Hybrid Closed Loop Status & Practical Challenges in Implementation

Transcription

1 Hybrid Closed Loop Status & Practical Challenges in Implementation Bruce Buckingham, MD Professor of Pediatric Endocrinology Stanford School of Medicine

2 Conflict of Interests Company Novo-Nordisk Sanofi BD Convatec Medtronic Insulet Dexcom Bigfoot Tandem Nature of Relationship Consulting Consulting Consulting Consulting Research Funding Research Funding Research Support Research Funding Research Funding, Consulting

3 Current State of Type 1 Diabetes Updated T1D Exchange K. Miller, Diabetes Care 38: 971

4 Insulin Pump Use Is Increasing 100% 80% 60% 40% Enrolled 9/1/2010-8/1/2012 Current 4/1/2014-4/1/ % 61% 62% 66% 65% 60% 61% 62% 58% 57% 56% 56% 60% 56% 50% 58% 20% 0% Overall < Age (years)

5 CGM Use Is Increasing % 40% 30% 32% Enrolled (8% use CGM overall) 25% 27% 27% 21% 20% 10% 17% 17% 10% 10% 6% 8% 12% 18% 14% 0% <

6 ADA HbA1c Targets Not Met by Most 100% 80% Enrolled Current A1c Goal = <7.5% A1c Goal = <7.0% 60% 40% 20% 24% 24% 20% 22% 22% 18% 17% 15% 31% 31% 28% 36% 28% 36% 0% < Age (years)

7 3-month Frequency of Severe Hypoglycemia* According to HbA1c 40% 30% *Seizure or Loss of Consciousness: 1 or more events in 3 mo from subset who completed insulin and device questionnaire 20% 10% 6% 7% 8% 6% 7% 8% 9% 6% 0% <6.0% 6.0%- <6.5% 6.5%- <7.0% 7.0%- <8.0% 8.0%- <9.0% 9.0%- 10.0%- 11.0% <10.0% <11.0% HbA1c %

8 Closed-Loop Advances Insulin pump advocated for children RT Glucose Sensors O Grady, Ly et. al. DC n=8, 2 nights Ly, Buckingham et. al. DC n=21, 6 days First commercial CL system - Released July s Weinzimer et. al. DC Pediatric n=17 34h Steil, DC N=10, 30 hours Phillip et. al. NEJM Pediatric n=56 1 night Russell et. al. NEJM Adults + adolescents n=52 5 days Thabit et. al. NEJM Adults n=32 3 months 670G Pivotal - JAMA Adults + adolescents, n=124 3 months

9 Dr. Arnold Kadish Am J Med Electronics 3:82-86, Measured Venous blood every 15 seconds with 7 min lag time Delivered insulin at 0.1 U/min if >150 mg/dl (8.3 mmol/l) Delivered glucagon at 0.05 mg/min if < 50 mg/dl (2.8 mmol/l)

10 Medtronic Inpatient Studies unit basal increments bolus increments 1 unit in 30 sec

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12 Medtronic 670G 2014

13 JDRF Modular Closed-Loop Control 2008

14 DiAs (UVA) System

15 Type Zero InControl

16 International Diabetes Closed-Loop Trial (idcl) 7 centers 3 month study Ages subjects Followed by 3 month study with Algorithm on Tandem Pump 84 subjects

17 FlorenceD2A closed-loop system Adults Children and adolescents DANA-R pump Dell Latitude tablet DANA-R pump Nexus 4 LG smartphone Nav 2 CGM receiver and translator Thabit, Tauschmann, Hovorka et. al. on behalf of APCam consortium and AP@home consortium, NEJM Sep 2015

18 Automated Closed-Loop System for Hovorka Studies

19 Multicenter Closed-loop Hovorka Study 7 centers 130 subjects 6 to 18 years old 1 Year day and night At home No remote monitoring

20 Bionic Pancreas

21 Outpatient bionic pancreas Mean glucose levels in adults Mean glucose levels in adolescents (8.7) 138 (7.7) Russell SJ et al. N Engl J Med 2014;371(4):

