disclosures progress in closing the loop · progress in closing the loop bruce buckingham, md...

Progress in Closing the Loop

Bruce Buckingham, MD

[email protected]

Professor of Pediatric Endocrinology

Stanford School of Medicine

Disclosures• Medical Advisory Board

– Medtronic– Tandem– Sanofi– Novo‐Nordisk– Convatec

• Research Support– Medtronic– Dexcom– Tandem– Bayer– Roche

Average Current HbA1c by Age

*≤2 years old and ≥80 years old are pooled

7

7.5

8

8.5

9

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Mea

n H

bA1c

Age (years)*

6yo

17yo

30yo

Current HbA1c: Slightly Worse in Youth Than at Enrollment

8.28.3

8.7

8.4

7.7 7.67.4

8.28.4

9.0

8.7

7.77.6

7.4

7.0%

7.5%

8.0%

8.5%

9.0%

<6 6-12 13-17 18-25 26-49 50-64 ≥65

Mea

n H

bA1c

Age (years)

Enrolled 2010-2012Current 2014-2015

6% 7% 8%6% 7% 8% 9%

6%

0%

10%

20%

30%

40%

<6.0% 6.0%-<6.5%

6.5%-<7.0%

7.0%-<8.0%

8.0%-<9.0%

9.0%-<10.0%

10.0%-<11.0%

≥11.0%

HbA1c %

3-month Frequency of Severe Hypoglycemia* According to HbA1c

*Seizure or Loss of Consciousness: 1 or more events in 3 mo from subset who completed insulin and device questionnaire

2% 2% 3% 4%7%

11%

18%

26%

0%

10%

20%

30%

40%

<6.0% 6.0%-<6.5%

6.5%-<7.0%

7.0%-<8.0%

8.0%-<9.0%

9.0%-<10.0%

10.0%-<11.0%

≥11.0%

HbA1c %

3-month Frequency of Diabetic Ketoacidosis* According to HbA1c

*1 or more DKA events in 3 mo from subset who completed insulin and device questionnaire

CGM Use Is Increasing But Still Low

4% 4% 3% 5%

17% 18%

10%

17%

10%6% 8%

25%21%

14%

0%

10%

20%

30%

40%

50%

<6 6-12 13-17 18-25 26-49 50-64 ≥ 65Age (years)

Enrolled 2010-2012 (8% use CGM overall)

Current 2014-2015 (12% use CGM overall)

Overview of Topics

• Inpatient – Research Center Based Studies

• Camp/Hotel – Closely supervised Studies

• Home studies

– With Remote Monitoring

– No Remote monitoring

• Hybrid vs. Full Closed Loop

• The Future

Dr. Arnold KadishAm J Med Electronics 3:82‐86, 1964

• 1964

• 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)

Closing the Loop

• Meters

• Sensors

• Pumps

• Algorithm

Medtronic Inpatient Studies ‐ 2009

• 0.025 unit basal increments

• 0.025 bolus increments

• 1 unit in 30 sec

2013 ‐ 2014

Medtronic 670G – 2014 JDRF Modular Closed‐Loop Control 2008

DiAs (UVA) System ‐ 2014FlorenceD2A closed‐loop system

Children and adolescents

Nexus 4 LG smartphone

Nav 2 CGM receiver and translator

Nav 2 CGM receiver

CGM transmitter

DANA‐R pump

DANA‐R pump

CGM transmitter

Dell Latitude tablet

Thabit, Tauschmann, Hovorka et. al. on behalf of APCam consortium and AP@home consortium, NEJM Sep 2015

Adults

Hovorka system for ambulatory adolescnetsTauschmann, DC 2016

Bionic Pancreas ‐ 2014

The iSlet ‐2015 The iSlet

Closing the Loop

• Meters

• Sensors

• Pumps

• Algorithm

Dexcom G4P Sensor PerformanceLy, Diabetes Care 37:2310‐2316,2014

• 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%

What happens in reality “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

Dexcom G4P Sensor Performance


– n=201

– Mean ARD 10.4 ± 9.1%


– n=740

– Mean ARD 17.5%

Enlite Sensor Performance


– All 16 subjects

– n=247

– Mean ARD 14.1 ± 11.6%


– n=798

– Mean ARD 19.2%

Enlite3 Sensor PerformanceLy, Diabetes Care 38:1205‐1211, 2015

• Inpatient Studies Compared To YSI Over First 2 Days Of Sensor Wear

– 8 subjects

– n=383

– Mean ARD 10.8% (8.8‐12.8)

• Camp Studies Compared to Bayer Next Meter

– n=752

– Mean ARD 12.6% (9.8‐13.8)

Closing the Loop

• Meters

• Sensors

• Pumps

• Algorithm

Infusion Sets

• The weak link in insulin pump delivery

Dermatologic complications in ChildrenWood, Diabetes Care: 29:2355, 2006

Schober, Pediatr Diabetes 10:198, 2009

• Scarring > 3mm in 12‐37%

• Erythematous nodules = 21‐42%

• Erythema without nodules = 25‐ 66%

• Abscesses in 8‐12%

Acute Infusion site Reactions

Scarring and Hyperpigmentation with at Infusion Sites

Scarring and Hyperpigmentation

Acute and Chronic Changes – Tape reaction Slight Desquamation at Infusion Set and Tape Reaction 3/31

