The Bio-Inspired Artificial Pancreas for the Home
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Sponsor: Imperial College London

Bio-inspired Artificial Pancreas for the Home Clinical Protocol v1.2 10/11/2017 
 
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Diabetes Endocrinology & Metabolism Section   
 
 
 
 
 
                  Ground Floor Medical School Building 
                                                                                                          St Mary’s Hospital Campus 
 
 
 
 
 
 
Norfolk Place, London W2 1PG 
 
 
 
 
 
 
Tel:   +44 (0)20 75942460 
 
 
 
 
 
 
Fax:   +44 (0)20 75942432  
 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
The Bio-inspired Artificial Pancreas for the Home 
 
Chief Investigator: Professor Nick Oliver 
 
General Information 
 
Authors:  
 
 
Dr Monika Reddy and Prof Nick Oliver 
 
Title:  
The Bio-inspired Artificial Pancreas for the Home 
 
Identifying Number:             Imperial College Joint Research Compliance Office:17HH3730 
 
Date:  
 
 
10.11.17 
 
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 
 
Principal Investigator: 
Professor Nick Oliver 
 
 
 
 
Diabetes Centre, 9th Floor East Wing 
Charing Cross Hospital, Fulham Palace Road,  
London, W6 8RF 
nick.oliver@imperial.ac.uk 
 
 
 
 
Telephone: 0203 311 1093 

Bio-inspired Artificial Pancreas for the Home Clinical Protocol v1.2 10/11/2017 
 
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Other departments:             Centre for Bio-Inspired Technology, Department of Electrical    
                                                and Electronic Engineering,  
Institute of Biomedical Engineering 
 
 
 
 
Bessemer Building, South Kensington Campus, 
Imperial College, London, SW7 2AZ 
 
 
1.0 Background ................................................................................................................................ 3 
The Bio-inspired Artificial Pancreas ................................................................................................... 4 
Clinical evaluation of the BiAP .............................................................................................................. 4 
The Advanced Bolus Calculator for Diabetes ................................................................................... 5 
The components of the closed-loop insulin delivery system ..................................................... 6 
Glucose sensor ......................................................................................................................................................... 6 
BiAP algorithm in a low-power handheld device ...................................................................................... 6 
ABC4D adaptive bolus calculator algorithm in a smartphone platform .......................................... 6 
Insulin infusion pump ........................................................................................................................................... 6 
Safety ............................................................................................................................................................................ 7 
Potential risks and benefits.................................................................................................................... 8 
Route of administration, dosage, dosage regimen, and treatment period ............................ 9 
2.0 Clinical study ............................................................................................................................. 9 
Trial Objectives and Purpose ............................................................................................................... 10 
Hypothesis .................................................................................................................................................. 10 
Trial Design ................................................................................................................................................ 10 
Methodology .............................................................................................................................................. 10 
Timescale .................................................................................................................................................... 11 
Population .................................................................................................................................................. 11 
Inclusion criteria ...................................................................................................................................... 11 
Exclusion criteria ..................................................................................................................................... 11 
Subject withdrawal criteria .................................................................................................................. 11 
Visit 1: Screening ...................................................................................................................................... 12 
Visit 2: CGM review .................................................................................................................................. 13 
Visit 3: 24 hours in clinic and start of 1st 6-week intervention period ................................. 13 
Visit 4: End of first 6-week intervention period ........................................................................... 14 
Visit 5: End of 2nd 6-week intervention period .............................................................................. 15 
Visit 6: End of 3rd 6-week intervention period and end of study ............................................ 15 
Table: Overview of activities at each visit for participants....................................................... 15 
3.0 Statistics .................................................................................................................................... 16 
Efficacy ......................................................................................................................................................... 16 
Primary outcome will be: ................................................................................................................................. 16 
Secondary outcomes will be: ........................................................................................................................... 16 
4.0 Data ............................................................................................................................................. 17 
Direct Access to Source Data/Documents ....................................................................................... 18 
5.0 Safety .......................................................................................................................................... 18 