22 The ilet -2015

23 The ilet

24 Gen 4 ilet % smaller than Gen 3

25 Beta Bionics Planned Studies Insulin-Only Bridging Study Late 2017, Early 2018 Bihormonal Bridging Study Early 2018

26 Bigfoot Biomedical

27 Bigfoot Clinical Studies Tested for 36 hours in research center Tested for extremes Missed meal bolus Meal overbolus Exercise Will use Abbott Libre Real Time Sensor Additional Clinical Trials Planned soon

28 Insulet Commercial System

29 Insulet Studies In research center for 36 hours Adults Adolescents 6-12 year olds In AirBnB 54 hours Adults Testing Exercise, Missed Meal Bolus, High Fat Meal, and Overbolus Starting AirBnB 5 days Free range during the day 6-12 year olds on Sunday

30 Tandem

31 Tandem Pipeline Using G5 Predictive Low Glucose Suspend Studies starting next month Once FDA approved immediately internet downloaded to current Tandem t:slim X2 Type Zero (UVA) algorithm on Pump

32 Closing the Loop Meters Sensors Pumps Algorithm

33 Dexcom G4P Sensor Performance Ly, Diabetes Care 37: ,2014 Inpatient Studies (YSI) = Day 1 of sensor wear n=201 Mean ARD 10.4 ± 9.1% Camp Studies (Contour Next) n=740 Mean ARD 17.5%

34 What happens in reality

35 Dirty Hands Clean 94 mg/dl (5.2) Blood and Wet Hand 85 mg/dl (4.7) Blood and Sugar Water 94 mg/dl (5.2) Blood and Milk 310 mg/dl (17.2) Blood and Jam 361 mg/dl (20.0) Blood and Pancake Syrup 526 mg/dl (29.2) Personal study by Bruce Buckingham

36 Effect of Handling Fruit on Meter BG First Drop Second Drop Washed Hands 153 mg/dl 157 mg/dl Finger Exposed To Fruit, No Washing After Washing Fruitexposed Finger 270 mg/dl 160 mg/dl 151 mg/dl 150 mg/dl Hortensius, (2011)

37 Effect of Handling Fruit on Meter BG Hortensius, (2011)

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39 Accuracy (MARD) of Sensors When Used in Pediatric Outpatient Studies Russell Dexcom G4 Accuracy Inpatient Reference Outpatient Accuracy with Adults Outpatient accuracy in Pediatrics 10.8%* 16.7%** 19.2%*** Ly Dexcom G4 10.4% 17.5% Ly Enlite 14.1% (first day) Ly Enlite % (first day) 19.2% Outpatient Using second Drop of blood 12.6% * Damiano, JDST 2014 ** Russell, NEJM 2014 *** Russell, Lancet 2016 Ly, Diabetes Care 2014 Ly, DTT 2016 Ly Diabetes Care 2015

40 Closing the Loop Meters Sensors Pumps Algorithm

41 Infusion Sets The weak link in insulin pump delivery

42 Integrated Sensor and Infusion Set

43 Summary of 353 Weeks of Testing for 7 days of Infusion Set Wear Mean Duration of Wear 5.0 ± 1.8 days Percent Lasting 7 days 40% Removal for unexplained hyperglycemia Removal for pain, infection or erythema Removal for other eg. pulled out adhesive failure, unknown 26% 17% 20%

44 Nocturnal Hypoglycemia In DCCT, 55% of severe hypoglycemia occurred during sleep In children, 75% of severe hypoglycemia occurred during sleep Real-time CGM provides nocturnal alarms But 71% of alarms are not responded to DCCT, Diabetes Care 18:1415, 1995 Davis, Diabetes Care 20:22, 1997 Buckingham, DTT 7:440, 2005

45 Overnight Glucose Control Preventing low Threshold suspend on low Predictive low glucose suspend Full Closed-loop at night

46 Duration of Nocturnal Hypoglycemia Prior to a Seizure - 16 year old Buckingham, Diabetes Care 31:2110, hr 15 min Seizure

47 Duration of Nocturnal Hypoglycemia Prior to a Seizure - 16 year old Buckingham, Diabetes Care 31:2110, 2008 Australian patient courtesy of Fergus Cameron 4 hrs 45 min

48 Off Duty

49 Low Glucose Suspend with Exercise Induced Hypoglycemia (50 subjects) DTT (2012) 14: Minute Horizon Threshold of 80 mg/dl