Infusion Set Abscess 4/16

Integrated Sensor and Infusion Set

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

26%

Removal for pain, infection or erythema

17%

Removal for other – eg. pulled out adhesive failure, unknown

20%

Conclusions From 7‐Day Studies

• Is specific to the individual

• No difference in set survival with Novolog or Humalog

• No difference between Sure‐T and Quick‐set at 7 days

– 15% Early failure rate with Quick‐set (within 12 hours)

• No difference with Lipohypertrophy

• No difference with Hyaluronidase

• Innovations in infusion sets are needed

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, 1995Davis, Diabetes Care 20:22, 1997Buckingham, DTT 7:440, 2005

12-month Frequency of Severe Hypoglycemia* According to Age (22,300 Participants)

*1 or more events: defined as seizure or coma / loss of consciousness

6% 4% 6% 7%11%

14%

0%

10%

20%

30%

40%

50%

<6 6-12 13-17 18-25 26-49 ≥ 50 Age (Years)

Duration of Nocturnal Hypoglycemia Prior to a Seizure ‐ 16 year old

Buckingham, Diabetes Care 31:2110, 2008Australian patient courtesy of Fergus Cameron

4 hrs 45 min

Duration of Nocturnal Hypoglycemia Prior to a Seizure ‐ 16 year old

Buckingham, Diabetes Care 31:2110, 2008

Seizure2 hr 15 min

Overnight Glucose Control

• Preventing low

– Threshold suspend on low

– Predictive low glucose suspend

– Full Closed‐loop at night

Off Duty

Low Glucose Suspend with Exercise Induced Hypoglycemia (50 subjects)DTT (2012) 14:205

Threshold of 80 mg/dl

30 Minute Horizon

Nocturnal Sensor Attenuation

• Suspend for no more than 120 out of every 150 minutes.

• Suspend for no more than 180 min/night

Demographics(Median, IQ’s)

4‐10 yrs 11‐14 yrs 15‐45 yrs

No. of Subjects 36 45 45

No of Nights 1,912 1,896 1,524

Age (yrs) 8 (6,10) 13 (11,13) 30 (22, 39)

Duration (yrs) 4 (2,5) 6 (3,9) 15 (12, 26)

HbA1c (%) 7.8 (7.5,8.0) 7.7 (7.3,8.2) 6.8 (6.4‐7.6)

52

• Maahs, Diabetes Care 2014; 37:1885‐1891• Buckingham, Diabetes Care 2015; 38: 1197‐1204

Predictive Low Glucose Suspend Trial Design

• In the morning a meter glucose and blood ketones were obtained

• 5,332 morning ketone measurements in subjects from 4 to 45 years old

Safety Data for Active and Control Nights

• No DKA

• No seizures

Potential Factors Affecting Morning Ketosis

11‐14 year old 4‐10 year old

Duration of Sleep 9.3 hrs 9.7 hrs

Bedtime Snack 46% 39%

Morning ketoneswith snack

2% 7%

Morning ketones without snack

2% 8%

% of Mornings with Ketones ≥ 0.6 mmol/L

Age Group

15-45 Years 11-14 Years 4-10 Years

% o

f M

orn

ing

wit

h K

eto

nes

>=

0.6

mm

ol/L

0

2

4

6

8

10

12

14Control NightsIntervention

P = 0.10

Predictive Low Glucose Suspend

4 – 10 Year Olds p 11 -14 Year Olds p 15-45 Year Olds p

Control SystemActive



# nights 755 769 941 955 970 942

% nights <60 for 120 min

5% 1% <0.001 8% 3% < 0.001 11% 3% <0.001

Mean OvernightSensor Glucose (mg/dl)

153 ± 14 160 ± 16 < 0.004 144 ± 18 152 ± 19 < 0.001 125 132 P<0.001


Predictive Low Glucose Suspend

4 – 10 Year Olds p 11 -14 Year Olds p 15-45 Year Olds p




# nights 755 769 941 955 970 942

% nights <60 for 120 min

5% 1% <0.001 8% 3% < 0.001 11% 3% <0.001

Mean OvernightSensor Glucose (mg/dl)

153 ± 14 160 ± 16 < 0.004 144 ± 18 152 ± 19 < 0.001 125 132 P<0.001


Time of Night for Hypoglycemic Events Full Closed Loop at Night

Potential Factors Affecting Morning Ketosis

11‐14 year old 4‐10 year old

Duration of Sleep 9.3 hrs 9.7 hrs

Bedtime Snack 46% 39%

Morning ketoneswith snack

2% 7%

Morning ketones without snack

2% 8%

Possible Etiologies Of Increased Ketosis In 4‐10 Years Old

• This is normal physiology to fasting in this age group

• Muscle primarily provides gluconeogenic precursors (such as alanine) during fasting

– Muscle mass is relatively lower compared to body weight in younger children

Full Closed Loop at Night

Medtronic Overnight Closed Loop Camp Studies

Min – Max YSI, mg/dL % In‐Range, Tighter (70 – 150, mg/dL)

% In‐Range (70 – 180, mg/dL)

Avg. YSI, mg/dL Sensor MARD, %

95 – 140 100 100 114.9 5.3

Admission Date: 6/29/2013 – 6/30/2013 (Subject 11RJ)CGM

YSI

Manual Bolus

Setpoint

Fault

Infusion Rate

Insulin Limits

Meter BG*

Training Err.

