Patient Empowerment Through Predictive Personalised Decision Support
Patient Empowerment Through Predictive Personalised Decision Support
Patient Empowerment through Predictive PERsonalised decision support (PEPPER) is an European
 Union (EU) funded research project to develop a personalised clinical decision support system
 for Type 1 Diabetes Mellitus (T1DM) self-management. The tool provides insulin bolus dose
 advice, tailored to the needs of individuals. The system uses Case-Based Reasoning (CBR), an
 artificial intelligence methodology that adapts to new situations according to past
 experience. The PEPPER system also incorporates a safety module that promotes safety by
 providing glucose alarms, low-glucose insulin suspension, carbohydrate recommendations and
 fault detection.The principal research objectives are to assess the usability, safety, and
 technical proof of concept and feasibility of the PEPPER in participants with T1DM.
 Evaluation of safety is a priority and will be assessed throughout the clinical studies. The
 safety components only of the PEPPER system will initially be evaluated in an out-of-clinic
 environment (phase 1) and will measure incidence and percentage time spent in hypoglycaemia,
 evaluate usability and incidence of technical faults. Following the initial safety study, the
 overall PEPPER system (integrated with the CBR algorithm) will be assessed (phase 2) and the
 primary outcome will be percentage time spent in hypoglycaemia.
1. Description of the components of the PEPPER system:

 Decision support algorithm The decision support algorithm is based on case-based reasoning
 (CBR). CBR is an artificial intelligence technique that tries to solve newly encountered
 problems by applying the solutions learned from solved problems encountered in the past. A
 combination of parameters makes up the case problem presented to the CBR algorithm. Using
 this information the algorithm will find a similar case scenario from the pool of previously
 encountered cases and recommend an improved solution (insulin dose) to achieve the best
 possible outcome (post-prandial blood glucose). Each new case includes information about the
 problem (e.g. capillary blood glucose, meal information etc), solution (recommended insulin
 dose) and outcome (post-prandial blood glucose).

 PEPPER offers a dual architecture for both Multiple Daily Injections (MDI) or Continuous
 Subcutaneous Insulin Infusion (CSII) therapy. In both cases, the user periodically wears a
 continuous glucose monitor (CGM) and an activity monitor.

 Handset CSII version: The handset is a portable touch-screen device, which communicates
 directly with the insulin pump. Its primary function in PEPPER is to allow the user to
 precisely manage insulin therapy by accepting or rejecting bolus insulin dose
 recommendations, calculated by the CBR based decision support algorithm, via a graphical
 interface. In addition, it measures and automatically records glucose levels (via a built-in
 Blood Glucose (BG) strip reader) and allows logging of food intake and other parameters.

 MDI version: This handset is a commercially available Smartphone with the insulin
 recommendation application running locally on a standard operating system such as iPhone
 Operating System (iOS) or Android. It has the same functionality as the CSII version, except
 that it does not have a built-in capillary blood glucose (CBG) reader but instead imports
 data wirelessly from external CBG monitors.

 Secure web server Revision: The handset wirelessly reports the user's case history to the
 secure portal, a web site which allows the clinician to add new patients, and review the
 cases to decide which ones should be kept. A case comprises multiple parameters such as
 carbohydrate intake, BG reading, meal composition, physical activity and hormone cycle.

 Personal Health Record on the secure portal allows patients and clinicians to view and update
 selected components of the detailed history.

 Insulin delivery system MDI: will continue using the same insulin they were on. CSII: will
 use the Cellnovo insulin pump.

 Continuous glucose monitoring system The glucose sensor that will be used throughout the
 clinical studies is the Dexcom sensor (CE marked, manufactured by Dexcom). This current is
 proportional to the glucose concentration in interstitial fluid and is calibrated against
 blood glucose a minimum of 12-hourly. The Dexcom CGM data is automatically transmitted to a
 secure web-based server and the secure PEPPER web-portal. Participants will be able to see
 their CGM data at all times and this will be used continuously throughout the studies.

