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

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

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

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

The artificial pancreas sensor insulin pump control algorithm

Outpatient Randomised Clinical Trials

Adolescents overnight camp study 1 night RCT Closed loop vs SAP Adolescents (n=56) Three-centre Baseline A1C 8.0% 23:00 to 07:00 data Fewer episodes below 3.5mmol/l Reduced number of hypos Phillip et al NEJM 2013; 368:824-833

Adolescent and adult overnight home study 6 week RCT Closed loop vs SAP Adults (n=24) One-centre Baseline A1C 7.5% 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): 3025-3032

Cambridge closed-loop prototypes 2014 2007 2012 2010 2013 2016

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

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 7.6% 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 2015 26;373(22):2129-40

Children and adolescents overnight home study 12 week RCT Closed loop vs SAP 6 – 18 years (n=25) Three-centre Baseline A1C 8.1% 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 2015 26;373(22):2129-40

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 8.5% 24hour data Time in target ↑19% Mean glucose ↓1.8mmol/l Improved time in target Tauschmann et al Diabetes Care. 2016 Nov;39(11):2019-2025

Well controlled adults home study 3 week RCT Closed loop vs conventional pump therapy Adults (n=29) Two-centre Baseline A1C 6.9% 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. 2017 pii: S2213-8587(17)30001-3

Free living home use: No remote monitoring or supervision

Pregnant women overnight home study 4 week RCT Closed loop vs SAP Adult (n=16) Single-centre Baseline A1C 6.8% Overnight data Time in target ↑15% Mean glucose ↓0.8mmol/l Improved time in target no change in hypo burden Stewart et al NEJM 2016 26;375:644-54

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

Cambridge home use: summary of results Time in target 3.9 to 10mmol/l Increase by 11-19 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

Adolescents overnight camp study 6 day RCT Closed loop vs SAP Adolescents (n=20) One-centre Baseline A1C 8.1% 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): 377-384

Adolescents and adults 24/7 camp study 6 day RCT (670G) Closed loop vs SAP Adolescents and adults (n=21) One-centre Baseline A1C 8.6% 24 hour data No change (Improvements over time) Ly et al Diabetes Care 2015 Jul; 38(7): 1205-1211

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

Adult 24/7 hotel vs home study 5 nights RCT Closed loop (hotel) vs SAP (home) Adults (n=10) Two-centre Baseline A1C 7.0% 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. 2015 Mar;17(3):203-9

Adult evening/night home study 8 week RCT Closed loop vs SAP Adults (n=32) Three-centre Baseline A1C 8.2% 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

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): 1180-1185

Bi-hormonal closed-loop system at camp 5 days diabetes camp RCT (usual therapy) Young children 6-11 years (n=19) Baseline A1C 7.8% 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

Bi-hormonal adult home monitored study 11 day RCT Closed loop vs conventional Adults (n=39) Three-centre Baseline A1C 7.7% 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 ;389:369-380

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

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

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

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

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

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

CLOuD study: newly diagnosed youth

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

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

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

Participants and families

Funders and Support