Corr. Bolus

Missed Tx

Start CL

Stop CL

Umin Timeout

Safe Basal

22 23 24 25 26 27 28 29 30 31 320

4080

120160200240280320

Glu

cose

(m

g/dL

)

Sbj #11

22 23 24 25 26 27 28 29 30 31 320

1

2

3

4

5

6

Infu

sion

Rat

e (U

/h)

Time (h)

Min – Max YSI, mg/dL % In‐Range, Tighter (70 – 150, mg/dL)

% In‐Range (70 – 180, mg/dL)

Avg. YSI, mg/dL Sensor MARD, %

119 – 174 67.8 100 139.3 10.9

Admission Date: 6/27/2013 – 6/28/2013 (Subject 04AM)CGM

YSI

Manual Bolus

Setpoint

Fault

Infusion Rate

Insulin Limits

Meter BG*

Training Err.

Corr. Bolus

Missed Tx

Start CL

Stop CL

Umin Timeout

Safe Basal

22 23 24 25 26 27 28 29 30 310

4080

120160

200240

280320

Glu

cose

(m

g/dL

)

Sbj #04

22 23 24 25 26 27 28 29 30 310123456789

10

Infu

sion

Rat

e (U

/h)

Time (h)

Sensor Glucose Values Full Closed-Loop Overnight

Camp Session with 15-35 Year Olds

Minutes from 11 PM(Ends at 7 AM)

0 100 200 300 400 500

Sen

so

r G

luc

ose

Va

lues

(m

g/d

l)

Mea

n ±

SD

20

40

60

80

100

120

140

160

180

200

220Control Full OCL

DiAs Overnight Closed‐LoopCamp Studies

Ly, Diabetes Care 37:2310, 2014

Camp Activities

0

50

100

150

200

250

23:00 23:50 0:40 1:30 2:20 3:10 4:00 4:50 5:40 6:30

Sensor Glucose‐mg/dL

Time

Per protocol closed‐loop

Sensor‐augmented pump

Glucose control during overnight closed‐loopLy, Diabetes Care 37:2310, 2014

Cambridge Control AlgorithmRoman Hovorka

• Model-predictive control algorithm

• Linear Kalman filter with interacting multiple model strategy

Personal communication, Roman Hovorka, 2009

start of closed-loopcontrol

limit for insulin infusion

insulin infusion modulated every 15 min

Artificial Pancreas Cambridge Study 01 (N = 12)

• Overnight closed-loop– increases time spent in target range

– reduces time spent in hypoglycaemia

– eliminates extreme hypo/hyper risk

Time (h)

18:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00

Glu

cose

(m

mo

l/L)

0

2

4

6

8

10

12

14

16CSII

dinner &prandial

bolus

Time (h)

18:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00

Glu

cose

(m

mol

/L)

0

2

4

6

8

10

12

14

16 Closed loop

No rescue carbohydrates given Hovorka et al, Diabetes, 57 (Suppl 1):A22, 2008

Overnight Closed Loop ‐ Home Studies Hovorka, Diabetes Care 37:1204, 2014

• 16 Adolescents 12‐18 years old

• 3 weeks of overnight closed‐loop in home

• Crossed‐over to 3 weeks sensor‐augmented pump

• No remote monitoring

Overnight Closed Loop ‐ Home Studies Hovorka, Diabetes Care 37:1204, 2014

MD‐logic Overnight Control For 6 Weeks At HomeNimri, Diabetes Care, 2014

• Cross over study with 6 weeks on sensor augmented pump (control) and 6 weeks on MD‐Logic

• 24 patients ages 12‐43 years old

• Remote monitoring

MD‐logic Overnight Control For 6 Weeks At HomeNimri, Diabetes Care, 2014

Variable Closed‐Loop Control (SAP) P

% time <70 mg/dl 2.53 5.26 0.02

% Time 70‐140 mg/dl 49 36 0.002

Daytime Closed-LoopWhat Are the Problems?

• Time Delays– SQ sensor lag times

– Onset of SQ Insulin Action

• Accuracy of Sensor

• Biologic Variability– Insulin action

– Meal absorption

• Exercise

DiAs System

Remote Monitoring

Three Day Tracing DiAs Hotel

Sensor Readings from DiAs Hotel Study July, 2014

Glucose Range (mg/dl)

<70 80-150 70-180 >150 >180 >250

% o

f S

enso

r R

ead

ing

s

0.00

20.00

40.00

60.00

80.00

100.003 Meter readings <50 mg/dl22 Meter readings <70 mg/dl

Camp Activities

Median ± 90%tile Envelope

Blue = Sensor Augmented PumpRed = Closed-loop

Overnight Glucose Control(11PM to 7AM)

Control Group Closed-loop p

% time 80-150 mg/dl 50 ± 4% 74 ± 4% 0.0003

% time <70 mg/dl 4 ± 1% 1 ± 0.4% 0.007

% time >180 mg/dl 29 ± 5% 8 ± 2% 0.002

Mean Blood Glucose mg/dl 150 ± 6 128 ± 4 0.003

# of events <70 mg/dl 1.6 ± 0.4 0.7 ± 0.2 0.08

# of events <50 mg/dl 0.2 ± 0.1 0.1 ± 0.1 0.3

Glucose Control Pre and Post Camp Closed-Loop Studies

Pre-CampA1c

eAG(mg/dl)