 Safety features Low and high glucose alarms will be incorporated to alert the user when hypo-
 and hyperglycaemia is detected to enable the user to act accordingly to bring the glucose
 levels back to target range.

 Glucose prediction algorithm for hypoglycaemia prediction The hypoglycaemia prediction
 algorithm will enable the system to automatically activate the low glucose suspension feature
 in pump participants (suspension of insulin delivery until glucose levels are within the
 target range) and/or trigger an adaptive carbohydrate adviser, which will recommend a
 personalised carbohydrate snack.

 Insulin safety constraints Personalised maximum insulin dose thresholds will be incorporated
 to prevent overdosing on insulin.

 Fault detection Insulin pumps and CGMs are well-established technologies, but faults in these
 devices (e.g. pump occlusion, loss of sensor sensitivity) may occur. A fault detection system
 will identify such faults and alert the user to recommend a corresponding action to revert to
 the normal state.

 Participants will have the opportunity to call a physician for medical support and an
 engineer for technical support 24 hours a day.

 2.2 Recruitment This is a multicentre study and recruiting for the clinical study will be
 undertaken in the diabetes clinics at the Institut d'Investigació Biomédica de Girona
 (IdIBGi) (Spain) and the Imperial College London (ICL) (UK) from registered research
 databases and from interested participants who contact us.

 2.3 Clinical studies: 2.3.1 Phase 1

 Objective: To demonstrate safety and technical proof of concept of the PEPPER safety system
 (without the CBR algorithm) in the participant's own environment.

 Primary outcome and secondary outcomes are defined in Outcome Measures.

 Timescale: Each participant will be in the study for 8 weeks: run-in period (2 weeks period)
 and intervention period (6 weeks period). It is anticipated that it will take 6 months to
 complete this phase.

 Population: 10 adults with T1DM (5 on MDI and 5 on CSII)

 Visit 1: Screening Attend the clinical research unit Signed and dated informed consent
 Demographics data (date of birth, gender, race and ethnicity) Medical and surgical history
 and allergies to medication Details of the diabetes history Menstrual history and
 contraception (females) Medications and supplements Social history including drinking,
 smoking and drug habits Vital signs ECG Random venous blood and urine sample Urine pregnancy
 test in female participants of childbearing age Basic diabetes education revision, Insulin
 treatment adjusted if needed Questionnaires to be completed Participants will be provided
 with the real-time (RT) CGM (Dexcom) The participant will be instructed how to make correct
 CGM calibration. Quality control testing will be performed on the study devices as
 recommended in the manufacturer guidelines Participants will be shown how to insert the
 sensor themselves, interpret the CGM data in real time and to set the hypo- and
 hyperglycaemia threshold alarms. The alarm threshold will be set at 4mmol/l and 11mmol/l and
 participants will be encouraged to keep it at those levels and not to reduce the
 hypoglycaemia threshold below 3.3mmol/L) Participants to complete a 2-weeks run-in period
 using RT-CGM (Dexcom) and a standard bolus calculator to familiarize themselves with RT-CGM
 Participants on MDI will be provided with the study CBG meter Participants on CSII will be
 provided with the Cellnovo study

 Visit 2: CGM review and study start Attend 2 weeks after visit 1 CGM data review Insulin
 treatment adjusted if needed A standardised physical activity monitor will be provided and
 participants will be shown how to use it.

 Switch on the PEPPER handset (CBR algorithm disabled) Detailed user guides (Cellnovo, Dexcom
 CGM, PEPPER handset) will be given to the participants and an instruction sheet with 24-hour
 contact information of the research team to address any problems or questions.

 Visit 3: 2-week visit Attend 2 weeks after visit 2 at clinical research unit CGM data review
 Insulin treatment adjusted if needed Review any technical issues.

 Visit 4: Final visit (6 weeks after visit 2) CGM data review Switch off PEPPER system and
 return device Participants to revert to their usual treatment Questionnaires to be completed.