Bio-inspired Artificial Pancreas for the Home Clinical Protocol v1.2 10/11/2017 
 
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Adverse Event Reporting ....................................................................................................................... 18 
Summary Reports .................................................................................................................................... 19 
6.0 Regulatory Issues ................................................................................................................... 19 
Ethics Approval ......................................................................................................................................... 19 
Consent ........................................................................................................................................................ 19 
Confidentiality ........................................................................................................................................... 20 
Indemnity .................................................................................................................................................... 20 
Sponsor ........................................................................................................................................................ 20 
Funding ........................................................................................................................................................ 20 
Audits............................................................................................................................................................ 20 
Study Management .................................................................................................................................. 20 
Publication Policy .................................................................................................................................... 21 
References ....................................................................................................................................... 21 
 
 
1.0 Background  
Type 1 diabetes mellitus (T1DM) is an autoimmune condition caused by destruction of the β-
cells in the pancreas that produce insulin. Current regimens for treating T1DM in clinical 
practice are mainly based on multiple daily injections of subcutaneous insulin in dosages 
determined by intermittent blood glucose measurements. Continuous subcutaneous insulin 
infusion (CSII) via a pump provides an alternative form of insulin therapy with the advantage 
of delivering variable basal rates throughout the day and fewer injections. However, a 
significant proportion of people with T1DM on current insulin regimens do not achieve 
optimal blood glucose control which increases the risk of complications including kidney 
failure, blindness, nerve damage and heart disease. Intensive treatment can lower this risk 
but may lead to potentially dangerous low blood glucose levels (hypoglycaemia). The 
Diabetes Control and Complications Trial demonstrated that intensive management reduced 
complications by 50-76% (1). This was at the expense of increased hypoglycaemia, 
especially at HbA1c levels <58mmol/mol (7.5%). Severe or prolonged hypoglycaemia is a 
major concern and can result in seizures, cardiac arrhythmias and is associated with the 
“dead-in-bed” syndrome (2, 3). Diabetes technologies, such as insulin pumps, bolus 
calculators, continuous glucose monitors and closed-loop insulin delivery systems, are 
important in aiding self-management and optimising glycaemic control in type 1 diabetes. 
 
A closed-loop insulin delivery system, also known as an artificial pancreas, provides the 
potential to improve HbA1c while avoiding hypoglycaemia.  It requires continuous glucose 
measurement by a subcutaneous continuous glucose sensor, a control algorithm and a 
pump for insulin delivery. Three main control algorithms (proportional-integral-derivative, 

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model predictive control and MD-logic) have been employed in out-of-clinic closed-loop 
clinical studies to date (4). Most closed-loop systems utilise insulin alone (5-7), while some 
groups use a bi-hormonal (insulin and glucagon) approach (8-9). 
 
To support mealtime insulin dosing, people with type 1 diabetes use bolus calculators to 
provide insulin dose recommendations. A standard bolus calculator uses a generic formula 
taking into account the target glucose level, current glucose level, carbohydrate content of 
meal (grams), insulin: carbohydrate ratio (the amount of carbohydrate (grams) covered by 1 
unit of insulin), insulin sensitivity factor (the reduction in blood glucose by 1 unit of insulin) 
and insulin-on-board (IOB, the remaining active insulin from the previous bolus). Some bolus 
calculators additionally consider parameters such as exercise, but all lack the ability to 
automatically adapt over time to respond to individual needs. Standard bolus calculators 
have been incorporated into insulin pumps and some glucose meters. 
 
The Bio-inspired Artificial Pancreas 
The diabetes technology group at Imperial College have developed a bio-inspired artificial 
pancreas (BiAP) system which uses a control algorithm based on a mathematical model of 
beta-cell behaviour derived from physiological experiments, carried out by other groups, 
which have demonstrated how the beta cells in the pancreas produce insulin in people 
without diabetes. Utilising the data from these experiments it has been possible to implement 
the behaviour of the beta cell in software (10-12) and we have used a simulator with 200 
virtual patients to demonstrate the safety and efficacy of the algorithm. The data from the 
simulator have previously been published (13). The simulator was developed from human 
data and takes into account glucose-insulin regulation, sensor errors, sensor placement, 
route of insulin administration and meal-time glucose absorption. It has been approved by 
the FDA in the United States as a step in the pathway of developing an artificial pancreas 
and has been validated against human data (14). The BiAP algorithm is implemented on a 
miniature silicon microchip within a portable handheld device, which interfaces the 
components of the artificial pancreas.  
 