Average Glucoseat Camp(mg/dl)

Estimated A1c from

Camp Mean

Glucose

SensorAugmented Pump (Control Group)

8.4% 194 156 7.1 %

Control to Range 8.0% 182 143 6.6 %

Damiano Camp Control

8.2% 189 162 7.3%

Damiano Camp Bionic Pancreas

8.2% 189 141 6.5 %

Glucose Control Pre and Post Camp Closed-Loop Studies

Pre-CampA1c

eAG(mg/dl)

Average Glucoseat Camp(mg/dl)

Estimated A1c from

Camp Mean

Glucose

SensorAugmented Pump (Control Group)

8.4% 194 156 7.1 %

Control to Range 8.0% 182 143 6.6 %


8.2% 189 162 7.3%


8.2% 189 141 6.5 %

Hybrid Closed-Loop 24/7 with UVA

• Started in November, 2014

• Funded by JDRF

• Multicenter – Virginia, Stanford, Santa Barbara, France, Italy, Israel

• 2 weeks of overnight closed-loop at home

• 2 weeks of hybrid closed-loop day and night at home– Remote monitoring with text messaging to staff

• Extension to 5 months of in-home use

Control-to-Range Subject 1 Overnight

Control-to-Range Subject 1 Daytime

Control-to-Range Subject 1 Evening and Overnight

DiAs in home for Two Weeks Overnight Closed Loopn =29 (Medians with 25-75% quartiles)

3.9

10

DiAs in home for Two Weeks 24 hour Closed Loop

n =29 (Medians with 25-75% quartiles)

3.9

10

Five Month Extension of DiAs in Home

• Will be presented at ADA, New Orleans, 2016

New Years Day – 201524/7 Closed-Loop Control

670G Hybrid Closed‐Loop Inpatient and Camp Studies

Ly, Diabetes Care 38:1205‐1211, 2015

• Inpatient Safety and Feasibility

– 8 subjects

– YSI

• Camp Safety, Feasibility and Efficacy Trial

– 20 subjects

– Randomized

• ½ on 530G

• ½ on 670G

Medtronic 670G

Enlite 3 sensor

Feasibility – 8 subjects in Research Center

• The system was quickly operational in all subjects

• The system functioned 99.4% of the time

• Study enrollment procedures and education on the system occurred within 2 hours for all subjects

Carbohydrate Intake Inpatient Studies

Weight TDI Carbohydrates in Grams, mean (min‐max)

Average Daily Total

Break Lunch Dinner HS

2 Females

60 kg 0.8 202 (195‐210)

45(30‐55)

41 (35‐50)

46 (38‐55)

28(15‐40)

6 Males

80 kg 1.0 338 (272‐481)

96 (60‐155)

80 (55‐121)

83 (48‐170)

53 (21‐90)

Making the 5 AM Rounds

0

50

100

150

200

250

300

350

7:00 9:00 11:00 13:00 15:00 17:00 19:00 21:00 23:00 1:00 3:00 5:00

Glucose‐mg/dL

Control group

MEAN

Time

Glucose control during camp session ‐ 670G vs. ControlLy, Diabetes Care 38:1205‐1211, 2015

530G Control

670G Closed‐loop

Percent time between 70‐180 mg/dl(3.9 ‐10 mmol/L) over 6 days (07:00 to 07:00)

Ly ,Diabetes Care 38: 1205‐2011, 2015

Percent time between 70‐180 mg/dl(3.9 ‐10 mmol/L) over 6 nights (23:00 to 07:00)

Ly ,Diabetes Care 38: 1205‐2011, 2015

Glucose Control in Closed‐Loop Studies, Pre and Post Camp

Pre‐CampA1c

eAG Average Glucose at Camp days

2‐5

Estimated A1c from Camp

Mean Glucose

670G All 8.5% 197 mg/dl 156 7.1 %

670G Adaptive Umax 8.4% 194 mg/dl 149 6.8 %

530G 8.6% 201 mg/dl 150 6.9 %


8.2% 189 mg/dl 141 6.5 %


8.2% 189 mg/dl 162 7.3%

Adult 670G StudiesMarch, 2015

• Multicenter study ‐ Stanford, Yale and Denver

• Supported by JDRF

• On Open‐loop for 5 days then Closed‐loop for 5 Days

• 9 subjects studied Mean age 28.5 ± 6.7 years (range 19-37) Mean A1c 7.0 ± 0.7% (range 6.1-7.9%) Mean duration of diabetes 18.9 ± 8.2 years

Medtronic 670G

Open Loop Compared to Closed‐Loop Open Loop Compared to Closed‐Loop

Open Loop Compared to Closed‐LoopFifteen Adolescents – 4 day study670G ‐ with Individualized CHO:I ratio

