1. University of Cambridge, UK
What is new in the artificial pancreas research and its clinical practice adoption?
Roman Hovorka
University of Cambridge, UK

2. Duality of interest declaration
Advisory Panel: Merck, Novo Nordisk, Artsana
Research Support: Minimed Medtronic, Abbott Diabetes Care
Speaker’s Bureau: Novo Nordisk, Eli Lilly
License fees: BBraun, Medtronic
Other: Patents and patent applications

3. Content (Not so) hot news Closed loop outpatient studies:
Randomised clinical trials
Outlook

4. US Launch spring 2017
Outside US launch spring 2018 (or later)

5. The artificial pancreas
sensor
insulin
pump
control
algorithm

6. Outpatient Randomised Clinical Trials

7. Adolescents overnight camp study
1 night RCT
Closed loop vs SAP
Adolescents (n=56)
Three-centre
Baseline A1C %
23:00 to 07:00 data
Fewer episodes below 3.5mmol/l
Reduced number
of hypos
Phillip et al NEJM 2013; 368:

8. Adolescent and adult overnight home study
6 week RCT
Closed loop vs SAP
Adults (n=24)
One-centre
Baseline A1C %
Overnight data
Time in target ↑13%
Hypo 3.9mmol/l ↓1.9%
Improved
time in target
and time in hypo
MD-logic algorithm
working with Medtronic on 690G pump (adding correction bolus to 670G)
Nimri et al Diabetes Care 2014 Nov; 37(11):

9. Cambridge closed-loop prototypes
2014
2007
2012
2010
2013
2016

10. Cambridge free-living studies since 2012
7 centres, adults pregnancy, adolescents, children
4 RCTs night only over 3 to 12 weeks
6 RCT 24/7 over 1 to 12 weeks
total closed loop operation
125,949 hours
4,248 days
14.4 years

11. Thabit, Tauschmann et al NEJM 2015 26;373(22):2129-40
Adult 24/7 home study
12 week RCT
Closed loop vs SAP
Adults (n=33)
Three-centre
Baseline A1C %
24 hour data
Time in target ↑11%
Mean glucose ↓0.6mmol/l
Hypo AUC ↓2/5
HbA1c ↓0.3%
Improved
time in target and
time below target
Thabit, Tauschmann et al NEJM ;373(22):

12. Children and adolescents overnight home study
12 week RCT
Closed loop vs SAP
6 – 18 years (n=25)
Three-centre
Baseline A1C %
Midnight to 08:00 data
Time in target ↑25%
Mean glucose ↓1.6mmol/l
Improved
time in target
no change in hypo burden
Thabit, Tauschmann et al NEJM ;373(22):

13. Tauschmann et al Diabetes Care. 2016 Nov;39(11):2019-2025
Teens 24/7 home study
3 week RCT
Closed loop vs SAP
Teens (n=12)
Single-centre
Baseline A1C %
24hour data
Time in target ↑19%
Mean glucose ↓1.8mmol/l
Improved
time in target
Tauschmann et al Diabetes Care Nov;39(11):

14. Well controlled adults home study
3 week RCT
Closed loop vs conventional pump therapy
Adults (n=29)
Two-centre
Baseline A1C %
24hour data
Time in target ↑11%
Mean glucose ↓0.4mmol/l
Hypo AUC ↓2/3
Improved
time in target and
time below target
Conventional pump therapy
Bally et al Lancet Diabetes Endocrinol pii: S (17)

15. Free living home use: No remote monitoring or supervision

16. Pregnant women overnight home study
4 week RCT
Closed loop vs SAP
Adult (n=16)
Single-centre
Baseline A1C %
Overnight data
Time in target ↑15%
Mean glucose ↓0.8mmol/l
Improved
time in target
no change in hypo burden
Stewart et al NEJM ;375:644-54

17. Overnight closed-loop at home in pregnant women
Courtesy of Dr Helen Murphy and Dr Zoe Stewart

18. Cambridge home use: summary of results
Time in target 3.9 to 10mmol/l
Increase by percentage points
Time in hypoglycaemia < 3.9 mmol/l
No change to halved
Largest reduction when comparator conventional pump therapy
Greatest benefits overnight
Closed-loop well tolerated by users and guardians

19. Adolescents overnight camp study
6 day RCT
Closed loop vs SAP
Adolescents (n=20)
One-centre
Baseline A1C %
23:00 to 07:00 data
Time in target ↑20%
Hypo 3.9mmol/l ↓14%
Increased time in target and reduced time in hypoglycaemia
Ly et al Diabetes Technol & Therap. 2016, 18(6):

20. Adolescents and adults 24/7 camp study
6 day RCT (670G)
Closed loop vs SAP
Adolescents and adults (n=21)
One-centre
Baseline A1C %
24 hour data
No change
(Improvements over time)
Ly et al Diabetes Care 2015 Jul; 38(7):

21. 670G Hybrid closed-loop PID controller N=124 3 months 14-75 years
HbA1c 7.4%(0.9)
Bergenstal et al JAMA 2016

22. Adult 24/7 hotel vs home study
5 nights RCT
Closed loop (hotel) vs SAP (home)
Adults (n=10)
Two-centre
Baseline A1C %
23:00 to 07:00 data
Time in target ↑22%
Mean glucose ↓1.7mmol/l
Improved
time in target and
no change in hypo burden
Brown et al Diabetes Technol Ther Mar;17(3):203-9