Clinical evaluation of the BiAP  
The existing bio-inspired artificial pancreas has already been evaluated in participants with 
T1DM during fasting conditions, overnight and following a standard meal (breakfast) 
challenge and the data have shown good glycaemic control with minimal hypo- or 
hyperglycaemic excursions (15). Following the feasibility studies, a 24-hour randomised 
control clinical trial demonstrated that the BiAP system significantly reduces hypoglycaemia 

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compared to standard insulin pump therapy (16). We have additionally shown that the BiAP 
remains safe in the event that a meal is unannounced or the carbohydrate content is 
underestimated (16).  
The BiAP system has also been evaluated in standard exercise studies with insulin only 
artificial pancreas control, insulin and glucagon artificial pancreas control and open-loop 
insulin pump therapy. These have demonstrated that the controller is able to manage the 
challenge of prolonged aerobic exercise and that the addition of glucagon does not impact 
on the risk of hypoglycaemia with physical activity, immediately after physical activity or up to 
16 hours after (17, 18) 
 
The Advanced Bolus Calculator for Diabetes 
The Imperial College Diabetes Technology team have developed an Advanced Bolus 
Calculator for Diabetes (ABC4D), a novel, adaptive decision support algorithm based on 
case-based reasoning (CBR) providing real-time insulin advice through a smartphone 
application. CBR is an artificial intelligence technique that solves newly encountered 
problems by applying the solutions learned from solving similar problems encountered in the 
past. ABC4D utilizes CBR where cases within a case-base are used to represent various 
meal scenarios (e.g. dinner after exercise). Each time a user requests a new insulin bolus 
recommendation, the current meal scenario is compared to all existing cases from the past. 
If a similar case is found the solution of this case is applied to calculate the insulin dose. If no 
similar case exists, then a new case is created. The outcome of each insulin advice is then 
revised by analysing the post-prandial glucose excursion provided by continuous glucose 
monitoring (CGM) data. The ABC4D algorithm has been validated in-silico using the FDA-
accepted UVa-Padova type 1 diabetes simulator (19).  
 
Clinical evaluation of the ABC4D 
The safety and feasibility of the ABC4D has been evaluated pilot clinical study over 6 weeks 
in 10 adult participants with T1DM. The clinical outcomes from the pilot study showed that 
ABC4D is safe and maintains glycaemic control with a trend suggesting improvement in 
post-prandial hypoglycaemia and overall glucose outcomes (20). A separate analysis of the 
case parameters used in ABC4D showed that the alcohol and exercise parameters were 
most frequently used suggesting a clinical benefit in terms of improving post-prandial 
hypoglycaemia (21). The usability and acceptability of the system architecture was 
favourable with 8 out of 10 users trusting the advice generated and 9 out of 10 happy to use 
ABC4D (22). A powered randomised controlled trial over 6 months is currently underway to 
assess whether the ABC4D system is superior to a non-adaptive bolus calculator. 
 

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The components of the closed-loop insulin delivery system 
The complete device used in this protocol comprises a commercial continuous 
subcutaneous glucose sensor (Dexcom G5 CGM system), the BiAP control algorithm 
implemented in a low-power handheld device (developed by the Imperial Diabetes 
Technology team), the ABC4D adaptive bolus calculator algorithm in a smartphone platform 
(developed by the Imperial Diabetes Technology team) and a commercial continuous 
subcutaneous infusion pumps (Tandem T-slim) to provide glucose control. Fig 1 gives an 
overview of the complete system architecture. If participants already have intraperitoneal (IP) 
access (DiaPort) then the insulin will be delivered via the intraperitoneal route in accordance 
with these participants’ standard care.  
 
Glucose sensor 
The glucose sensor that will be used throughout the clinical validation studies is a CE 
marked and MHRA approved device commercially available (Dexcom G5 Mobile CGM 
system). Subcutaneous sensors sit just under the skin and sample 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.  
 
