carolinas chapter/american association of …...consultant: abbott, janssen, medtronic, novo...

CAROLINAS CHAPTER/AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS

2016 Annual MeetingHILTON HEAD ISLAND

FRIDAY HANDOUTSeptember 9-11, 2016 ~ Sonesta Resort ~ Hilton Head Island, SC

This continuing medical education activity is jointly provided by theCarolinas Chapter, AACE and Southern Regional Area Health Education Center

8.25 CME Credits!

1

Bruce W. Bode, MD, FACE

Atlanta Diabetes Associates

Associate Professor of Medicine, Emory University

Atlanta, Georgia

Artificial Pancreas Systems

DISCLOSURE STATEMENT

Research and Grant Support to Employer: Abbott, Animas, Biodel, DexCom, GSK, Janssen, JDRF, Lexicon, Lilly/BI, MannKind, Medtronic, NIH, Novo Nordisk, Pfizer, Sanofi, Sensonics

Consultant: Abbott, Janssen, Medtronic, Novo Nordisk, Sanofi, Thermalin, Valeritas

Speaker’s Bureau: Astra Zeneca, Janssen, Insulet, Mannkind, Medtronic, Merck, Novo Nordisk, Sanofi

STATUS OF TYPE 1 DIABETES CARE IN USA: THERAPY ADVANCES NEEDED

The Type 1 Exchange, n=25,000 subjects, 67 sites2

Not at Goal Excess Hypoglycemia

The average type-1 patient has:

• Two symptomatic hypoglycemic events per week1

• One or more episodes of severe, temporally disabling hypoglycemia per year

• Nocturnal hypoglycemia occurs ~ 8.5% of nights2

2

INSULIN PUMP USE - CURRENT

61% 62% 66%60% 56%

65% 62% 58%

0%

20%

40%

60%

80%

100%

Overall <6 6-12 13-17 18-25 26-49 50-64 ≥65

Age (years)

58%50%

58% 57% 56%61% 60%

56%61% 62% 66% 60%

56%

65%62% 58%

0%

20%

40%

60%

80%

100%

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

Enrolled 9/1/2010 - 8/1/2012

Current 4/1/2014 - 4/1/2015

INSULIN PUMP USE IS INCREASING

PUMP MANUFACTURER

Animas 23%

Medtronic 61%

Insulet 11%

Tandem 3%Roche 1%Other 1%

3

CONTINUOUS GLUCOSE MONITOR USE

12%17%

10%6% 8%

25%21%

14%

0%

10%

20%

30%

40%

50%

Overall <6 6-12 13-17 18-25 26-49 50-64 ≥65

Age (years)

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)

CGM USE BY INSULIN DELIVERY METHOD

23%

14%

9%12%

32%28%

18%

6%2% 1% 3%

11%10% 9%

0%

10%

20%

30%

40%

50%

<6 6-12 13-17 18-25 26-49 50-64 ≥65

Age (years)

Pump Injection

4

LOWER A1C IN INSULIN PUMP USERS

8.7%

9.2%

7.8%

8.2%

8.6%

7.5%

7.0%

7.5%

8.0%

8.5%

9.0%

9.5%

<13 13-25 ≥26

Mea

n H

bA1c

%

Age (years)

Injection Insulin Pump

LOWER A1C IN CGM USERS

8.4%

8.9%

7.7%7.8%

8.1%

7.3%

7.0%

7.5%

8.0%

8.5%

9.0%

<13 13-25 ≥26

Mea

n H

bA1c

%

Age (years)

Non CGM Users CGM Users

LOWER A1C IN CGM USERS REGARDLESS OF INSULIN DELIVERY METHOD

8.7

9.3

7.8

8.38.6

7.67.9 8.0

7.2

7.88.1

7.2

7.0%

7.5%

8.0%

8.5%

9.0%

9.5%

<13N=3050

13-<26N=6855

≥26 N=4077

Mea

n H

bA1c

%

Age (years)

Injection only Pump only

Injection + CGM Pump + CGM

5

LOWER A1C WITH INCREASED SMBG (EXCLUDES CURRENT CGM USERS)