23. Adult evening/night home study
8 week RCT
Closed loop vs SAP
Adults (n=32)
Three-centre
Baseline A1C %
Data 20:00 to 08:00
Time in target ↑7%
Mean glucose ↓0.3 mmol/l
Hypo 3.9mmol/l↓1.6%
HbA1c ↓0.2%
Improved
time in target and
time below target
Kropff et al Lancet Diabetes Endocrinol 2015;3:939–947

24. 5-9 year old 24/7 camp study Increased mean glucose
3 days RCT
Closed loop vs SAP
Preadolescents (n=30)
One-centre
Baseline A1C 7.3%
Overnight data
Mean glucose ↑1.3mmol/l
Hypo 3.9mmol/l ↓2.2%
Increased mean glucose
reduced time below target
Del Favero et al Diabetes Care 2016 Jul; 39(7):

25. Bi-hormonal closed-loop system at camp
5 days diabetes camp RCT
(usual therapy)
Young children 6-11 years (n=19)
Baseline A1C %
24 hour data
Time in target ↑23%
Mean glucose ↓1.7 mmol/l
Hypo 3.3mmol/l↓1.6%
Overnight data
Time in target ↑32%
Mean glucose ↓2.6 mmol/l
Hypo 3.3mmol/l↓2.2%
Russell et al, Lancet Diabetes Endocrinol. 2016;4(3):233-43

26. Bi-hormonal adult home monitored study
11 day RCT
Closed loop vs conventional
Adults (n=39)
Three-centre
Baseline A1C %
24 hour data
Time in target ↑17%
Mean glucose ↓1.1mmol/l
Time below tgt ↓1.3%
Improved
time in target and
time below target
El-Khatib et al Lancet 2017 ;389:

27. Single vs dual hormone overnight closed loop at camp
Adolescents and adults
N=28
2 nights per treatment
Haidar et al, JCEM 2016

28. Dual hormone closed-loop
Benefits
Increased hypoglycaemia protection
More aggressive insulin delivery
Challenges
Room-temperature stable glucagon
Dual-chamber pumps (and two catheters)
Insulin “trumps” glucagon
Meal bolus required
Chronic sc delivery – biological risks
Cost
Russell et al, Diabetes Care, 2012
Castle et al, Diabetes Care, 33, 2010
El Khatib et al, Sci Transl Med, 2, 2010

29. Summary: RCT outpatient studies
Study outcomes
Reduced mean glucose and reduced hypoglycaemia
Reduced mean glucose
Reduced hypoglycaemia
No change
Increased mean glucose and reduced hypoglycaemia
Other groups in the field have also performed out-of hospital and home studies.
Compared to ours, these were done under close supervision and/or remote monitoring, where researchers could intervene when technical or glycaemic issues arises during the study.
Thus, comparing studies to each other is difficult, due to differences in patient supervision/monitoring, design and sensors which have different errors in measurements, all which could affect outcomes.
Algorithm matters
and/or
Baseline characteristics/population/settings matter 29 29

30. Variability in insulin requirements (adults)
Ruan Y et al, Diabetes Care. 2016;39:830-2

31. Commercialisation of artificial pancreas
single
single
dual
single
single
dual
single
single
Kropff et al, Diabetes Technol Ther. 2016;18 Suppl 2:S253-63

32. Large outcome studies Large outcomes studies planned/underway
80 – 1,500 subjects
Lasting 3 months to 2 years
Children, adolescents, adults, newly diagnosed
US, Australia, Europe
Prototype systems & prototype systems

33. CLOuD study: newly diagnosed youth

34. Clinical practice adoption
Adoption challenges
Approved system
Target populations
Training
Reimbursement
Performance barriers
Speed of insulin absorption/reliability of insulin delivery
Sensor reliability

35. Cambridge AP Group, February 2017
Acknowledgement
Helen Murphy
David Dunger
Mark Evans
Cambridge AP Group, February 2017
Carlo Acerini

36. UK and further afield King’s College University of Sheffield
University College London
Leeds Teaching Hospital
Norfolk and Norwich University Hospital
University of Manchester
University of Southampton
University of Edinburgh
University of Swansea
University of Oxford
Southampton NHS Trust
Nottingham NHS Trust
Alder Hey Liverpool
Edinburgh NHS Trust
Jaeb Centre
University of Graz
Profil Institute
Pediatric Hospital of Luxembourg
Stanford University
Yale University
University of Denver
Park Nicollet, Minnesota
UCLA
University of Innsbruck
University of Vienna
University of Leipzig
Heva Heor
University of Bern
Stefanie Amiel, Pratik Choudhary
Simon Heller
Peter Hindmarsh
Fiona Campbell
Nandu Thalange
Lalantha Leelarathna
Kath Barnard
Julia Lawton
Steve Luzio
Julie Edge. Rachel Besser
Nicola Trevelyan
Tabitha Randell
Atrayee Ghatak
Daniela Elleri
Judy Sibayan, John Lum, Craig Kollman
Thomas Pieber, Elke Froehlich-Reiterer, Julia Mader
Lutz Heinemann, Carsten Benesch, Sabine Arnolds
Carine de Beaufort
Bruce Buckingham
Stuart Weinzimer
Viral Shah
Richard Bergenstal, Amy Criego
Steven Fox
Sabine Hofer
Birgit Rami-Berhar
Thomas Kapellen
Stephane Roze
Christoph Settler, Lia Bally

37. Participants and families

38. Funders and Support