Adaptive, Real-time, Intelligent System to Enhance Self-care of Chronic Disease
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Sponsor: Imperial College London

ARISES Clinical Trial Protocol 
 
IRAS ID: 240662 
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Clinical Trial Protocol NCT03643692  
 
Adaptive, Real-time, Intelligent System to Enhance Self-care of 
chronic disease (ARISES) 
 
Chief investigator:  
Professor Nick Oliver  
Co-Investigators:  
Dr Chukwuma Uduku, Dr Monika Reddy, Dr 
Pantelis Georgiou, Dr Pau Herrero, Prof 
Robert Spence, Dr Kezhi Li, Mr John Daniels 
General information 
 
 
 
 
 
 
Title:  
Adaptive, Real-time, Intelligent System to Enhance Self-care of 
chronic diseases (ARISES) 
 
Identifying Number:  
Imperial College Joint Research Office – 18HH4410 
 
Date:  
 
 
Version 1.0 
18/12/2017 
 
Sponsor: 
 
 
Imperial College London 
Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare NHS 
Trust 
Room 215, Level 2 Medical School Building 
Norfolk Place 
London, W2 1PG 
 
 
Sponsor Contact: 
 
Becky Ward 
Research Governance Manager 
Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare  
NHS Trust 
Room 215, Level 2 Medical School Building 
Norfolk Place, London, W2 1PG 
Email: becky.ward@imperial.ac.uk 
  
 
 
 
Telephone: 0207 594 9459 
 
Chief Investigator 
(clinical): 
 
 
Nick Oliver 
 
 
 
 
St. Mary’s Hospital Medical School Building, 
 
 
 
 
Imperial College, London, W2 1PG, UK 
 
 
 
 
Nick.oliver@imperial.ac.uk 
 
 
 
 
0207 594 2460 
 
 
 
 
 
Protocol Authorised by: 
Name & Role  
 
Date 
 
 
Signature 
 

ARISES Clinical Trial Protocol 
 
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Clinical Queries: Clinical queries should be directed to Dr Chukwuma Uduku who will direct 
the query to the appropriate person 
 
 
Funder: The project is being funded by an Engineering and Physical Sciences Research 
Council (EPSRC) grant 
 
This protocol describes the ARISES study and provides information about procedures for 
entering participants. Every care was taken in its drafting, but corrections or amendments 
may be necessary.  These will be circulated to investigators in the study. Problems 
relating to this study should be referred, in the first instance, to the Chief Investigator. 
This study will adhere to the principles outlined in the NHS Research Governance 
Framework for Health and Social Care (2
nd edition). It will be conducted in compliance with 
the protocol, the Data Protection Act and other regulatory requirements as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Contents 
 
1.0 Introduction 
  1.1 Background ...................................................................................................... 4 
  1.2 Components: ................................................................................................................. 6 
  1.3 Safety measures: .......................................................................................................... 7 
 
2.0 Study objectives and design ............................................................................. 8 
  2.1 Focus Groups ................................................................................................... 8 
Objectives ............................................................................................................................ 8 
Timescale ............................................................................................................................ 8 
Recruitment ......................................................................................................................... 8 
Format ................................................................................................................................. 8 
  2.2 Clinical studies ................................................................................................. 9   
  2.2.1 Physiological and environmental data collection ...................................... 9 
Objectives .......................................................................................................................... 10 
Methods ............................................................................................................................. 10 
Recruitment ....................................................................................................................... 10 
Inclusion criteria ................................................................................................................ 10 
Exclusion criteria ............................................................................................................... 10 
Withdrawal criteria ............................................................................................................. 11 
Screening visit ................................................................................................................... 11 
Assessment and follow-up ................................................................................................ 12 
Statistics and data analysis ............................................................................................... 13 
3.0 Safety ................................................................................................................ 14 
Adverse event definitions .................................................................................................. 14 
Adverse event reporting procedures ................................................................................. 14 
4.0 Regulatory Issues ............................................................................................ 15 
Ethics Approval ................................................................................................................. 15 
Consent ............................................................................................................................. 15 
Confidentiality .................................................................................................................... 15 
Indemnity ........................................................................................................................... 15 
Sponsor ............................................................................................................................. 16 
Funding ............................................................................................................................. 16 
Audits ................................................................................................................................ 16 
 