BiAP algorithm in a low-power handheld device 
As outlined above 
 
ABC4D adaptive bolus calculator algorithm in a smartphone platform 
As outlined above 
 
Insulin infusion pump 
The pump is a small (6cm x 4cm) device, containing a cartridge that can be filled with insulin, 
which delivers a continuous infusion of insulin into the subcutaneous (fat) tissue or 
intraperitoneal space via a tube connected to a pump cannula. The pump device used 
throughout the clinical validation is the Tandem t:slim which is FDA-approved and 
commercially available in the United States for use with Insulin Aspart (Novorapid) and 
Insulin Lispro (Humalog). The insulin pump is not CE-marked and not commercially available 
in Europe at present and will be labelled “exclusively for clinical investigations”. Participants 
will continue on their usual insulin, but the insulins used will be restricted to Insulin Aspart 
(Novorapid) and Insulin Lispro (Humalog).  
 
 

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Fig 1. System architecture 
Glucose data from the Dexcom G5 transmitter are sent by Bluetooth LE to the BiAP 
handheld unit where the bio-inspired algorithm is operating and insulin microbolus data are 
sent on to the Tandem t:slim pump at appropriate intervals (e.g. 5 minutes). At mealtimes 
(any meal or snack containing 15g or more of carbohydrate), the study participants will 
inform the smartphone of a meal and enter a carbohydrate estimate before eating. The 
pump will deliver a bolus calculated either according to a fixed or adaptive algorithm. The 
controller and smartphone will, at all times, know insulin-on-board, ensuring safety. Data will 
be fed by wifi or cellular data (3G/4G) to the research team but will not be monitored in real-
time. 
 
Safety 
Remote monitoring will not be routinely used but all participants will have 24-hour access to 
engineering and clinical support and will have a clear written plan in case of technical 
challenges. The facility to share data in real-time will be provided on the handset using 
Bluetooth to mirror data on the smartphone device with WiFi or 3G communication, to enable 
the support team to provide timely and appropriate advice. 
 

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To ensure participant safety, individualised constraints based on patient specific parameters 
(insulin:carbohydrate ratio, insulin sensitivity factor and insulin-on-board) are applied to the 
insulin calculated by the controller. Hypoglycaemia prevention strategies including insulin 
infusion reduction and suspension are employed for forecasted glucose concentrations 
below predefined thresholds. An alarm system alerting for device communication errors, 
sensor failures, hyper- and hypoglycaemia is in place and in case of sensor or controller 
failure insulin infusion will revert to a safe basal rate (% of a pre-programmed optimum). 
Finally, remote monitoring of RT-CGM, reflecting artificial pancreas functioning, will be 
available to the study team using a CE marked smartphone application (Dexcom Follow 
App). The study team will not be monitoring the data continuously, but will be able to use this 
information if participants seek technical/clinical support. 
 
Potential risks and benefits 
The potential risks and burdens for research participants are as follows: 
 
Some visits involve taking a venous blood test. These have the potential to cause 
discomfort. This will be minimised by experienced research personnel and appropriate use 
of equipment.  
 
Throughout the study, participants will have a subcutaneous insulin infusion pump cannula 
inserted and these need to be replaced every 3 days. All participants will use subcutaneous 
insulin infusion pumps for routine care. Participants will also have the glucose sensor 
inserted and these need to be changed every 7 days. Both pump cannula and glucose 
sensor insertion can be associated with some discomfort but the insertion devices are 
spring-loaded with introducers, making the process rapid and often painless. Any discomfort 
will be minimised by adhering to manufacturer's instructions. 
 
During the closed-loop study periods there is a risk from the new technology. The controller 
may suggest an excess or relatively deficiency of insulin infusion. Participants will be 
advised to check their capillary blood glucose as per routine care and in addition they will 
have access to real-time CGM. glucose values are frequently monitored to prevent adverse 
events related to elevated or low glucose values. To date the BiAP system and the ABC4D 
system have been evaluated in clinical studies in participants with T1DM without incidents of 
severe hypo- or hyperglycaemic excursions. 
 

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It is well-known that insulin requirements change during pregnancy and hence participants 
who are female and of childbearing age will have a urine pregnancy test done at screening 
and prior to each intervention. Participants will be excluded from the study if they are 
pregnant or planning pregnancy within the study time frame, to minimise any potential risk.  
 
It is acknowledged that the clinical schedule is demanding of subject's time and includes 
overnight visits. This inconvenience is necessary to adequately and safely ensure 
participants receive the appropriate training on how to use the device and we will minimise 
the burden as much as possible by providing entertainment (TV, radio, reading material, 
internet access) in a comfortable environment with privacy. We will also ensure to make 
every effort to schedule visits around participants’ lifestyles. 
 