Stanford, Barbara Davis Center and Yale

Red = 670G

Blue = SAP

Median with 25‐75% quartiles

2.78

13.88

5.55

11.1

8.33

mmol/L

Summary for Groups

Age TDDU/Kg

CHO:I Ratios for Breakfast Subjects<50 mg/dl

Average CL

Glucose

Average OL

Glucose

Usual Starting CL

Final Increased for lows

Group 1 16.6 0.9 5.9 4.9 5.6 2 2 145.5 182.6

Group 2 16.4 1.0 8.7 7.0 7.9 2 1 153.3 156.5

Group 3 16.3 1.0 7.0 8.8 9.2 2 0 160.0 171.9

NEJM.org, published 17:46 Central European Time on Thursday, September 17, 2015

Three Months of Artificial Beta Cell in Home Use

Thabit, NEJM Sep 2015

• 33 Adults – day and night

• 25 Children and adolescents ‐ Night only

• No remote monitoring

• 2‐8 week run in

• Crossover study with 4‐6 week washout between arms

• Comparator is Sensor Augmented Pump

• 3 months on each study arm

FlorenceD2A closed‐loop system

Children and adolescents

Nexus 4 LG smartphone

Nav 2 CGM receiver and translator

Nav 2 CGM receiver

CGM transmitter

DANA‐R pump

DANA‐R pump

CGM transmitter

Dell Latitude tablet

Thabit, Tauschmann, Hovorka et. al. on behalf of APCam consortium and AP@home consortium, NEJM Sep 2015

Adults

Day and Night Closed Loop: adults Closed‐loop

(n=32)

Control

(n=33)

Paired difference*

(95% CI)P value

Time spent at glucose level (%), 24h

70 to 180 mg/dl 67.7±10.6 56.8±14.2 11.0 (8.1, 13.8) <0.001

>180 mg/dl 29.2±11.4 38.9±16.6 ‐9.6 (‐13.0, ‐6.3) <0.001

AUCday <63mg/dl 169 (35, 344) 198 (74, 479) 0.61(0.49, 0.76)** <0.001

< 50 mg/dl 0.3 (0.1, 0.7) 0.4 (0.1, 0.9) 0.45(0.31, 0.65)** <0.001

Mean glucose (mg/dl) 157±19 168±28 ‐11 (‐17, ‐6) <0.001

Total Insulin (U/day) 48.8±16.1 48.1±15.4 0.7 (‐1.8, 3.3) 0.57

HbA1c results (%) – Screening HbA1c 8.5 ± 0.7

HbA1c pre 7.6 ± 0.9 7.6 ± 0.8

HbA1c post 7.3 ± 0.8 7.6 ± 1.1 ‐0.3 (‐0.5 to ‐0.1) 0.002

Data are presented as mean±SD, or median interquartile range. * mean difference with 95 % CI **ratio of closed‐loop over control

Night time Only: children and adolescentsClosed‐loop

(n=25)

Control

(n=24)

Paired difference*

(95% CI)P value

Time spent at glucose level (%), midnight to 08:00 hours

70 to 145 mg/dl 59.7±11.5 34.4±11.0 24.7 (20.6, 28.7) <0.001

>145mg/dl 37.2±12.1 60.7±13.2 ‐22.9 (‐28.2, ‐17.6) <0.001

AUCday <63mg/dl 137 (57, 297) 295 (81, 553) 0.78 (0.38, 1.61)** 0.48

< 50 mg/dl 0.3(0.1, 0.5) 0.6(0.1, 1.1) 0.64 (0.26, 1.55)** 0.31


Overnight Insulin (U) 7.6 (5.0, 12.5) 7.7 (5.0,12.3) 1.05 (0.99, 1.11) 0.11

HbA1c results (%) Screening HbA1c 8.1 ± 0.9

HbA1c pre 7.8 ± 0.7 7.8 ± 0.6

HbA1c post 7.6 ± 1.1 7.9 ± 0.6 ‐0.3 (‐0.6 to 0.1) 0.17

Data are presented as mean±SD, or median interquartile range * mean difference with 95 % CI **ratio of closed‐loop over control

Closed‐loop (n=32)

Control(n=33)

Paired difference*(95% CI) P value

Time spent at glucose level (%), 24h for Adults

70 to 180 mg/dl(3.9‐10) 67.7±10.6 56.8±14.2 11.0 (8.1, 13.8) <0.001

>180 mg/dl (10) 29.2±11.4 38.9±16.6 ‐9.6 (‐13.0, ‐6.3) <0.001

< 50 mg/dl (2.8) 0.3 (0.1, 0.7) 0.4 (0.1, 0.9) 0.45(0.31, 0.65)** <0.001

Mean glucose (mg/dl)157±19(8.7±1.1)

168±28(9.3±1.6)

‐11 (‐17, ‐6)‐0.6 <0.001

Total Insulin (U/day) 48.8±16.1 48.1±15.4 0.7 (‐1.8, 3.3) 0.57

HbA1c results (%) – Screening HbA1c 8.5 ± 0.7

HbA1c pre 7.6 ± 0.9 7.6 ± 0.8

HbA1c post 7.3 ± 0.8 7.6 ± 1.1 ‐0.3 (‐0.5 to ‐0.1) 0.002Data are presented as mean±SD, or median interquartile range. * mean difference with 95 % CI **ratio of closed‐loop over control

Results: children and adolescentsThabit, NEJM Sep 2015

Closed‐loop

(n=25)

Control

(n=24)