5.0 Study Management ....................................................................................................... 16 
 
6.0 Publication Policy ......................................................................................................... 16 
 
 

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1.1 Background 
 
Diabetes affects more than 3 million UK inhabitants with a global prevalence that has almost 
doubled since 19801. Type 1 diabetes (T1DM) accounts for 10% of the UK diabetes 
population and is characterised by insulin deficiency and impaired glucose homeostasis 
secondary to autoimmune destruction of pancreatic beta cells2 (Diabetes UK: Annual report 
2016 
https://diabetes-resources-production.s3-eu-west-1.amazonaws.com/diabetes-
storage/2017-08/Annual_Report_2016.pdf).  
Therapeutic insulin replacement aims to replicate physiological insulin secretion in response 
to glycaemia. The most accessible mode of insulin delivery is by multiple daily subcutaneous 
injections (MDI). Alternatively, continuous subcutaneous insulin infusion (CSII) via an insulin 
pump delivers variable basal insulin rates throughout the day with the benefit of fewer 
injections.  
There is evidence to advocate intensive insulin therapy to limit blood glucose excursions and 
reduce the risk of microvascular complications3. However, intensive insulin therapy is 
associated with an increased risk of recurrent hypoglycaemia and in severe cases its 
dangerous sequalae of seizures, coma and death456. Subcutaneous continuous glucose 
monitoring (CGM) has been shown to help improve overall glycaemic control and reduce the 
incidence of hypoglycaemia7.  
Insulin bolus calculators have been developed to help overcome hypoglycaemia and post 
prandial excursions associated with insulin carbohydrate mismatch8,9. Most insulin pump 
devices and a growing number of capillary glucose meters have insulin bolus calculators 
integrated into the hardware. Standard bolus calculations are derived from a formula 
requiring current blood glucose levels, target blood glucose, total carbohydrate in meals 
(grams), insulin-to-carbohydrate ratio (ICR, grams of CHO per 1 unit of insulin), insulin 
sensitivity factor (ISF, glucose reduction per 1 unit of insulin) and insulin on board (IOB, 
active insulin from previous bolus administrations). Structured education remains an 
important part of empowering self-management in T1DM by encouraging appropriate self-
glucose monitoring, carbohydrate (CHO) counting and insulin dose-adjustment10.  
Over 15 million people in the UK have a long-term chronic illness and are at risk of the 
physical and psychosocial ramifications that arise with sub-optimal management 
(Department of Health (2012). Report. Long-term conditions compendium of Information: 3rd 
edition 
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/216528/dh_13
4486.pdf). In the case of diabetes, associated complications such as ischaemic heart 
disease, stroke, blindness and disability following limb amputation all carry a significant 
socioeconomic burden. Effective diabetes self-management has been shown to reduce the 
risk of complications.  
The Adaptive, Real-time, Intelligent System to Enhance Self-care of chronic diseases 
(ARISES) is a novel mobile platform capable of collecting data from multiple sources to 
empower people to more effectively self-manage chronic disease through therapeutic and 
lifestyle decision support (Figure 1). Using wearable sensors and smartphone technology, a 
wide range of biological, environmental and behavioural data will feedback into the system to 
facilitate local real-time decision support and adaptive personalised care using machine 
learning and Case-Based Reasoning (CBR) (Figure 2). CBR is an artificial intelligence 
methodology capable of solving problems by referring to historic data and outcomes from 
previously encountered scenarios (cases). A case consists of the problem description (e.g. 

