VIRTUAL PATIENTS DERIVED FROM THE CARELINK DATABASE Benyamin Grosman PhD Senior Principle Scientist Medtronic Diabetes
WHY VIRTUAL PATIENT MODELING? Reduce the cost of clinical trials Use models in conjunction wit h smaller clinical t rials t o prove safet y and efficacy Faster, more robust design iterations Clinical t rials Smaller clinical t rials + Virt ual t rials Virt ual t rials only Now Fut ure 2
SENSOR AUGMENTED PUMP (SAP) Cont inuous glucose monit or (CGM) Calibrated using finger-st icks and a separat e blood glucose meter Communicates measurements to insulin delivery device Insulin pump Subcutaneous insulin delivery User interface Therapy algorit hms CareLink Uploads pump and CGM dat a int o dat abase Serves therapy reports to pat ient s and healt hcare providers 3
THE MATHEMATICAL MODEL STRUCTURE 4 Presentation Title (Edit on Slide Master) June 1, 215 Confidential, for Internal Use Only
DIABETES PHYSIOLOGY MODEL MATHEMATICAL DESCRIPTION Different ial Equat ions Physiological Response Unmodeled activity Unmodeled stress True Model 5
DIABETES VIRTUAL PATIENT DEFINITION Key Parameters that describe each virtual patient Meal behaviors Carbohydrate intake Meal times Meal rate of appearance Insulin needs Tot al daily dose Fasting insulin level Circadian insulin gain Blood glucose charact erist ics Fasting blood glucose level Blood glucose time constant Demographics: Age Race Zip code Time since diagnosis Gender Comorbidities Currently not available 6
GENERAL FLOW OF VIRTUAL PATIENT IDENTIFICATION Download CareLink data. Need 2 sequential days. Mark model regions that have large error for exclusion from future simulation results. Extract data for model fit. CGM Me als Insulin Optimize model driven by meal events and insulin data to obtain best fit to CGM data. 7
VIRTUAL PATIENT POPULATION DISTRIBUTION OF AGE AND DAILY INSULIN 287 virtual patients have been identified so far Distributions of patient characteristics allow for targeted simulations on particular sub-populations 8
MODEL VALIDATION COMPARISON TO CLINICAL DATA Physiological to published data Pharmacokinet ics Insulin effectiveness Meal absorption rates ASPIRE s t udy 247 patients with type 1 diabetes 121 using SAP with t hreshold suspend feature 126 control, SAP only Primary efficacy outcome is area under curve for nocturnal hypoglycemic events 67G Pivotal Study 124 patients with type 1 diabetes 2 week run-in using standard SAP therapy 3 month study period using hybrid closed-loop cont rol of basal insulin Descriptive endpoints include: Time below 7 mg/dl Time between 7 18 mg/dl Time above 18 mg/dl 9
INSULIN SENSITIVITY DISTRIBUTION Comparison of the user s insulin sensitivity factor (ISF distribution), as recorded in CareLink (light green), and the theoretical ISF of the virtual patients (dark green). 8 CareLink average ISF number of patients 6 Simulated average ISF 4 2 2 4 6 8 ISF [mg/dl/u] 1 Presentation Title (Edit on Slide Master) June 1, 215 Confidential, for Internal Use Only