Research participants will benefit from being in the study by having increased access to 
diabetes professionals and more frequent visits to hospital with an emphasis on improved 
glycaemic control. They will also have the opportunity to use continuous glucose monitoring 
and review the results with a consultant diabetologist experienced with monitoring. The 
benefits to people with T1DM include the potential to carry forward technology to improve 
the risks of high glucose concentration leading to complications and distressing low glucose 
values. 
 
Route of administration, dosage, dosage regimen, and treatment period  
Insulin will be administered subcutaneously or intraperitoneally (in those who already have 
IP access with a DiaPort). This is the standard route of administration for insulin in T1DM. 
Alternative routes of administration include intravenous or inhaled. Intravenous insulin is 
used clinically in people with diabetes who are acutely unwell or those unable to eat and 
drink, inhaled insulin is no longer commercially available in the UK. The insulin dosage will 
be expressed as units infused subcutaneously as microboluses and will be calculated by the 
control algorithm of the closed-loop at 5-minute intervals. The treatment periods are defined 
by time spent in closed-loop insulin delivery.  
 
2.0 Clinical study 
The trial will be conducted in compliance with the protocol, GCP and the applicable 
regulatory requirement(s). 
 

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Trial Objectives and Purpose  
The main objectives of the research study is to evaluate the safety, efficacy and cost-
effectiveness of a bio-inspired artificial pancreas (BiAP) with, and without, the addition of an 
adaptive bolus calculator (ABC4D) compared to gold-standard sensor-augmented pump 
therapy.  
 
Hypothesis 
1. A bio-inspired artificial pancreas (BiAP) device has a positive impact on glucose 
control, as measured by time in target after 6 weeks of use, when compared with 
sensor-augmented pump with low-glucose suspend (LGS). 
2. A bio-inspired artificial pancreas (BiAP) device with an adaptive bolus controller 
(ABC4D) has an additional positive impact on post-prandial glucose control. 
 
Trial Design  
A 3-way crossover randomized controlled trial (Fig 3). Description of the three arms: 
1. Sensor augmented pump (open-loop) 
2. BiAP with a fixed bolus calculator 
3. BiAP with the Advanced Bolus Calculator for Diabetes (ABC4D) 
 
The primary outcome from the studies will be % time spent with a glucose concentration in 
the target range (3.9-10.0mmol/l). This outcome incorporates safety as it ensures 
participants do not have low or high glucose excursions and is the principal measure of 
efficacy for closed-loop insulin delivery systems in the scientific literature. Other measured 
outcomes will be % time spent in euglycaemia (3.9-7.8mmol/l), % time spent in 
hypoglycaemia (<3.9mmol/l), % time spent in hyperglycaemia (>10mmol/l), mean venous 
blood and sensor glucose, glycaemic variability as measured by standard metrics (SD, 
CONGA, LI, JINDEX, GRADE, MODD, MAGE, ADDR, MVALUE, MAG), glycaemic risk as 
measured by low blood glucose index (LBGI) and high blood glucose index (HBGI), closed-
loop error grid analysis, glucose area under the curve. All measures have been previously 
published and validated. Quality of life, treatment satisfaction and device acceptability 
outcomes will be measured using mixed methods (questionnaires and semi-structured 
interviews). 
 
Methodology Randomised controlled cross-over open label study 
 

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Timescale It is anticipated that the study will take 1 year, each subject will be in the study for 
up 6 months, with a total of 6 visits in that timeframe. 
 
Population  
n = 20  
 
Inclusion criteria  
• 
Adults over 18 years of age 
• 
Type 1 diabetes confirmed on the basis of clinical features and a random c-peptide 
<200 pmol/L 
• 
Type 1 diabetes for greater than 1 year 
• 
Continuous subcutaneous insulin infusion for greater than 6 months 
• 
Structured education done (either 1:1 or group education) 
• 
HbA1c <10% (86mmol/mol) 
• 
A negative pregnancy test in female participants of childbearing age 
 