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exercise), the solution (recommended snack) and the outcome (blood glucose post 
exercise). Automated (e.g. ambient temperature) and manual (e.g. meal macronutrient 
content) parameter inputs will be fed into the CBR algorithm as case problems. The 
algorithm proceeds to filter through previously encountered scenarios to retrieve a similar 
case and adapt the case information to recommend an improved solution. Proposed 
solutions are evaluated, and potentially useful outcomes are stored in the case base. The 
ARISES CBR algorithm will run locally on a smartphone device. The system will be designed 
to offer decision support applicable and specific to patients receiving MDI and CSII methods 
of insulin delivery. 
 
Figure 1: Illustration of the ARISES concept 
 
 
Figure 2: The CBR cycle 
 

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ARISES aims to use participants with T1DM as an exemplar case study. The system will 
target self-management to optimise glucose control through insulin dose recommendation 
(therapeutic advice), exercise and physical stress support, hypoglycaemia prevention 
through timely carbohydrate and snack recommendation and behavioural change through 
educational (lifestyle advice). Measures to safeguard patients will be ensured through 
education, predictive glucose alarm and carbohydrate recommendation. Patients with T1DM 
will be recruited as part of the design team to offer feedback on user requirements and 
ergonomic interface development throughout the project. 
 
This protocol details the semi-structured focus groups aimed at designing a user friendly 
ARISES mobile platform. Focus groups will be comprised of investigators and patients with 
T1DM. The protocol also outlines a six-week observational clinical study (phase 1) aiming to 
monitor and assess key inputs affecting glycaemia in patients with T1DM. Physiological and 
environmental data parameters will be assessed using wearable technologies and manual 
data will be logged by the participant into a mobile app. Data drawn from the study will serve 
as a training set to assist the development of CBR artificial intelligence to be integrated into 
the completed ARISES platform. ARISES is a feasibility study beyond the work outlined in 
this protocol. The project requires the outputs derived from the observational study and 
focus groups for final study design (phase 2). 
 
 
1.2 Components of data collection study (phase 1)  
Continuous glucose monitoring 
The Dexcom glucose sensor (CE marked and a licensed medical device in the UK, 
manufactured by Dexcom) will be used throughout the clinical trials. The sensor is deployed 
subcutaneously and samples interstitial fluid using an enzyme electrode. A small voltage is 
applied across the sensor and a current is fed back to the sensor instrumentation. This 
current is proportional to the glucose concentration in interstitial fluid and is calibrated 
against blood glucose a minimum of 12-hourly. Dexcom CGM data will be transmitted and 
stored wirelessly to a mobile smart phone device and uploaded to a secure cloud-based 
server using the Diasend app. Participants will be non-blinded to CGM data throughout the 
clinical studies.  
 
Insulin delivery system 
MDI – Participants on MDI will continue using the same insulin therapy they were on and 
inject into subcutaneous tissue. 
CSII – Participants using CSII will continue using the pump device and basal insulin rate 
profiles they were on. The pump will deliver insulin from a cartridge reservoir through 
cannula tubing and into subcutaneous tissue.  
 
 
 

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Sensor devices 
Empatica E4 – Real time physiological data will be recorded continuously using the 
Empatica E4 wireless multi-sensor wristband. The Empatica E4 wristband houses a 
photoplethysmography (PPG) sensor capable of monitoring heart rate and heart rate 
variability; an electrodermal activity (EDA) sensor used to measure sympathetic activity in 
response to activity and stressful stimuli; an infrared thermophile for measuring peripheral 
skin temperature; and a 3-axis accelerometer to detect motion-based activity. All the above 
data parameters will be uploaded to a secure proprietary cloud-based platform via a wired 
connection to a personal computer. 
 
Smartphone – Apple iPhone devices will monitor and locally store location and ambient 
temperature data using built in GPS and WIFI technology. Using the myTracks app, these 
parameters will be retrieved retrospectively to assess their impact on glycaemia. Manual 
data inputs such as insulin dose, meal macronutrient composition in grams and exercise will 
be logged by the participant using the mySugr mobile application. 
 