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51 Time of Night for Hypoglycemic Events

52 Overnight closed-loop control Artificial-pancreas nights Control nights Phillip M et al. N Engl J Med 2013;368(9):

53 Overnight closed-loop: home studies 16 adolescents, years of age 3 weeks of overnight closed-loop at home Crossed over to 3 weeks SAP No remote monitoring SAP, sensor-augmented pump. Hovorka R et al. Diabetes Care 2014;37(5):

54 Glucose profiles Adults Children and adolescents 33 adults 3 months SAP 3 months 24/7 hybrid-closed 25 children and adolescents 3 months SAP 3 months overnight closed-loop SAP, sensor-augmented pump. Thabit H et al. N Engl J Med 2015;373(22):

55 Three weeks of closed-loop in adolescents 12 adolescents Initial A 1c = 8.5% Crossover study Compared to 21-day SAP Hybrid closed-loop A 1c, haemoglobin A 1c ; SAP, sensor-augmented pump. Tauschmann M et al. Diabetes Care 2016;39(11):

56 DiAs System

57 Remote Monitoring

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59 Three Day Tracing DiAs Hotel

60 Camp Activities

61 Median ± 90%tile Envelope Blue = Sensor Augmented Pump Red = Closed-loop

62 Glucose Control Pre and Post Camp Closed-Loop Studies Pre- Camp A1c eag (mg/dl) Average Glucose at Camp (mg/dl) Estimated A1c from Camp Mean Glucose Sensor Augmented Pump (Control Group) 8.4% % Control to Range 8.0% % Damiano Camp Control Damiano Camp Bionic Pancreas 8.2% % 8.2% %

63 Glucose Control Pre and Post Camp Closed-Loop Studies Pre- Camp A1c eag (mg/dl) Average Glucose at Camp (mg/dl) Estimated A1c from Camp Mean Glucose Sensor Augmented Pump (Control Group) 8.4% % Control to Range 8.0% % Damiano Camp Control Damiano Camp Bionic Pancreas 8.2% % 8.2% %

64 Ski camps done safely for 20 years at BDC Early 90 s Dr. Chase

65 Ski Camp Study: UVA/BDC 2017

66 The Present Medtronic 670G Enlite 3 sensor

67 Admission Date: 6/29/2013 6/30/2013 (Subject 11RJ) Glucose (mg/dl) Infusion Rate (U/h) Sbj # Time (h) * CGM YSI Meter BG Setpoint Manual Bolus Fault Training Err. Infusion Rate Insulin Limits Corr. Bolus Missed Tx Umin Timeout Safe Basal Start CL Stop CL Min Max YSI, mg/dl % In-Range, Tighter (70 150, mg/dl) % In-Range (70 180, mg/dl) Avg. YSI, mg/dl Sensor MARD, %

68 Open Loop Compared to Closed-Loop

69 Open Loop Compared to Closed-Loop

70 Important to Understand what it can and cannot do This is a basal rate modulator Works well overnight Still requires meal boluses, correction bolus, and many fingersticks Diabetes tasks during the day are not decreased There are more alarms

71 670G Safety Features If at minimal insulin deliver for 2 ½ hours, defaults to safe basal To detect sensor failure If at >300 for 1 hour, or >250 for 2 hours, requires glucose entry To detect infusion set failure Sensor performance is checked with impedance spectroscopy

72 Enlite 3 Sensor Accuracy is 10.6% with two fingersticks/d Accuracy is 9.6% with four fingersticks/d Has impedance spectroscopy as a built in second measure of sensor function

73 Impedance Spectroscopy

74 Initialization Requires a minimum of 2 days of sensor and pump data to be initialized the first time it is used or not used for 2 weeks If pump is suspended or turned off for more than 4 hours, then aa 5 hour warm-up is required to recalculate active insulin (insulin-on-board)

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76 Controller Adaptability and Settings Blood glucose target of 120 Can temporarily change to 150 for a set duration For activities such as sports or driving The controller gain (how aggressive it is), maximum basal insulin delivery limit, insulin sensitivity factor, and safe basal rates are adapted daily Based on glucose levels overnight and total daily insulin dose

77 Tunable parameters Carbohydrate to insulin ratios Can have multiple ratios throughout the day Duration of insulin action Insulin Bolus Speed

78 Different bolus speeds 20 subjects, studied twice 15-unit bolus Animas pump over 30 seconds Minimed 512 over 10 minutes Regittnig W et al. Diabetes 2013;62(Suppl. 1):Abstract 966-P.