Paired difference*

(95% CI)P value

Time spent at glucose level (%), midnight to 08:00 hours

70 to 145 mg/dl 59.7±11.5 34.4±11.0 24.7 (20.6, 28.7) <0.001

< 50 mg/dl 0.3(0.1, 0.5) 0.6(0.1, 1.1) 0.64 (0.26, 1.55)** 0.31


Overnight Insulin (U) 7.6 (5.0, 12.5) 7.7 (5.0,12.3) 1.05 (0.99, 1.11) 0.11

HbA1c results (%) Screening HbA1c 8.1 ± 0.9

HbA1c pre 7.8 ± 0.7 7.8 ± 0.6

HbA1c post 7.6 ± 1.1 7.9 ± 0.6 ‐0.3 (‐0.6 to 0.1) 0.17

Data are presented as mean±SD, or median interquartile range * mean difference with 95 % CI **ratio of closed‐loop over control

Glucose profilesThabit, NEJM Sep 2015

Adults Children and adolescents

Glucose profilesThabit, NEJM Sep 2015

Adults Children and adolescents

Day‐and‐Night Hybrid Closed‐Loop Insulin Delivery inAdolescents With Type 1 Diabetes: 12 Days, No Remote Monitoring

Tauschmann, Diabetes Care, 2016

70 mg/dl

180 mg/dl

• 12 adolescents, mean age 15.4 ± 2.6 years

• Mean HbA1c = 8.3 ± 0.9%

• Duration of diabetes 8.2 ± 3.4 years

• Two 7‐day periods – Sensor Augmented Pump or Closed‐Loop



70 mg/dl

180 mg/dl



157 mg/dl

182 mg/dl

Bionic Pancreas Bihormonal Features Translatable to an Insulin Only (BPIO) System

• Initialize with weight only – no prior insulin or glucose data

• Rapid adaptation to insulin requirements

• No Carbohydrate counting

• Meal Adaptation

Tandem Pumps and Dexcom Sensor –Bionic Pancreas

Outpatient Bionic PancreasRussell, NEJM 371: 313, 2014

• 20 Adults (ages 21-75) and 32 Adolescents (ages 12-20)

• 5 Days on Bionic Pancreas and 5 days on their own pump (study sensor data was blinded to them

• Hemocue Blood glucose meter to calibrate Dexcom G4 sensor

• Two Tandem pumps

• Controller on dedicated iPhone

Outpatient Bionic PancreasRussell, NEJM 371: 313, 2014

154138

157

138

(7.7)

(8.7)

First Day of Bionic Pancreas

AVG 133 (7.33 mmol/L)

Subject 08, Day 4

AVG 136 (7.55 mmol/L)

Subject 10, Day 9

AVG 156 (8.66 mmol/L)

Study Design• Open-label, non-randomized, pilot safety and feasibility• Week 1 = Usual Care • Week 2 = Fixed glucose set-point (115 -130 mg/dl)• Week 3 = Dynamic set-point between 115 to 130 mg/dl

• On Sunday, if no glucose values <65 mg/dl and average glucose was >180 mg/dl, the set point was lowered to 115 mg/dl (One subject)• In all three study periods subjects were remotelymonitored for a glucose <50 mg/dl.

Week 1Fr, Sat, Sun, M, Tu, W, Th, Fr



CGM Evaluation Period



Bionic Pancreas – Insulin Only

Mean 145 mg/dl eA1c = 6.7%<70 mg/dl = 5.5%

Mean 159 mg/dl eA1c = 7.2%<70 mg/dl = 1.8%

Mean 154 mg/dl

eA1c = 7.0%<70 mg/dl =

2.7%

HOTEL TRIAL OF A FULLY CLOSED-LOOP ARTIFICIAL PANCREAS

Using only CGM and accelerometer data for insulin dosingNo Meal Announcement

Faye Cameron, Trang T. Ly, Gregory P. Forlenza, Stephen D. Patek, Nihat Baysal, Laurel H. Messer, Paula Clinton, David M. Maahs, Bruce A. Buckingham, B. Wayne Bequette

On behalf of the MMPPC Study Group

5 February 2016 [email protected]

Full Closed-Loop Multiple Model Probabilistic Controller

• No premeal bolus, no meal announcement

• No exercise announcement– Wear accelerometer

• 10 Adult Subjects over age 21

• Studied at Stanford and Barbara Davis Center

Low Carbohydrate Diet (Strives for <30 grams/d)

Average Sensor Glucose 101 mg/dl ± 27 mg/dl5.6 ± 1.5 mmol/L

The Paleo Diet Summary Modal Day (All Subjects)146

Mean Sensor Glucose = 152 mg/dl; eA1c = 6.9%1.5% of time <70 mg/dl

BB1

Glucose Control with Full Closed LoopMMPPC Controller

mg/dl <50 50- 70 70-180 >250

mmol/L 2.78 2.78 – 3.89 3.89-10 >13.89

% time in given rangeMean ± SD

0.03 ± 0.1 1.8 ± 2.4 78 ± 9.9 3.8 ± 4

Mean Reference Blood Glucose = 141 mg/dl (7.8 mmol/L)Mean CGM glucose = 149 mg/dl (8.3 mmol/L)

Subjects ate an average of 292 ± 119 g CHO per study day.