1.3 Safety measures 
Hypo and Hyperglycaemia alarms 
The Dexcom mobile CGM system will send an audio alarm to the user’s smartphone or 
receiver to alert them of impending hypo and hyperglycaemia. This will enable participants to 
bring glucose levels back to target range in a timely fashion and limit periods spent in 
extreme glycaemia. 
 
 
Fault detection system 
The Dexcom mobile CGM system will identify and send an audio alarm to the user’s 
smartphone or receiver to alert them of hardware faults.  
 
 
Hypoglycaemia management education 
Participants will receive formal education and assessment on hypoglycaemia management 
during screening visit. 
 
 
 
 
 
 
 
 
 

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2.0. Study Objectives and Design 
 
The key research objectives are to assesses the usability, safety and proof of concept of 
ARISES in chronic disease using participants with T1DM as an exemplar case study.  
 
This protocol describes the semi-structured focus groups aimed at designing a user friendly 
ARISES mobile platform and a six-week observational study (phase 1) to monitor and 
evaluate key inputs affecting glycaemia using wearable technologies. Safety will be 
assessed throughout the clinical studies. Dexcom RT-CGM will be used throughout all 
clinical trial phases.  
 
 
 
2.1 Focus Groups 
Semi-structured focus groups made up of patients with T1DM, and observed by clinicians, 
engineers and experts in human computer interaction will provide a forum to gather 
feedback and ideas on data representation and presentation. The meetings will also allow an 
opportunity to acquire patient feedback on clinical study protocols and logistics.  
Objectives:  
• 
Establish important usability requirements to incorporate into the ARISES mobile 
interface design. 
• 
Collaboratively design a user friendly mobile application interface that adheres to 
standard procedures using human computer interaction and follows relevant 
standards (IEC 62366). 
• 
Design will focus on intuitive and easy access to decision support with as few device 
interactions as possible whilst maintaining sight of real time outcomes on glycaemia. 
 
Timescale: Twelve 2-hourly focus meetings will be held over the entire course of the study. 
Participants: 10 participants with T1DM will be expected to attend at least 6 focus groups. 
Meetings will be observed by a diabetes specialist clinician, engineers and experts in human 
computer interaction. 
Recruitment: Participants with T1DM will be recruited from the Imperial College Healthcare 
NHS trust type 1 diabetes outpatient clinics, from registered research databases and from 
interested participants who contact us.  
Format: Focus group discussions will be chaired by a diabetes specialist clinician. The 
specific objectives for each meeting will vary depending on design ideas and issues 
encountered following feedback from previous focus group meetings.  
Focus groups will be interactive and follow a semi-structured format as outlined below: 
• 
A questionnaire with topics for discussion will be sent to participants in advance.  
• 
15-minute presentation by a member of the investigative team to illustrate current 
design ideas and concepts. 
• 
40-minutes focused discussion and feedback on presentation objectives 
• 
40-minutes focussed discussion on questionnaire. 
• 
20-minutes open floor discussion. 

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• 
5- minutes conclusion. 
Responses to planned questions, additional ideas and points of discussion will be 
documented by an attending member of the investigative team on a prepared template. With 
agreed consent and anonymity respected, useful quotes will be taken from participants. 
 
Questionnaires and templates will vary for each meeting depending on newly conceived 
interface ideas and the outcomes from previous focus meetings. 
 
Outcomes from each focus group meeting, including collected participant questionnaire data, 
will be anonymously shared among all attendees for validation. Outcomes will subsequently 
be discussed among the investigative team and where appropriate considered for integration 
in the mobile interface design. 
 
