDREN GWB G2B (Pediatric Diabetes)(DirecNet) i)Mean Difference*-17 mg/dl 2.1 mg/dl ii)Absolute Difference**34 mg/dl30.8 mg/dl iii) MARD*** 21% 22% *Mean Difference = Sensor value – Lab value **Absolute Difference= Absolute value of difference **MARD = Mean Absolute Relative Difference = Sensor value – lab value x 100 lab value lab value

20 ACCURACY STUDIES IN CHILDREN GWB G2B GWB G2B (Pediatric Diabetes)(DirecNet) iv) Correlation Coef v) Consensus Error97% 97% Grid (A + B) Grid (A + B) vi) Paired Values 76% 74% within 20% within 20%

21 ACCURACY STUDIES IN CHILDREN:HYPOGLYCEMIA Overnight Hypoglycemia (<70mg/dl) 1)18 episodes by G2B (DirecNet) 2) 10 episodes = Lab glucose matched 8 episodes = not confirmed 8 episodes = not confirmed

BG BG yo on CSII Basal rates had been erased Accidentally put in rates 12 hours off True lows detected by alarm 4/74/84/94/10

23 BG yo on CSII with correct/new basal rates in place HbA1c = 7.4% 4/12 4/13

24 Part III: HOME PILOT STUDY Use of the GlucoWatch Biographer (GWB) in Children with Type 1 Diabetes (T1DM) Chase HP, Roberts MD, Wightman C, Klingensmith G, Garg SK, et al. Pediatrics 111: ,2003. Objective: To determine the usefulness of the GWB for: 1) detection of hypoglycemia 2) improving glucose control in children and adolescents with T1DM in a home environment

25 40 Randomized Study Subjects Age 7-17 years; mean = 12.4 yrsAge 7-17 years; mean = 12.4 yrs Type 1 diabetes 1 yr (mean = 6.3 yrs)Type 1 diabetes 1 yr (mean = 6.3 yrs) HbA1c >8% on 2 occasions during prior 6 monthsHbA1c >8% on 2 occasions during prior 6 months Absence of clinically significant disease or condition that would interfere with participation in the trialAbsence of clinically significant disease or condition that would interfere with participation in the trial No history of severe hypoglycemia for 6 months preceding entry into the trial (many had prior history of severe hypoglycemia >6 months before study)No history of severe hypoglycemia for 6 months preceding entry into the trial (many had prior history of severe hypoglycemia >6 months before study) Willingness to be randomly assigned to standard care or standard care with Biographer monitoring 4 times/weekWillingness to be randomly assigned to standard care or standard care with Biographer monitoring 4 times/week

26 Study Plan Randomization to two treatment groupsRandomization to two treatment groups –standard care in the home environment –standard care in the home environment with GlucoWatch Biographer monitoring Biographer alerts set to 70 and 300 mg/dLBiographer alerts set to 70 and 300 mg/dL Confirmation of alerts by conventional blood glucose monitoringConfirmation of alerts by conventional blood glucose monitoring Both groups: weekly review of SMBG data (±GWB data) and a phone call from HPCBoth groups: weekly review of SMBG data (±GWB data) and a phone call from HPC

27 Outcome Measures HbA1c measured at baseline, and at 1 and 3 months (DCA-2000)HbA1c measured at baseline, and at 1 and 3 months (DCA-2000) Hypoglycemia events determinedHypoglycemia events determined - Biographer alert = 70 mg/dl - Hypoglycemic event = SMBG <70 mg/dl SurveysSurveys –Fear of Hypoglycemia –Quality of Life (DCCT)

28 GWB: HOME USE Week #Uses/wk %Hi BG* %Lo BG* *GWB readings

29 Frequency of Hypoglycemia Home Meter Blood Glucose < 70 mg/dL * * * p<0.05versuscontrol * p<0.05 versus control * * * *

30 Median HbA1c by Group vs. Time * p<0.05 versus control group *

31 Summary and Conclusions Biographer use was well tolerated in the home environmentBiographer use was well tolerated in the home environment HbA1c was significantly lower (p<0.05) in the Biographer treatment group compared to the control group after 3 months of treatmentHbA1c was significantly lower (p<0.05) in the Biographer treatment group compared to the control group after 3 months of treatment Biographer users detected significantly more hypoglycemia during the day and night than non- usersBiographer users detected significantly more hypoglycemia during the day and night than non- users The Biographer is useful for improving glucose control and detecting hypoglycemia in children and adolescents with type 1 diabetesThe Biographer is useful for improving glucose control and detecting hypoglycemia in children and adolescents with type 1 diabetes

32 Using DCCT data, a decline in HbA1c from 9.0 to 8.4 for 100 subjects for a lifetime would: 1) 1)Prevent severe eye disease in 20 people 2) 2)Prevent blindness in 6 people 3) 3)Prevent gross kidney damage in 20 people (8 needing transplants) 4) 4)Prevent 6 cases of neuropathy Reduction in Complications: Eastman RC, Chase HP and Leptien AD Pediatric Diabetes 4:82-86, 2003

33 Slept through alarms Picked up low at calibration 0733 BG GWB tracings Pre-teen girl IDDM x 5yrs Patient at slumber party 2008 BG 56 4/18 4/194/ BG BG 259

34 4/25 5/ bg Piano teacher gave candy but did not test 1357 bg175 Pre-teen girl IDDM x 5yrs 0908 bg bg45 Went to office No snack given Low alarm at same time as last week (1530) No bg test 1759 bg bg80

35 Part IV: DIRECNET STUDY GROUP DIabetes REsearch in Children NETwork i)NIH funded collaborative study group (NICHD and NIDDK) ii)5 Centers: Denver, Iowa, Nemours (FL), Stanford and Yale. + Coordinating Center: = Jaeb Center for Health Research, Tampa, FL

36 DIRECNET STUDY GROUP DIRECNET STUDY GROUP iii) Objective = to critically evaluate the clinical usefulness of current and future glucose sensors in youth with T1DM. iv) Initial inpatient study= accuracy of G2B and of CGMS. Abstracts #156 OR, #432-P and #387-P. v) Next study: Similar to the GWB Pilot Trial done in Denver, but with 200 children x 6 months.

37 Part V: SUMMARY Purpose of the GlucoWatch Biographer: To detect trends and to track patterns in glucose levels as a supplement to SMBG (not to replace SMBG). Conclusion: The level of accuracy is sufficient for detecting trends. Pilot data shows the GWB is useful for improving glycemic control and detecting hypoglycemia in children and adolescents with T1DM.