Lauren M. Huyett1,5, Trang T. Ly2, Suzette Reuschel-DiVirgilio2,

S. Michelle Clay4, Wendy Bevier5, Ravi Gondhalekar1,5,

Eyal Dassau3,5, Gregory P. Forlenza4, Francis J. Doyle III3,5,

Jordan E. Pinsker5, David M. Maahs4, Bruce A. Buckingham2

Outpatient Closed-Loop Control with Unannounced Moderate Exercise in

Adolescents using Zone Model Predictive Control

ATTD 2015Milan, Italy

5 February 2016

1Department of Chemical Engineering, University of California Santa Barbara2Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Stanford University

3John A. Paulson School of Engineering & Applied Sciences, Harvard University4Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus

5Research Division, William Sansum Diabetes Center

Lauren M. Huyett ATTD Milan

Clinical Protocol Timeline

1495/2/16

72 hours continuous closed-loop control

Stanford Site:

Denver Site:

Challenging, free-choice meals at

restaurants

Announced Meals: Subjects estimated carbohydrates and entered meal informationFault Detection: Sensor and infusion set used until failure to test detection

Lauren M. Huyett ATTD Milan

Detailed Comparison Between Closed-Loop and SAP

5/2/16 150

BB1 The X axis needs to be in Time of Day.Bruce Buckingham, 1/19/2016

Sensor Augmented Pump Compared to Closed-loop Glucose Control

(Pilot study of infusion set and sensor failure alerts)

Mean CGM eA1c % <70 mg/dl

Sensor Augmented Pump (Control Group)

173 7.7%4.2

Closed-Loop ZMPC 151 6.9% 2.5

13 of 16 infusion set failure alarms were appropriateAccording to the physician on call

Night Control with Full-Closed LoopOutpatient Studies

Author Journal YearType of Closed-loop

n durationmean age

pre mean BG

mean BGpre % <70

post %<70

Russell Lancet DM 2016 Bihormnal-BP 19 5 days 9.8 169 122 4.7 1.8Russsell NEJM 2014 Bihormnal-BP 32 5 days 16 157 124 4 2.6Russell NEJM 2014 Bihormnal-BP 20 5 days 40 169 126 6.2 1.8Hovorka DC 2014 Insulin -MPC 16 3 weeks 16 151 137 0.9 1.4Thabit NEJM 2015 Insulin -MPC 33 3 months 40 162 143 4 2.4Thabit NEJM 2015 Insulin -MPC 25 3 months 12 176 146 3.5 2.2Ly DC 2015 Insulin -670G 21 6 days 19 149 146 4.2 1.7Ly DC 2014 Insulin- DiAs 20 5 days 15 146 147 6 1Nimri DC 2014 Insulin -FL 24 6 weeks 21 161 148 5.2 2.53Thabit Lancet DM 2014 Insulin -MPC 25 4 weeks 43 162 148 2.1 1.8Leelaranthna DC 2014 Insulin -MPC 17 8 days 34 167 149 3.2 3.1Kropff Lancet DM 2015 Insulin -Dias 32 2 months 47 167 162 3 1.7Nightime Summary 161 142 4 2.03

Night and day Nighttime only 8PM to 8AM

Day and Night OutpatientHybrid Closed-Loop Studies


n DurationMean Age

Enrollement A1c

Control eA1c%

Closed-loop

eA1c%

Russell Lancet DM

2016Bihormnal-BP

19 5 days 9.8 7.8 7.4 6.4

Russell NEJM 2014Bihormnal-BP

32 5 days 16 8.2 7.1 6.6


20 5 days 40 7.1 7.2 6.3

Ly DC 2015Insulin-670G

21 6 days 19 8.6 6.7 7.1

LeelaranthnaDC 2014Insulin-MPC

17 8 days 34 7.6 7.1 6.7

Thabit NEJM 2015Insulin-MPC

33 3 month 40 7.6 7.5 (7.6) 7.1 (7.3)

AVERAGE 7.8 7.2 6.7

Day and Night Glucose Control Bihormonal Compared to Insulin Only

Type of Closed-loop

Number of Studies

Control eA1c

Closed-Loop eA1c

Control % <70

Closed-loop %<70

Bihormonal 3 7.2 ± 0.2 6.4 ± 0.2 6.1 ± 1.2 3.4 ± 0.6

Insulin Only 3 7.1 ± 0.4 7.0 ± 0.2 3.8 ± 1.3 2.7 ± 0.9

p NS 0.04 NS NS

Current State of Type 1 Diabetes Updated T1D Exchange - 2015

K. Miller , Diabetes Care 38: 971

6.5

Bihormonal Closed-Loop

Insulin-only Closed-Loop

Percent <70 mg/dl for those in Day and Night Closed-loop studies Lasting > 5 days