 
2.2. Clinical studies 
 
2.2.1 Clinical physiological and environmental data collection  
This first phase clinical study protocol will serve as a training set for data collection and 
evaluation of blood glucose correlations against measured physiological and environmental 
case parameters. During this study glucose levels will be monitored continuously using RT 
CGM alongside various physiological parameters (see Table 1) using the Empatica E4 
wristband. Using the myTracks app, location and ambient temperature data will be 
automatically logged and retrospectively accessed from iPhone devices either owned by or 
issued to participants during the study. Data requiring manual input (e.g. exercise, meal 
macronutrients and alcohol intake) will be logged in the mySugr app installed on the 
participant's smartphone for retrospective analysis. Participants will have access to CGM 
data which they will be supported to use in their self-management and they will continue with 
their normal insulin regimen during this phase. 
Issued iPhone devices and the Empatica wristbands will be returned at the end of the study. 
 
Table 1 
Automated inputs 
(Empatica E4 wristband) 
Manually entered inputs 
(mySugr App) 
Retrospectively sourced 
inputs (myTracks app) 
Heart rate 
Meals – time and 
macronutrient composition 
(carbohydrate, protein and fat) 
Geolocation 
Blood volume pulse 
Alcohol – time and amount in 
units 
Ambient temperature 
Peripheral skin temperature 
Exercise – time, duration and 
type (intensity) 
 
Motion activity 
Intercurrent stress 
 
Sympathetic activity 
 
 
Electrodermal 
activity/Galvanic skin 
response 
 
 
 

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Objective - Derive useful blood glucose correlations against measured parameters to 
incorporate into CBR algorithm development and important wearable technology to 
maximise use and outcomes in the final ARISES platform feasibility study (phase 2).  
Methods – Non-randomised open study 
Timescale – Each participant will be in the study for 6 weeks, with a total of 3 visits in that 
timeframe. The availability of six Empatica E4 wristbands to be shared among 12 
participants obligates the study to last for a total of 12 weeks. 
Primary outcome – This clinical study will be a data collection exercise with no set primary 
outcomes. Nonetheless, this study can provide questionnaire and feasibility outcomes for 
combining both CGM and a physiological data acquisition sensor.  
Recruitment – Participants for all the clinical studies will be recruited from the Imperial 
College Healthcare NHS trust T1DM outpatient clinics, from registered research databases 
and from interested participants who contact us. Participant information sheets will be given 
to potential participants and, after a minimum of 48 hours and following any questions, 
informed consent will be taken. 
Participants – Twelve adults with T1DM 
Participant inclusion criteria 
• 
Adults ≥18years of age 
• 
Diagnosis of T1DM for > 1 year 
• 
Structured education completed in last 3 years and capable of CHO counting 
• 
CBG measured at least twice daily for CGM calibration 
• 
Capacity to follow the protocol and sign the informed consent 
• 
Access to a personal computer/laptop 
Participant exclusion criteria 
• 
Severe episode of hypoglycaemia (requiring 3rd party assistance) in last 6 months  
• 
Diabetic ketoacidosis in the last 6 months prior to enrolment 
• 
Impaired awareness of hypoglycaemia (based on Gold score) 
• 
Pregnant or planning pregnancy over time of study procedures 
• 
Breastfeeding 
• 
Enrolled in other clinical trials 
• 
Active malignancy or being investigated 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 

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• 
Oral steroids 
• 
Regular use of the paracetamol, 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 
• 
Recurrent severe hypoglycaemia (requiring 3rd party assistance to manage) 
• 
Diabetic ketoacidosis 
• 
Pregnancy 
• 
Terminal illness 
 
Withdrawal will be immediate, and participants will be followed up in the appropriate out-
patient diabetes clinic within 4 weeks of withdrawal. 
 