79 Different bolus speeds Animas 15 units over 30 sec Medtronic units over 10 min Onset of insulin action 21 ± 2.5 min 34.3 ± 2.7 min Time to peak effect 98 ± 11 min 125 ± 16 min Insulin AUC from 0 to 60 min ± ± 865 AUC, area under the curve. Regittnig W et al. Diabetes 2013; 62(Suppl. 1):A247.

80 Fixed parameters Correction factor Based on total daily dose divided into 1800 Requires a fingerstick glucose value Automatically corrects to a target of 150 mg/dl if glucose is >150 mg/dl

81 Daily Use Need to take a fingerstick glucose before each meal Recommended to wait at least 10 minutes after taking bolus before eating Need to respond to alarms to keep in Closed-loop

82 670G Study Subject Download Average glucose = 153 (ea1c = 7.5%), 1% of readings < 70 mg/dl

83 Adolescent male, 78 kg Carbohydrates vary from 160 to 971 grams a day Insulin varies from 73 to 267 units a day Mean Glucose = 124 ± 52 mg/dl

84 Day of 971 grams of CHO

85 670G Pivotal Study Characteristic Adolescents age 21 (N=30) Adults age >21 (N=94) Age yr 16.5± ± Diabetes Duration - years Total daily insulin dose U/kg/day HbA1c % at screening 7.7 ± ± ± ± ± ±0.91

86 All Patients in 670G Pivotal Study A

87 Adults in 670G Pivotal B C

88 Adolescents in 670G Pivotal C

89 Statistics for All Subjects in 670G 94 Adults, 30 Adolescents Run In (Baseline) 3 month Data HbA1c 7.4 ± ± 0.6 <0.001 % <70 mg/dl 6.4 ± ± 2.0 <0.001 % ± ± 8.8 < TDI 47 ± ± 27 < p

90 Statistics for All Subjects in 670G 94 Adults, 30 Adolescents Run In (Baseline) 3 month Data HbA1c 7.4 ± ± 0.6 <0.001 % <70 mg/dl 6.4 ± ± 2.0 <0.001 % ± ± 8.8 < TDI 47 ± ± 27 < p

91 Statistics for All Subjects in 670G 94 Adults, 30 Adolescents Run In (Baseline) 3 month Data HbA1c 7.4 ± ± 0.6 <0.001 % <70 mg/dl 6.4 ± ± 2.0 <0.001 % ± ± 8.8 < TDI 47 ± ± 27 < p

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93 Low Alert on High Minimal insulin delivery

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95 Does A1c determine who is a good candidate?

96 670G Greatly improves overnight control Start the day with a good glucose Improved sensor - MARD 10.3% Need to optimize meal coverage - insulin:carbohydrate ratio Understand the causes of auto-mode exit, and do a little work to stay in closed loop Calibrate at least every 12 hours Bolus before eating

97 3-month Frequency of Severe Hypoglycemia* According to HbA1c 40% 30% *Seizure or Loss of Consciousness: 1 or more events in 3 mo from subset who completed insulin and device questionnaire 20% 10% 6% 7% 8% 6% 7% 8% 9% 6% 0% HbA1c %

98 670G and Severe Hypoglycemia 65,000 days and nights of 670G wear This represents 178 patient years From T1D Exchange data there should have been at least 12 severe hypoglycemic events with seizure or loss of consciousness Actual number of severe hypoglycemic events = 0 CDC estimates there are 300,000 ER visits in adults each year for hypoglycemia Average cost per visit is about $1,161 (Foos, J Med Econ, 2015) The 670G allows for a good, safe nights sleep, without the risk of a severe, costly hypoglycemic event