Age in Years

5 10 15 20 25 30 35 40 45

% <

70

mg

/dl

0

2

4

6

8

10

Control % <70 Mean Age vs Bihormonal Insulin Only Closed-loop %<70

Night Control with Full-Closed LoopOutpatient Studies


n duration mean ageControl

mean BG

Closed-Loop

mean BG

Control% <70

Closed-loop%<70

Russell Lancet DM 2016 Bihormnal-BP 19 5 days 9.8 169 122 4.7 1.8

Russsell NEJM 2014 Bihormnal-BP 32 5 days 16 157 124 4 2.6

Russell NEJM 2014 Bihormnal-BP 20 5 days 40 169 126 6.2 1.8

Hovorka DC 2014 Insulin -MPC 16 3 weeks 16 151 137 0.9 1.4

Thabit NEJM 2015 Insulin -MPC 33 3 months 40 162 143 4 2.4

Thabit NEJM 2015 Insulin -MPC 25 3 months 12 176 146 3.5 2.2

Ly DC 2015 Insulin -670G 21 6 days 19 149 146 4.2 1.7

Ly DC 2014 Insulin- DiAs 20 5 days 15 146 147 6 1

Nimri DC 2014 Insulin -FL 24 6 weeks 21 161 148 5.2 2.53

Thabit Lancet DM 2014 Insulin -MPC 25 4 weeks 43 162 148 2.1 1.8

LeelaranthnaDC 2014 Insulin -MPC 17 8 days 34 167 149 3.2 3.1

Kropff Lancet DM 2015 Insulin -Dias 32 2 months 47 167 162 3 1.7

Nightime Summary 161 142 4 2.03

Night and day Nighttime only8PM to 8AM

Overnight Glucose Control Bihormonal compared to Insulin Only

Type of Closed-loop

Number of Studies

Control Mean BG

Closed-Loop Mean BG

Control % <70

Closed-loop %<70

Bihormonal 3 165 ± 7 124 ± 2 5.0 ± 1.1 2.1 ± 0.5

Insulin Only 9 160 ± 10 147 ± 7 3.6 ± 1.5 2.0 ± 0.6

p NS <0.001 NS NS


n DurationMean Age

Control Mean BG

Closed-loop

Mean BG

Control % <70

Closed-loop

%<70

Russell Lancet DM

2016 Bihormnal-BP 19 5 day 9.8 167 137 6.1 2.9

Russsell NEJM 2014 Bihormnal-BP 32 5 16 158 142 4.9 3.1Russell NEJM 2014 Bihormnal-BP 20 5 40 159 133 7.3 4.1Ly DC 2015 Insulin-670G 21 6 days 19 147 157 2.4 2.1

Leelaranthna DC 2014 Insulin-MP 17 8 days 34 158 146 5 3.7

Thabit NEJM 2015 Insulin-MP 33 3 month 40 168 157 4 2.4AVERAGE 160 145 5.0 3.1


n DurationMean Age

Enrollement A1c

Control eA1c%

Closed-loop

eA1c%

Russell Lancet DM

2016Bihormnal-BP

19 5 days 9.8 7.8 7.4 6.4

Russsell NEJM 2014Bihormnal-BP

32 5 days 16 8.2 7.1 6.6


20 5 days 40 7.1 7.2 6.3

Ly DC 2015Insulin-670G

21 6 days 19 8.6 6.7 7.1

LeelaranthnaDC 2014 Insulin-MP 17 8 days 34 7.6 7.1 6.7

Thabit NEJM 2015 Insulin-MP 33 3 month 40 7.6 7.5 (7.6) 7.1 (7.3)

AVERAGE 7.8 7.2 6.7

Mean Overnight Blood Glucose Levels

Age of subjects in Years

0 10 20 30 40 50

Blo

od

Glu

co

se m

g/d

l

100

120

140

160

180

200Controls Mean of Controls



0 10 20 30 40 50

Blo

od

Glu

co

se m

g/d

l

100

120

140

160

180

200Controls Mean of ControlsInsulin OnlyMean Insulin Only



0 10 20 30 40 50

Blo

od

Glu

co

se

mg

/dl

100

120

140

160

180

200Controls Mean of ControlsInsulin OnlyMean Insulin OnlyBihormal Mean of Bihormona


Age in Years

5 10 15 20 25 30 35 40 45

% <

70

mg

/dl

0

2

4

6

8

10

Control % <70 Control mean


Age in Years

5 10 15 20 25 30 35 40 45

% <

70

mg

/dl

0

2

4

6

8

10

Control % <70 Control meanClosed-loop %<70 Closed-loop mean

Nocturnal Hypoglycemia% of sensor values <70 mg/dl

Years of Age

0 10 20 30 40 50

% <

70

mg

/dl

0

1

2

3

4

5

6

7Controls

Controls Mean


Years of Age

0 10 20 30 40 50

% <

70

mg

/dl

0

1

2

3

4

5

6

7Controls

Controls Mean

Insulin Only

Insulin Only Mean


Years of Age

0 10 20 30 40 50

% <

70

mg

/dl

0

1

2

3

4

5

6

7Controls

Controls Mean

Bihormonal

Bihormonal Mean

Insulin Only

Insulin Only Mean

Pathway to Commercialization

Controlled, research center studies

Closely monitored Hotel/Camp Studies

In Home Studies – Safety/Efficacy

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?

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!”

The Future

• Hybrid Closed-Loop During the Day and Full Closed-loop Overnight– Premeal bolus

– Remove carbohydrate counting

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

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

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

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

The Future

• Full Closed-Loop

• No CHO counting, no premeal bolus

• Less than perfect, but may be good enough Thank You

Bruce Buckingham

[email protected]

disclosures progress in closing the loop · progress in closing the loop bruce buckingham, md...

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