6.5%

7.0%

7.5%

8.0%

8.5%

9.0%

9.5%

10.0%

0-3 4-6 6-9 ≥10

SMBG # Per Day

Pump Injection

Age <18

0-3 4-6 6-9 ≥10SMBG # Per Day

Age ≥18

CURRENT PUMPS ON THE USA MARKET

CONTINUOUS MONITORING SYSTEMS IN USA

Paradigm or Guardian REAL-Time DexCom G5 Platinum

CGMS® iPro™ Recorder

6

pump + sensor uploader mobile device any Internet-enabled device

MINIMED CONNECT

For care partners:online access to diabetes information

For healthcare providers: automatic CareLink uploads

For people with diabetes: discreet display of pump and CGM information

A better connection to diabetes care

Dexcom G5 Mobile

Dexcom Share/Follow

G5 App

CGM Use

0%

20%

40%

60%

80%

Age ≥25 Age 15-24 Age 8-14

Pe

rce

nta

ge

of

su

bje

cts

<4.0 days/week

4.0-<6.0 days/week

≥6.0 days/week

Change in glycated hemoglobin-0.8

-0.6

-0.4

-0.2

0.0

0.2

Ch

an

ge

in g

lyc

ate

d h

em

og

lob

in

JDRF CGM Study Group. N Engl J Med 2008; 359:1464-76.

7

8.3%

7.3%

7.5% 7.5% 7.5%

8.0% 8.0%8.1% 8.1%

7.0%

7.5%

8.0%

8.5%

0 3 6 9 12

Months

A1C

MDT STAR 3 SENSOR-AUGMENTED PUMP TRIAL

Values are means ± SE. Comparisons between SAP group and MDI group are significant for each time period (P<0.001).

The SAP group achieved a greater A1C reduction vs. MDI at 3 months and sustained it over 12 months

A1C Reduction for SAP and MDI Groups

= MDI= SAPn = 244 n = 241

- 0.6P<0.001

∆ -0.2

∆ -0.8

- 0.6P<0.001

A1C Reduction Correlates to Increased Sensor Use

Values are the difference between the means ± SE. p=0.003 for association between sensor wear and A1C reduction at 1 year. Only 7 participants had sensor use of 20% or less, with a change in A1C of -0.43 at 1 year vs. baseline.

• The majority of patients used sensors ≥61% of the time

• Patients who used sensors ≥81% of the time reduced their mean A1C by 1.2% at 1 year vs. baseline

-0.19

-0.64-0.79

-1.21-1.5

-1

-0.5

0

21-40% 41-60% 61-80% 81-100%Frequency of Sensor Use (% of Time)

Ch

ang

e in

A1C

at

1 Y

ear

vs B

asel

ine

n =27 n =46 n =108 n =56

DCCT (Adolescents & Adults)Severe Hypo Rate: 62.0 per 100 pt-yrs,

A1C: 9.0% → 7.2%

STAR 3 SAP (Pediatrics & Adults)Severe Hypo Rate: 13.3 per 100 pt-yrs,

A1C: 8.3% → 7.5%

JDRF CGM (Adults, 1 Subject excluded)Severe Hypo Rate: 20.0 per 100 pt-yrs,

A1C: 7.6% → 7.1%

Nathan et al. The New Engl J Med. 1993; 329(14); Tamborlane et al. The New Engl J Med. 2008;359:1464-1476.:Bergenstal et al. N Engl J Med. doi:10.1056/NEJMoa1002853: Battelino et al. Diabetologia DOI 10.1007/s00125‐012‐2708‐9

SENSOR-AUGMENTED PUMPS IMPROVE A1C WITHOUT INCREASING HYPOGLYCEMIA

8

FUNDAMENTALS OF CLOSED-LOOP SYSTEMS

HCL FCLTS PLGM

Subject Burden Automation

Regulatory Ease System Complexity

FIRST COMMERCIAL STEP IN THE ARTIFICIAL PANCREAS

Threshold Suspend

EXAMPLE OF THRESHOLD SUSPEND CYCLE

24

Suspend time maximum = 2 hrs

Insulin infusion stops

Basal insulin infusion will resume even if glucose is below Thresh Suspend limit

Basal Insulin Basal Insulin2 Hour Suspend

Insulin Suspends for 2 hours / Resumes for 4 hours

Automatically suspends insulin delivery if sensor glucose reaches the user-set limit

9

Threshold Suspend Manual Suspend(Not represented in above report)

Daily Detail Report

Threshold Suspend in CareLink® Professional

THRESHOLD SUSPEND: ASPIRE IN-HOME STUDY

nducted with Veo pump that is not FDA approved and not commercially available in the US. Study data and final report have not been submitted to FDA.al RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-232.