 2.3.2 Phase 2: Clinical evaluation of safety, feasibility and usability of the PEPPER system.

 Objective: To demonstrate safety and technical proof of concept of the overall PEPPER system
 (integrated with the CBR algorithm).

 Primary outcome and secondary outcomes are defined in Outcome Measures.

 Timescale and population are the same as in phase 1.

 Visit 1: Screening Same as for phase 1

 Visit 2: CGM review and study start Switch on the PEPPER handset (CBR algorithm and PEPPER
 safety system enabled) The rest of steps the same as in phase 1 visit 2

 Visit 3: 2-week visit Same as in phase 1 visit 3

 Visit 4: 6-week visit (6 weeks after visit 2) Same as in phase 1 visit 4

 Visit 5: Final visit Step 5 of usability study

 2.3.3 Usability study

 Usability of the system will be evaluated throughout the clinical trial phases and
 redevelopment of the system will be done accordingly.

 Objectives: to evaluate usability of the PEPPER handsets over a sustained time period.

 Step 1: Training observation Participants will be trained in use of devices. The handset will
 be filmed during the training to see which aspect is being described.

 Step 2: Contextual interview The aim is to gather data at an early stage of the usability
 engineering process. They will be used to understand the intended use of all parts of the
 system and the characteristics that relate to safety, within an everyday context. The
 interview will be semi-structured with choice of questions.

 Step 3: Diary study Data will be collected via the Smartphone in a variety of formats. The
 study follows on from the contextual interview and concludes with an exit interview.
 Participants will also be phoned at weekly intervals to see how they are finding the bolus
 advice and to check that there are no problems.

 Data collection. Participants will be asked to make diary entries each time they use the
 PEPPER bolus advisor. Data will be collected using a Smartphone app. It may take a variety of
 formats including photos, voice memos, text. In addition, written notes will be made after
 each weekly phone call.

 Step 4: Diary exit interview The purpose is to drill down into some of the diary entries to
 discover supplementary information. Participants will be asked to review each of the diary
 entries, giving further explanation.This will be followed by an unstructured interview.

 The diary will be filmed during the conversation to see which entry is being described.

 Step 5: Contextual group All of the members of the feasibility study will be invited to a
 social meeting in an informal location. The purpose of the session will be to validate the
 findings from the previous steps.The researcher will endeavour to be an unobtrusive bystander
 in the discussion, and not offer personal opinions but listen for common issues and themes.

 Data collection. Data will be gathered on a notepad or laptop in a visible way.

 Data will be gathered using an audio recorder in steps 1-4.

 2.4 Statistics The sample size is comparable to other technology pilot safety studies, is a
 realistic number for recruitment and provides robust safety data. The study is not powered to
 show a change in the primary or secondary outcomes compared with usual care but is an
 assessment of a new technology.

 2.5 Confidentiality of data collected during interviews To ensure security, data obtained
 during the course of the interviews will be encrypted and stored securely, with access
 limited solely to the researchers. Data will be de-identified such that only the researchers
 will be able to link the data to the participant involved using reversible codes. This is
 done purely for the purpose of comparison and evaluation across the separate interviews. Any
 resulting publications using the data will not identify the participants, and any quotes will
 kept anonymous should participants consent to this.

 2.6 Electronic data storage on secure web-server Data security and privacy will be a priority
 whilst dealing with medical data such as that held in the PEPPER system. During the clinical
 studies (phases 1-2) anonymous clinical data will be entered and stored on a secure
 web-server. Anonymous data collected by the PEPPER handset (such as glucose, meal
 information, physical activity, alcohol, exercise) and the Dexcom CGM system will be
 automatically transmitted to the secure web-server. For this purpose, EU regulatory
 procedures (Directives 95/46/EC and 2002/58/EC) will be observed. Medical data will be stored
 and protected against non-authorised access; transmission of data will be secured; only
 authorised users will have access to services and stored data. Authentication will be
 required for application use and data synchronisation. PEPPER will operate according to
 standard interoperability guidelines (e.g. HL7), so that information can be exchanged
 seamlessly between the various components. Authorised users will include study team members
 from the PEPPER collaborators. Collaborators will only be able to view anonymous PEPPER
 handset data.