Visit 1: Screening 
• 
Participants will attend clinical research unit at 09:00 
• 
Signed and dated informed consent 
• 
Demographics (age, gender, date of birth, ethnicity) 
• 
Clinical history, including current medicines, supplements and allergies 
• 
Routine clinical examination including blood pressure, weight 
• 
ECG 
• 
Non-fasting venous blood taken for HbA1c, creatinine, lipids, liver function tests, full 
blood count and thyroid function test 
• 
Urine pregnancy test in females of child bearing age 
• 
Entry questionnaire completed by participant 
• 
Structured education revision by a qualified healthcare professional (carbohydrate 
counting and hypoglycaemia management 
• 
Real-time continuous glucose monitor (Dexcom G5) will be sited in the anterior 
abdominal wall according to manufacturer’s instructions. 
• 
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. 
• 
Participants will use their existing capillary glucose meter for both glucose 
measurements and CGM calibration. 
• 
Participants who do not own an iPhone will be provided with an iPhone 5 to monitor 
geolocation and ambient temperature. 
• 
Participants will be provided with an Empatica E4 wristband to wear on either wrist 
according to manufacturer’s instructions  
• 
Participants will have the Empatica Real-time application installed on their 
smartphone device 
• 
Participants will be required to have access to a personal computer/laptop and will be 
shown how to install and use the Empatica connect software. 

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• 
Participants will have the myTracks, Diasend and mySugr applications installed on 
their iPhone devices. 
• 
Instructions to participants to ensure: 
o CGM calibration every 12 hours and sensor change after 7 days wear as per 
manufacturer’s instructions. 
o All calibrations and CBG measurements will be undertaken by the participant. 
o Food diary (macronutrient composition - carbohydrate, fat and protein in 
grams), alcohol intake (units), intercurrent stress, and physical activity 
(duration and nature of exercise) to be logged in the mySugr smartphone 
application throughout the 6 weeks. 
o mySugr logbooks are exported as a spreadsheet on a weekly basis. 
o Empatica E4 wristband is connected to a personal computer (Windows or 
Mac) for an hour every day. This affords time for the wristband to charge and 
uploaded captured data using the proprietary Empatica connect software to a 
secure cloud-based platform. 
 
Visit 2: Telephone consultation (Week 1) 
• 
Investigator will communicate with participants 7 days following visit 1 to discuss 
o Any encountered technical issues 
o Uploaded CGM data reviewed remotely using the Diasend application 
o Uploaded Empatica E4 wristband data reviewed remotely using the E4 
connect software 
o mySugr logbook spreadsheet sent to the investigator and reviewed remotely  
 
Visit 3: Final visit at the end of 6 weeks 
• 
Attend clinical research unit 
• 
CGM data review with participant 
• 
Empatica E4 and mySugr logbook review with participant 
• 
Retrieve myTracks data from iPhone 
• 
Empatica E4 and issued iPhone devices will be returned 
• 
Exit questionnaire completed by participant 
 
Usual care will be maintained for diabetes throughout the study. Participants will be offered 
support for their diabetes throughout the study. Participants will have the opportunity to call a 
physician for medical support and an engineer for technical support 24 hours a day. 
Captured CGM and physiological data using the Dexcom glucose sensor and Empatica 
wristband respectively will be uploaded to a secure password encrypted cloud-based server. 
The Diasend and Empatica connect software will allow investigators to access this data 
remotely using encrypted passwords. Participants will be allocated a study number to ensure 
anonymity. 
Each participant will have an individual patient ID number to enable labelling of samples sent 
to the Imperial College Healthcare Trust laboratories for immediate analysis. 
 
 

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Statistics 
12 participants planned to be enrolled. This is not a randomised study and there are no 
comparison or control groups. Outcomes from the study are absolutes as described above. 
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.  
 