MEALS RATE OF ABSORPTION AND RATE OF APEARANCE The median IQR meal rate of appearance (Ra) in the plasma per a heterogeneous meal of 5 gram of CARB content for the virtual patients breakfast, lunch, and dinner; figure (a)-(c), respectively. This is in good agreement with published data 1,2 that estimated Ra to peak at around 3 minutes with oral glucose tolerance test and around 6 minutes with homogenized meals. Ra [mg/dl/min] 15 1 5 T m a x =41.2875 +/- 26.732 2 4 Time minutes Ra [mg/dl/min] 15 1 5 T m a x =44.8821 +/- 26.5516 2 4 Time minutes Ra [mg/dl/min] 1 5 T m a x =51.2881 +/- 27.9717 1 2 3 4 Time minutes The 48 minutes glucose increase a none-boluse d heterogeneous meal of 5 gram of CARB content of the virtual patients breakfast, lunch, and dinner; figure (a)-(c), respectively. Pehling et al 3, measured showed glycemic peak after around 15-18 minutes from the time of meal intake and the glycemic maximum level reaching 2 mg/dl above the initial level 4 T m a x =167.289 +/- 62.36 A. A. 4 T m a x =175.4722 +/- 6.862 B. B. 4 3 T m a x =188.6688 +/- 62.6675 C. C. G [mg/dl] 2 G [mg/dl] 2 G [mg/dl] 2 1 1 2 3 4 Time minutes 1 2 3 4 Time minutes 1 2 3 4 Time minutes 1. Dalla Man C, Camilleri M, Cobelli C. A system model of oral glucose absorption: validation on gold standard data. IEEE transactions on bio-medical engineering 26;53:2472-8. 2. Basu R, Di Camillo B, Toffolo G, et al. Use of a novel t riple-tracer approach to assess postprandial glucose metabolism. American Journal of Physiology - Endocrinology and Metabolism 23;284:E55-E69. 3. Pehling G, Tessari P, Gerich J E, Haymond MW, Service FJ, Rizza RA. Abnormal meal carbohydrate disposit ion in insulin-dependent diabetes. Relative contributions of endogenous glucose production and initial splanchnic uptake and effect of intensive insulin therapy. The Journal of clinical invest igation 1984;74:985-91. 11 Presentation Title (Edit on Slide Master) June 1, 215 Confidential, for Internal Use Only
VIRTUAL PATIENT VS CLINICAL STUDIES ASPIRE STUDY 3 Virtual patient simulation captures the dynamics of hypoglycemia and rebound hyperglycemia TH = 9 Simulation 2 1 TH = 7-18 -15-12 -9-6 -3 3 6 9 12 15 18 21 24 27 3 33 36 Insulin suspended Aspire st udy 12
VIRTUAL PATIENT VS CLINICAL STUDIES ASPIRE STUDY The percentages of sensor glucose values in various ranges following 2-hour threshold suspend events are shown below for the 1385 events with data at 2 hours (left) with Aspire data and on 732 and 1232 events with simulation studies with threshold set 7 and 9 mg/ dl, respectively. 12 1 <7 mg/dl 7 to 2 mg/dl >2 mg/dl 8 percent 6 4 2 Aspire Simulation TH = 9 Simulation TH = 7 13
SIMULATION EXAMPLE ARTIFICIAL PANCREAS SYSTEM SIMULATION Virtual patient model integrated into a closed loop simulation CGM subsystems 67G Pump Virtual Patient Model 14
VIRTUAL PATIENT VS CLINICAL STUDIES 67G PIVOTAL STUDY ADULT POPULATION Run-in and st udy pivot al t rial dat a, Adult s, age > 19 (N=93) Run-in and st udy Simulat ion St udy, Adult s, age > 28 (N=9) Run-in Study P Run-in Study P Sensor glucose, mg/dl 146.1±22.3 148.3±13.5.4 Sensor glucose, mg/dl 149.4±19.5 147.4±1.7.35 Percent of SG values in range <7 mg/dl 6.4±4.3 3.4±2.1 <.1 71-18 mg/dl 68.8±11.9 73.8±8.4 <.1 >18mg/dL 24.9±13.5 22.8±8.9.1 >3mg/dL 1.8±4.1 1.3±1.7.38 TDD,U 44.9±23.7 47.9±28 <.1 Percent of SG values in range <7 mg/dl 6.6±6.4 3.1±3.7 <.1 71-18 mg/dl 67.8±5.9 77.7±6.4 <.1 >18mg/dL 25.6±9.5 2.2±6.7 <.1 >3mg/dL 1.9±2.1 1.2±1.2 <.1 TDD,U 4.2±13.2 37.1±11.9 <.1 Pivotal study results include 93 Adults for 3 months Simulation results include 9 virtual patients Adults for 13 days Does not account for many disturbances Missed meal announcements (eating without bolusing) Exercise, illness, stress 15
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