FINAL PUBLISHABLE SUMMARY REPORT Grant Agreement number: 216592 Project acronym: DIAdvisor Project title: Personal Glucose Predictive Diabetes Advisor Funding Scheme: Theme: ICT – Information and Communication Technologies, Call: FP7-ICT-2007-1. Topic: ICT-2007.5.1 Personal Health Systems for Monitoring and Point-of-Care diagnostics Period covered 1st March 2008 – 30th June 2012 Name of the scientific Jens Ulrik Poulsen representative of the project Senior Project Manager coordinator: Novo Nordisk A/S Telephone: +45 3075 9692 E-mail: [email protected] Project Website Address www.diadvisor.eu 1. Executive summary ................................................................................................................. 3 2. Abbreviations ........................................................................................................................... 4 3. Summary Description of Project Context, Objectives and Outcome ....................................... 5 3.1 Diabetes mellitus – a global health problem ........................................................................ 5 3.2 DIAdvisor Concept ............................................................................................................... 7 3.3 Project structure ................................................................................................................... 8 3.4 Objectives and Outcomes .................................................................................................... 9 4. Scientific and Technical Foregrounds .................................................................................... 11 4.1 Work Package 1 – Physiological Modelling ....................................................................... 11 4.2 Work Package 2 – Data Based Modelling and Integration ................................................ 15 4.3 Work Package 3 – Predictive Control and Advisory System ............................................. 19 4.4 Work Package 4 – DIAdvisor Device Platform and Realisation ......................................... 24 4.5 Work Package 5 – Clinical Tests and Assessment ........................................................... 29 5. Potential Impact ..................................................................................................................... 36 5.1 Contribution to improve diabetes control and outcomes .................................................... 36 5.2 Contribution to stabilisation of the costs of the health care systems ................................. 36 5.3 Improving quality and efficiency of healthcare ................................................................... 37 5.4 Contributing to IDF-Europe strategy recommendations .................................................... 37 5.5 Added value of a European level project ........................................................................... 38 6. Project Public Website ........................................................................................................... 39 7. Consortium ............................................................................................................................ 39 2 of 39 1. Executive summary Diabetes mellitus is a chronic disease characterised by the inability of the organism to autonomously regulate the blood glucose level due to insulin deficiency (Type 1) combined with insulin resistance (Type 2), thus leading to serious health damages and very high personal and enormous social costs. It affects millions of patients in Europe and the rest of the world, a number expected to increase significantly in the coming years. From onset of Type 1 and during late progression of Type 2 diabetes, treatment is based on insulin. Tight control of blood glucose concentration is needed to prevent short and long term health complications. In spite of continuous improvements in insulin preparations, delivery devices and monitoring of blood glucose, insulin therapy remains one of the most difficult therapies to manage. This is because treatment outcome strongly depends on the patient’s skill in making daily decisions about insulin delivery. Availability of a device empowering the patients to make the most adequate decisions can potentially contribute to better treatment outcomes, reduced complications and health costs. Against this background, the DIAdvisor1 project has developed a personalised on-the-spot handheld blood glucose predicting and treatment advisory system, utilising minimally invasive sensors registering physical information, mathematical models for prediction of short-term blood glucose levels and calculating treatment advices. Testing of the DIAdvisor prototype in a short term feasibility trial has demonstrated that blood glucose predictions, more than 40 minutes ahead and advises of high quality, are achievable. Furthermore, a randomized control clinical trial including 57patients has demonstrated that time spent in debilitating hypoglycaemia can be reduced by about 40%, time spent in normal blood glucose range can be increased by about 8% and time spent in hyperglycaemia inducing long term complications can be reduced by about 9%. Extending the treatment improvements found in the latter DIAdvisor clinical trial to longer periods, the effect of providing BG prediction and advice can be translated to overall better blood glucose control leading to better treatment outcomes, potential reduced complications and eventual higher quality of life and lower health costs. 1 The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7) under grant agreement n° 216592. 3 of 39 2. Abbreviations BG Blood Glucose bpm beats per minute CGM Continuous Glucose Measurement CG-EGA Continuous Glucose-Error Grid Analysis CRC Clinical Research Centre DAFNE Dose Adjustment For Normal Eating DAQ Data Acquisition Trial DCCT Diabetes Control and Complications Trial DIAdvisor Personal Glucose Predictive Diabetes Advisor DIAdvisor1 First DIAdvisor™ in-vivo trial DIAdvisor2 Second DIAdvisor™ in-vivo trial DM Diabetes mellitus eAG estimated Average Glucose EU European Union FP7 7th Framework Program FTP File Transfer Protocol HbA1c Hemoglobin A1c HBGI High Blood Glucose Index HCP Health Care Provider, health centre, medical advisor, nurse, doctor IPR Intellectual Property Rights LBGI Low Blood Glucose Index MDD Medical Device Directive MOMM Modified Oral Minimal Model MPC Model Predictive Control OMM Oral Minimal Model SD Standard Deviation SMBG Self Monitoring of Blood Glucose Type 1 diabetes Insulin depended diabetes, juvenile diabetes Type 2 diabetes Adult-onset diabetes, obesity related diabetes UMPC Ultra Mobile PC WP Work Package YSI Yellow Spring Instrument glucose analyser 4 of 39 3. Summary Description of Project Context, Objectives and Outcome 3.1 Diabetes mellitus – a global health problem Diabetes mellitus (DM) is a chronic disease characterised by the inability of the organism to regulate autonomously the blood glucose level due to insulin deficiency or resistance, thus leading to serious health damages and very high personal and enormous social costs. It affects currently 366 million patients worldwide and is expected to affect around 552 millions by 20302. A study3 performed in eight European countries reported that in 1999, around €29 billion were spent in these countries for direct medical costs related to diabetes, i.e. a yearly estimated cost of €2.834 per patient. Of note, 55% of these expenses were due to hospitalisations related to diabetes. Moreover, the CODEIRE study4 performed in Ireland reported that a diabetic patient affected by microvascular or macrovascular complications was responsible for a cost 1.8 or 2.9 times that of a non-complicated patient, respectively. Average cost related to a patient affected by both types of complications reached 3.8 times that of a non-complicated patient. From the beginning of Type 1 diabetes or during disease progression of Type 2 diabetes, treatment happens to be based essentially on insulin delivery. Large intervention trials performed in EU5 and US6 showed how tight control avoiding hyperglycaemia, could prevent long term complications, but also reported the associated risk of induced hypoglycaemia that underscores the crucial need of exact and timely insulin dosage. Insulin therapy is vital for patients affected by Type 1 diabetes, essential for blood glucose control and prevention of complications in many Type 2 diabetic patients and extremely, valuable for non- diabetic patients in critical situations that impair physiological glucose homeostasis like intensive care. However, in spite of continuous improvements in insulin preparations (insulin analogues), insulin delivery devices (user-friendly insulin pens, wearable pumps) and monitoring of blood glucose (capillary blood glucose measurements, glucose sensors for continuous monitoring), insulin therapy remains one of the most difficult therapies to manage. While treatment targets become narrower to mimic normal glucose variations, fine-tuning of insulin delivery requires an increased availability of data on blood glucose and multiple factors that influence insulin effectiveness. Moreover, slight deviations of blood glucose out of aimed target range (normal7 blood glucose level) have a quick and dangerous impact on patient status (hypoglycaemia), and long term impact on health outcome8 (hyperglycaemia). Because sustained hyperglycaemia is associated with severe long-term outcomes (retinopathy,