Exclusion criteria  
• 
More than one episode of severe hypoglycaemia (defined as hypoglycaemia 
requiring 3rd party assistance) in the preceding year  
• 
Impaired awareness of hypoglycaemia (Gold score >4)  
• 
Pregnant or planning pregnancy  
• 
Breastfeeding 
• 
Enrolled in other clinical trials 
• 
Have active malignancy or under investigation for malignancy 
• 
Severe visual impairment 
• 
Reduced manual dexterity 
• 
Ischaemic heart disease 
• 
Anti-anginal medications (e.g. GTN) 
• 
Regular use of paracetamol 
• 
Unable to participate due to other factors, as assessed by the CI 
 
Subject withdrawal criteria  
Participants will be withdrawn from the study in the case of: 
1. Loss of capacity to give informed consent 
2. Cessation of CSII as usual care for type 1 diabetes 

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3. Recurrent (>1 episode) severe hypoglycaemia (defined as needing 3rd party 
assistance) 
4. Terminal illness 
Withdrawal will be immediate and participants will be followed up in the appropriate 
outpatient diabetes clinic within 4 weeks of withdrawal. 
 
Recruiting will be undertaken in the insulin pump clinics at Imperial College Healthcare NHS 
Trust, 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. 
 
Usual care will be maintained for diabetes throughout the study. No concomitant medical 
therapies are contra-indicated, except for GLP-1 analogues and high dose steroids. 
 
 
 
 
Fig.3 Study design.  
CSII – Continuous Subcutaneous Insulin Infusion, SAP – Sensor Augmented Pump, CGM – 
Continuous Glucose Monitoring, BiAP – Bio-inspired Artificial Pancreas, ABC4D – Advanced 
Bolus Calculator for Diabetes 
 
Visit 1: Screening  
• 
Routine clinical examination 
• 
ECG 
• 
Venous blood taken for glucose, c-peptide, HbA1c, lipids, creatinine 
Screening
Randomisation
CSII
CGM
ArtificialPancreas
Fixedboluscalculator
ArtificialPancreas
Fixedboluscalculator
ArtificialPancreas
Fixedboluscalculator
CSII
SAP
ArtificialPancreas
ABC4D
ArtificialPancreas
ABC4D
ArtificialPancreas
ABC4D
CSII
SAP
CSII
SAP
0
30
28
2
16
14
42
Weeks

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• 
Urine pregnancy test in female participants of childbearing age 
• 
Random urine sample for albumin: creatinine ratio (UACR) ratio and c-peptide 
creatinine ratio (UCPCR) 
• 
Gold score 
• 
Continuous glucose monitoring (Dexcom) will be connected according to 
manufacturer’s instructions.  Participants will be shown how to insert the sensor 
themselves and written instructions on how to calibrate the CGM every 12 hours and 
sensor change every 7 days as per manufacturer’s instructions will be provided. 
Participants will be asked to wear the CGM for 2 weeks in total.  
• 
Participants will be provided with the study pump and receive training on how to use 
it.  
• 
Mixed methods psychological assessment: Diabetes quality of life (DQOL), Diabetes 
Treatment Satisfaction Questionnaire (DTSQ) and PAID Questionnaire to be 
completed. Semi-structured interviews by the investigators will be carried out.  
 
Visit 2: CGM review  
• 
14 days following visit 1 
• 
Remove CGM, upload data and review results with the participant. 
• 
Make adjustments to insulin: carbohydrate ratio(ICR), insulin sensitivity factor (ISF), 
insulin basal infusion rates if necessary. 
 
Randomisation: 
The order of the three intervention arms will be completely randomised using sealed 
envelope (www.sealedenvelope.com).  
 
Irrespective of which intervention the participants are allocated to for the first 6 weeks they 
will spend the first 24 hours at the clinical research facility for education and training on how 
to use the BiAP system as a whole (as outlined under visit 3). 
 
Visit 3: 24 hours in clinic and start of 1st 6-week intervention period 
• 
Attend the CRF at 16:00 until next day at 18:00. 
• 
Participant will be connected to the BiAP system at 17:00. 
• 
Finger prick blood sampling will be done eight times (before after each meal, bet-
time, one random during night) and analyzed immediately for glucose concentration 
using a standard glucometer. 