 The data generated by the study will be analysed by the collaborative PEPPER research team at
 their respective sites. The analysis will be on anonymised data which will be aggregated
 during joint meetings on either clinical site.

 Missing, unused, and spurious data will be assessed on an individual basis and may be
 ignored, withdrawn or the visit may be removed from the analysis with appropriate
 justification adjudicated by the Principal Investigator.

 2.7 Adverse Events (AEs) Reporting Procedures All adverse events will be reported. Depending
 on the nature of the event the reporting procedures below will be followed. Any questions
 concerning adverse event reporting will be directed to the Chief Investigator in the first
 instance.

 Non serious AEs: All such events will be recorded.

 Serious Adverse Events (SAEs): An SAE form will be completed and faxed to the Chief
 Investigator within 24 hours. However, hospitalisations for elective treatment of a
 pre-existing condition do not need reporting as SAEs.

 Reports of related and unexpected SAEs will be submitted within 15 days of the Chief
 Investigator becoming aware of the event. The Chief Investigator will also notify the Sponsor
 of all SAEs, where in the opinion of the Chief Investigator, the event is:

 'related', i.e resulted from the administration of any of the research procedures; and
 'unexpected', i.e an event that is not listed in the protocol as an expected occurrence Local
 investigators will report any SAEs as required by their Local Research Ethics Committee,
 Sponsor and/or Research & Development Office.
Inclusion criteria:

 -  Adults ≥18 years of age

 -  Diagnosis of T1DM for > 1 year

 -  On MDI using a basal-bolus insulin regime or CSII (insulin pump) for at least 6 months

 -  Structured education done and good ability perform CHO counting

 -  HbA1c ≥ 48mmol/mol and ≤ 86mmol/mol

 -  Using ICR and ISF to calculate the mealtime bolus

 -  An understanding of and willingness to follow the protocol and sign the informed
 consent

 -  CBG measurements at least 2 times per day for calibration of the CGM

 Exclusion criteria:

 -  Severe episode of hypoglycaemia (requiring 3rd party assistance) in the6 months prior
 to enrolment

 -  Diabetic ketoacidosis in the last 6 months prior to enrolment

 -  Impaired awareness of hypoglycaemia (based on Gold score)

 -  Pregnancy, breastfeeding or intention of becoming pregnant over time of study
 procedures

 -  Enrolled in other clinical trials

 -  Have active malignancy or under investigation for malignancy

 -  Suspected or diagnosed endocrinopathy like adrenal insufficiency, unstable
 thyroidopathy, endocrine tumour

 -  Gastroparesis

 -  Autonomic neuropathy

 -  Macrovascular complications (acute coronary syndrome, transient ischaemic attack,
 cerebrovascular event within the last 12 months prior to enrolment in the study)

 -  Visual impairment including unstable proliferative retinopathy

 -  Reduced manual dexterity

 -  Inpatient psychiatric treatment

 -  Abnormal renal function test results (calculated GFR <40 mL/min/1.73m2)

 -  Liver cirrhosis

 -  Not tributary to optimization to insulin therapy

 -  Abuse of alcohol or recreational drugs

 -  Oral steroids

 -  Regular use of the acetaminophen, beta-blockers or any other medication that the
 investigator believes is a contraindication to the participant's participation.

 Participant withdrawal criteria:

 -  Loss of capacity to give informed consent

 -  The subject has a serious event related to study

 -  Cessation of MDI of insulin as usual care for T1DM

 -  Severe hypoglycaemia (defined as any episode of hypoglycaemia requiring the assistance
 of a third party actively to treat, or requiring the direct assistance of healthcare
 professionals)

 -  Diabetic ketoacidosis

 -  Positive pregnancy test

 -  Terminal illness

 -  Investigators initiated discontinuation of study due to participant or equipment
 concerns