The severity and/or duration of nocturnal hypoglycemic events was lower in the Threshold Suspend Group.

1547 980 1406 1568

37.5% reduction (p<0.001)

THRESHOLD SUSPEND: ASPIRE IN-HOME STUDY

Hypoglycemic events were less frequent in the Threshold Suspend Group.


30% reduction (p<0.001)

32% reduction (p<0.001)

10

ASPIRE IN-HOME STUDY: RESULTS

∆A1C was similar in the two groups. The 95% CI of the difference in ∆A1C (-0.05, 0.15) did not include the non-inferiority limit of 0.4%.


2

*Measured as sensor glucose values

SmartGuard™ Technology

Protection from lows*

Takes action when patients need it most

√√

630G640G670G

Systems

530G System

MDT PATHWAY TO HYBRID CLOSE LOOP

PIVOTAL TRIALOF A HYBRIDCLOSED-LOOP SYSTEM (MDT 670G) IN TYPE 1 DIABETES

11

INVESTIGATORSName Affiliation and Location

Richard M. Bergenstal, MD International Diabetes CenterMinneapolis, MN

Bruce A. Buckinham, MD Stanford UniversityStanford, CA

Satish Garg, MD Barbara Davis Center for Childhood DiabetesAurora, CO

Stuart A. Weinzimer, MD Yale UniversityNew Haven, CT

Ronald Brazg, MD Rainier Clinical ResearchRenton, WA

Jacob Ilany, MD Sheba Medical CenterTel-Hashomer, Israel

Bruce Bode, MD, FACE Atlanta Diabetes AssociatesAtlanta, GA

Timothy Bailey, MD, FACE AMCR InstituteEscondido, CA

Stacey M. Anderson, MD University of VirginiaCharlottesville, VA

Robert Slover, MD Barbara Davis Center for Childhood DiabetesAurora, CO

John Shin, PhD, MBAScott W. Lee, MDFrancine R. Kaufman, MD

Medtronic plcNorthridge, CA

BACKGROUND

Pump systems that automatically suspend insulin delivery can reduce hypoglycemia, but no commercially-available systems can increase the insulin delivery rate to prevent or mitigate hyperglycemia.

Hybrid closed-loop (HCL) systems can automatically increase or decrease basal insulin, but boluses require user input and confirmation.

The 670G system was evaluated in a pivotal clinical trial of adults and adolescents with type 1 diabetes that included supervised hotel and 3-month unsupervised home use of the system 24 hours per day.

Investigational device, not approved for sale or use.Bergenstal R, et al. Poster presented at the 76th Scientific Sessions of the American Diabetes Association, June 10-14, 2016, New Orleans. LA. P-99.

SYSTEM COMPONENTS

The MDT 670G system included the new pump platform, closed-loop algorithm, and CGM display for the investigational 4th-generation subcutaneous glucose sensor and transmitter.

Sensors were calibrated with readings from the CONTOUR®NEXTLINK blood glucose meter (not shown).


12

METHODS

The study was conducted at 10 sites in the US and Israel

Patients had type 1 diabetes for ≥2 years

A1C <10%, were age 14-21 years old (adolescents) or 22-75 years old (adults)

Using pump therapy for ≥6 months, with or without CGM

The pump was used in open-loop mode during a 2-week run-in phase

Then the pump was used in closed-loop mode in a 3-month study phase that included a 6-day, 5-night hotel stay for supervised activity and frequent venous BG measurements (during one 24 hour period) with a reference instrument (i-STAT)


PARTICIPANTS


STUDY FLOW


13

COMPARING OPEN LOOP TO HYBRID CLOSED LOOP BETTER GLUCOSE CONTROL AS AUTOMATION ADVANCES

Patient with Diabetes – Open Loop Insulin Delivery System

Patient with Diabetes-Closed Loop Insulin Delivery System

Investigative device not approved for sale or use

HIGHLIGHTS OF THE 670G SYSTEM

Auto Mode- target set at 120 mg/dl; option to

raise to 150 mg/dl for exercise, etc

- Patients must put carbs in pump to deliver meal insulin

- If sensor glucose is above 300 mg/dl or not working, system is placed into manual mode