99 Insurance Coverage for the 670G COVERED Aetna Cigna Humana United Health Care Sutter Health Valley Health Plan Tricare West Blue Shield of California Health Net California California Children s Services (County and Individual Specific) (1 yes) NOT COVERED Anthem Blue Cross Blue Shield California Children s Services (County and Individual specific) (7 no) Not covered with Anthem Blue Cross Blue Shield

100 Assessment and Progress A 4/9/2017-4/22/2017 (14 Days) employee, 670 B 3/26/2017-4/8/2017 (14 Days) Generated: 5/25/ :46:38 PM Data Sources: MiniMed 670G (NG H) Page 2 of 8 Percentile comparison 25-75% 0-90% Average A Carb Ratio A 9 (g/u) * B A Hypoglycemic patterns(3) 6:46 PM- 7:41 PM 8:48 PM- 9:13 PM (2 occurrences) (1 occurrences) 10:42 PM- 11:17 PM (1 occurrences) Hyperglycemic patterns(0) None Time in range 1% 10% 88% 40 1% 50 A 70 * Most recent pump settings are displayed B 2% 11% 85% 2% mg/dl Auto Mode Exits No Calibration High SG Auto Mode Exit 0 Auto Mode max delivery 0 Auto Mode min delivery 0 BG required for Auto Mode 0 Sensor Algorithm Underread 2 Sensor Updating Sensor Updating 0 A 0 B 0 2 No SG values 0 0 Sensor Expired 0 1 Auto Mode disabled by user 2 0 Alarms 0 0 Pump Suspend by user 0 0 Large time/date change 0 0 Unidentified Statistics A Auto Mode (per week) 92% (6d 11hrs) Manual Mode (per week) 8% (13hrs) Sensor Wear (per week) 92% (6d 10hrs) Average SG ± SD 137 ± 34 mg/dl Estimated A1C 6.4% Average BG 145 ± 43 mg/dl BG / Calibration (per day) 11.6 / 3.5 Total daily dose (per day) 46 units Bolus amount (per day) 23U (50%) Auto Basal / Basal amount (per day) 23U (50%) Set Change 4 Reservoir Change 4 Meal (per day) 7.6 Carbs entered (per day) 154 ± 39g Active Insulin time 3:00 hrs B 83% (5d 19hrs) 17% (1d 05hrs) 98% (6d 20hrs) 137 ± 39 mg/dl 6.4% 147 ± 48 mg/dl 10.9 / units 20U (49%) 21U (51%) ± 46g 3:00 hrs

101 Current State of Type 1 Diabetes Updated T1D Exchange K. Miller, Diabetes Care 38: 971 Insulin-only Closed-Loop Bihormonal Closed-Loop 6.5

102 What Do Participants Think? Great to wake up with a good glucose and no lows overnight Sensors are much better Feel liberated from food constraints Not perfect during the day When can I get one of these?

103 670G Pivotal Study Our daughter went XC skiing on Sunday noon-3pm. I think she did really well at staying in closed loop. Usually her BG would have been all over the place. We love this system! I know that I will be able to get a good night's sleep knowing that the pump is taking care of things. If she's high, it will bring her back in range, and if she's low, it will make sure she comes up to a safe range. And all the while both of us will be sleeping soundly in our own beds, with no alarms to disturb us. I've seen the future of diabetes management and it is bright!

104 The Future Hybrid Closed-Loop During the Day and Full Closed-loop Overnight Premeal bolus Remove carbohydrate counting

105 New Insulin Preparations and Adjunctive Therapy to Improve Post Prandial Control Fast Aspart Biochaperone Lispro Afrezza GlP-1 agonists to delay gastric emptying and lower postprandial glucagon

106 The Future Algorithms will continue to improve Adapting to individuals Modifying set points Modifying overnight basal Modifying meal responses Adapting over time Short term for acute changes Long term for weekly and monthly patterns

107 The Future Use of Accelerometers and Heart Rate Monitors Detect and adjust automatically for activity Allows detection of sleep to modify algorithm Integration into Consumer Devices Apple/Apple Watch Google Android

108 The Future Improved infusion sets Longer duration of wear Combined with sensors Improved Sensors MARD less than 10% Duration of wear 2 weeks Factory Calibration

109 The Future Full Closed-Loop No CHO counting, no premeal bolus Less than perfect, but may be good enough

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112 THANK YOU Bruce Buckingham