Table overview of activities (Phase 1) 
Visit / Interaction no 
1 
2 
3 
Additional information  
Consent 
x 
 
 
 
Medical History taking 
x 
 
 
 
Clinical examination 
(including weight and 
blood pressure) 
x 
 
 
 
ECG 
x 
 
 
 
Urine Pregnancy test 
x 
 
 
 
Venous blood test 
x 
 
 
 
Questionnaire(s) 
x 
 
x 
 
Insertion of CGM 
sensor 
x 
 
 
Participants will change the sensor every 
week at home throughout the study (24 
weeks 
Attaching Empatica E4 
wirstband 
x 
 
 
 
Issuing iPhone 5 and 
installing Diasend, 
mySugr and myTracks 
apps 
x 
 
 
 
Empatica connect 
computer installation 
and training 
x 
 
 
 
CGM review with 
participant 
 
x 
x 
 
Empatica E4 review 
with participant 
 
x 
x 
 
mySugr logbook review 
with participant 
 
x 
x 
Participant will send excel of mySugr 
logbook to investigator 
Removal of CGM 
 
 
x 
 

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Removal of Empatica 
E4 wristband 
 
 
x 
 
Return issued iPhones 
and Empatica E4 
wristbands 
 
 
x 
 
Retrieving myTracks 
data 
 
 
x 
 
 
 
3.0 Safety 
 
Adverse Events 
 
Definitions: 
Adverse Event (AE): Any untoward medical occurrence in in participants, users or other 
persons whether or not related to the investigational medical device. 
 
Serious Adverse Event (SAE): Adverse event that: 
• 
Results in death, injury or permanent impairment to a body structure or a body 
function 
• 
Is life-threatening 
• 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Results in foetal distress, foetal death or a congenital anomaly or birth defect 
 
Planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered a serious 
adverse event. 
 
 
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, whether expected or not, will be recorded.   
 
Serious AEs 
A SAE form will be completed and faxed or e-mailed to the Chief Investigator within 24 
hours.  However, death and 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, using the NRES SAE form for non-IMP studies. 
The Chief Investigator will notify the Sponsor and MHRA of all SAEs. 
 

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Contact details for reporting SAEs 
Fax: 0207 594 2432, attention Prof Nick Oliver 
nick.oliver@imperial.ac.uk 
Please send SAE forms to:  
Diabetes, Endocrinology and Metabolism Medicine 
Imperial College 
Room G3, Medical School Building 
St Mary’s Campus 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 2460 (Mon to Fri 09.00 – 17.00) 
 
Direct Access to Source Data/ Documents  
The investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s), providing direct access to source data/ documents. 
 
 
 
4.0 Regulatory Issues 
 
Ethics Approval 
The Chief Investigator has obtained approval from the Bloomsbury Research Ethics 
Committee and the HRA. The study will be conducted in accordance with the 
recommendations for physicians involved in research on human participants adopted by the 
18th World Medical Assembly, Helsinki 1964 and later revisions.  
 
Consent 
Consent to enter the study will be sought from each participant only after a full 
explanation has been given, an information leaflet offered, and time allowed for 
consideration. Signed participant consent will be obtained. The right of the participant to 
refuse to participate without giving reasons will be respected. All participants are free to 
withdraw at any time from the protocol treatment without giving reasons and without 
prejudicing further treatment. 
 
Confidentiality 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. 
 
All appropriate data and documentation related to study will be stored for 10 years and may 
be used to support other future research and may be shared anonymously with other 
researchers.  
 
Indemnity 
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this study/ Imperial College Healthcare NHS Trust holds standard NHS 
Hospital Indemnity and insurance cover with NHS Litigation Authority for NHS Trusts in 
England, which apply to this study (delete as applicable) 
 

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Sponsor 
Imperial College London will act as the main Sponsor for this study.  Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.  
  
Funding 
This study is being funded by the Engineering and Physical Sciences Research Council 
(EPSRC) under grant agreement EP/P00993X/1 
 
Audits 
The study may be participant to inspection and audit by Imperial College London under their 
remit as sponsor and other regulatory bodies to ensure adherence to GCP and the NHS 
Research Governance Framework for Health and Social Care (2nd edition). 
 