- Must troubleshoot the system to get back into Auto Mode

HCP- Can only adjust Insulin to Carb

ratio and Active Insulin Time- During trial, patients upload daily

for 2 weeks then weekly thereafter

RESULTSMODAL DAY SENSOR (SG) GLUCOSE TRACINGS


14

RESULTSA1C VALUES ANDPROPORTIONS OF NOCTURNAL VALUES ≤ 50 MG/DL


RESULTSDISTRIBUTION OF A1C VALUES

0%

20%

40%

60%

80%

100%

5 6 7 8 9 10

Cu

mu

lati

ve P

erce

nta

ge

A1C (%)

Run-In

End of Study


RESULTSKEY ENDPOINTS


15

RESULTS

NUMBER OF SUBJECTS, ∆ A1C AND ∆ SD AS FUNCTIONS OF STARTING A1C


RESULTS

SENSOR ACCURACY AND DISTRIBUTION OF i-STAT AND SG VALUES DURING HOTEL PHASE


DEVICE RELATED ADVERSE EVENTS


16

STRENGTHS

Multicenter design to evaluate safety

Large number of subjects, both adults and adolescents, using the system for 24 hours/day

Three months of unsupervised home use of system

Time in target confirmed by reference BG measurements during hotel stay


LIMITATIONS

Single-arm, nonrandomized design with no pre-specified efficacy endpoints

Data quantity imbalance between run-in (2 weeks) and study phase (3 months)

Exclusion of subjects with A1C >10%, recent episodes of severe hypoglycemia or recent DKA


SUMMARY

Three months of unsupervised at-home use of the HCL system (670G) was safe, with no severe hypoglycemia or DKA.

The 4th-generation sensors were accurate.

Compared to the run-in phase, HCL control was associated with less glycemic variability, more time in the target range, less exposure to hypo- and hyperglycemia, and reductions in A1C.


17

CONCLUSIONS

Hybrid closed-loop insulin delivery can help patients reduce hypo- and hyperglycemia and safely achieve ADA-recommended A1C goals.

This study suggests that the 67G HCL system should be considered for non-investigational use in adults and adolescents with type 1 diabetes in the home setting.

FDA has approved subjects to remain on the Hybrid Closed Loop system till approved

FDA approval is under review

If approved, hopeful launch in 1st to 2nd quarter 2017


MDT ALGORITHMS FOR CLOSED LOOPTHE PATH TO REDUCING PATIENT BURDEN

Pat

h t

o C

lose

d L

oo

p

Threshold/ Low GlucoseSuspendMiniMed® 530G System and MiniMed 630G System

Predictive Suspend*

Hybrid Closed Loop**

Towards PersonalizedClosed Loop***

Automatically doses insulin with minimal mealtime and exercise inputs from the patient

Suspends delivery when the system predicts a low is approaching

Suspends delivery when a low occurs

Improving interface & meal announcement: small, medium, large meal bolus settings and set meal insulin delivery buttons

Pattern recognition

Additional sensor inputs: Activity, food, heart rate, sleep, free fatty acids

Detecting sensor or infusion set failure

Advanced HybridClosed Loop***

Addition of meal detection algorithm, allows for more front-loading of meal insulin and earlier delivery of correction post meal

PID for insulin delivery & MPC for safety

Suspension protocol based on actual values

Suspension protocol w/ predictive algorithm

PID for delivery MPC for safety, FL for meals

PID, MPC & Fuzzy logic + cognitive computing

Partners / Collaborators:

Current USA

Standard

Next Advancemen

t

*Investigative device not approved for sale in the U.S.** Investigational device, not approved for sale or use ***Conceptual device

THE RACE TO THE CLOSED LOOPHOW THE COMPANIES LINE UP

5

Group ControllerType

Hormone Time InteractionRequired

Medtronic Next Generation with DreaMed

PID Fuzzy Logic Insulin 24 hour Meals, Exercise

Bigfoot Biomedical Proprietary Algorithm

Insulin 24 hour Meals, Exercise

University of Cambridge

MPC Insulin 24 hour Meals, Exercise

University of Virginia Type ZERO

MPC Insulin 24 hour Meals, Exercise

Boston University MPC Insulin + Glucagon 24 hour Meals, Exercise

Animas MPC:Treat-to-RangeHypo-Hyper Minimizer

Insulin 24 hour Meals, Exercise

18

CONCLUSIONS

Closed Loop Technology is evolving quickly

HCL technology is a game changer for both both patients and HCPs

Studies on cost effectiveness are under development and will start later this year

Progression from Hybrid Closed Loop to fully Closed Loop is undergoing investigation currently but approval will be in the future

carolinas chapter/american association of …...consultant: abbott, janssen, medtronic, novo...

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