5.0 Study Management 
The day-to-day management of the study will be co-ordinated by Chief Investigator at each 
recruiting site. Weekly research meetings and monthly data reviews will be chaired by the 
chief investigator or other senior researcher. Annual reports to the funder and sponsor will 
be written and submitted. The management team will meet at the conclusion of each phase 
of the study to review data and ensure that no events have occurred requiring progression to 
the study to be halted. The management team will meet again prior to commencing the next 
phase to ensure appropriate action is taken to mitigate risk of further events. The 
management team includes a lay member with diabetes and a consultant diabetologist not 
involved with the study. 
  
6.0 Publication Policy 
The study will be registered on the clinicaltrials.gov system and results will be disseminated 
by peer reviewed scientific journals, internal report, conference presentation and publication 
on websites. No identifiable personal data will be published. Anonymised quotes may be 
included in publications if the participant has given informed written consent. All 
anthropometry and personal clinical data will be expressed as mean/ median and spread of 
the population in the study. All participants will be informed of the results by letter at the 
conclusion of the study and details of any publications that arise from the study will be 
disseminated to participants.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ARISES Clinical Trial Protocol 
 
IRAS ID: 240662 
Version 1.1 
16/02/2018 
17 
 
 
 
 
References 
 
1.  
NHS Digital 1 Trevelyan Square, Boar Lane, Leeds, LS1 6AE, United Kingdom. 
Quality and Outcomes Framework. http://content.digital.nhs.uk/qof. Accessed 
December 19, 2017. 
2.  
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: 
a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 
(London, England). 2016;387(10027):1513-1530. doi:10.1016/S0140-6736(16)00618-
8. 
3.  
Nathan DM, DCCT/EDIC Research Group  for the DR. The diabetes control and 
complications trial/epidemiology of diabetes interventions and complications study at 
30 years: overview. Diabetes Care. 2014;37(1):9-16. doi:10.2337/dc13-2112. 
4.  
Group TDC and CTR. Hypoglycemia in the Diabetes Control and Complications Trial. 
The Diabetes Control and Complications Trial Research Group. Diabetes. 
1997;46(2):271-286. doi:10.2337/DIAB.46.2.271. 
5.  
Halawa I, Zelano J, Kumlien E. Hypoglycemia and risk of seizures: A retrospective 
cross-sectional study. Seizure. 2015;25:147-149. doi:10.1016/j.seizure.2014.10.005. 
6.  
Sovik O, Thordarson H. Dead-in-bed syndrome in young diabetic patients. Diabetes 
Care. 1999;22 Suppl 2:B40-2. http://www.ncbi.nlm.nih.gov/pubmed/10097898. 
Accessed October 31, 2017. 
7.  
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group 
TJDRFCGMS, Bode B, Beck RW, et al. Sustained benefit of continuous glucose 
monitoring on A1C, glucose profiles, and hypoglycemia in adults with type 1 diabetes. 
Diabetes Care. 2009;32(11):2047-2049. doi:10.2337/dc09-0846. 
8.  
Garg SK, Bookout TR, McFann KK, et al. Improved glycemic control in intensively 
treated adult subjects with type 1 diabetes using insulin guidance software. Diabetes 
Technol Ther. 2008;10(5):369-375. doi:10.1089/dia.2007.0303. 
9.  
Lepore G, Dodesini AR, Nosari I, Scaranna C, Corsi A, Trevisan R. Bolus calculator 
improves long-term metabolic control and reduces glucose variability in pump-treated 
patients with Type 1 diabetes. Nutr Metab Cardiovasc Dis. 2012;22(8):e15-6. 
doi:10.1016/j.numecd.2012.04.001. 
10.  
(UK) NCGC. Type 1 Diabetes in Adults: Diagnosis and Management. National 
Institute for Health and Care Excellence (UK); 2015. 
http://www.ncbi.nlm.nih.gov/pubmed/26334079. Accessed October 31, 2017.