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• 
Standardized meals will be provided at 19:00 (dinner), 07:00 (breakfast) and 12:00 
(lunch). 
• 
The research team will ensure that the participants are comfortable with the BiAP 
system, particularly in the following situations: 
➢ How to switch the system from open-loop to closed-loop and vice versa.  
➢ When to calibrate the CGM system. 
➢ When to seek help. 
➢ Should the participant want a snack overnight they can record the carbs on the 
smartphone. For snacks of 15g or below participants will be advised not to bolus, but 
in cases of larger snacks they can calculate the bolus using the meal announcement 
button on BiAP/smartphone. Participants will be shown how to do this.  
• 
They will be free to go home at 18:00 with the BiAP device to continue the remaining 
6 weeks.  
• 
Participants will be trained to use the sensor, controller and insulin pump. 
• 
They will have a structured education refresher. 
• 
All training will be delivered by the study team and will be supported with written 
information. Participants will be expected to be able to self-manage the sensor, 
controller and pump prior to leaving the clinical research facility and competencies 
will be clearly recorded. Videos to support sensor insertion, and pump cannula and 
reservoir operations will be provided to all participants via email or on a USB stick 
and can be uploaded to participants’ smartphones for off-line use. Contact details for 
clinical and technical support will be provided. 
• 
The study team will phone the participants on day 1, day 3, day 7 and at 3 weeks.  
 
Visit 4: End of first 6-week intervention period 
• 
Attend the clinical research facility. 
• 
Review any issues with the technology used. 
• 
Download data from the study pump (the pump stores data for 90 days). 
• 
Provide consumables (sensors, transmitter, insulin infusion sets) for the next 6-week 
intervention period. 
• 
Gold score 
• 
Mixed methods psychological assessment: Diabetes quality of life (DQOL), Diabetes 
Treatment Satisfaction Questionnaire (DTSQ) and PAID Questionnaire to be 
completed. Semi-structured interviews by the investigators will be carried out. 
• 
Acceptability questionnaire to be completed. 
• 
Repeat urine pregnancy test in female participants of childbearing age 

Bio-inspired Artificial Pancreas for the Home Clinical Protocol v1.2 10/11/2017 
 
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• 
Participants will be instructed to revert back to their usual care for 2 weeks (wash-out 
period) before commencing the next intervention for 6 weeks. 
 
Visit 5: End of 2nd 6-week intervention period 
• 
Attend the clinical research facility. 
• 
Review any issues with the technology used. 
• 
Download data from the study pump. 
• 
Provide consumables (sensors, transmitter, insulin infusion sets) for the next 6-week 
intervention period. 
• 
Gold score 
• 
Mixed methods psychological assessment: Diabetes quality of life (DQOL), Diabetes 
Treatment Satisfaction Questionnaire (DTSQ) and PAID Questionnaire to be 
completed. Semi-structured interviews by the investigators will be carried out. 
• 
Acceptability questionnaire to be completed. 
• 
Repeat urine pregnancy test in female participants of childbearing age 
• 
Participants will be instructed to revert back to their usual care for 2 weeks (wash-out 
period) before commencing the next intervention for 6 weeks. 
 
Visit 6: End of 3rd 6-week intervention period and end of study 
• 
Attend the clinical research facility. 
• 
Review any issues with the technology used. 
• 
Gold score 
• 
Mixed methods psychological assessment: Diabetes quality of life (DQOL), Diabetes 
Treatment Satisfaction Questionnaire (DTSQ) and PAID Questionnaire to be completed. 
Semi-structured interviews by the investigators will be carried out. 
• 
Acceptability questionnaire to be completed. 
• 
Participants will be asked to return all components of the study device and will be 
instructed to revert back to their usual care. 
 
Table: Overview of activities at each visit for participants  
Activity  /  Visit no 
1 2 3 4 5 6 Additional information  
Insertion of CGM sensor 
x 
 
 
 
 
 
Participants will change the sensor 
every week at home throughout the 
study  
CGM review with participant 
 
x 
 
 
 
 
 
Randomisation + Initialise the 
 
 
x 
x 
x 
 
 

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intervention/control 
Update CBR algorithm with new 
cases 
 
 
 
 
 
 
This will be done automatically in 
the BiAP+ABC4D intervention 
Clinical examination 
x 
 
 
 
 
 
 
Weight measurement 
x 
 
 
 
 
 
 
Venous blood test 
x 
 
 
 
 
 
 
Urine test 
x 
 
 
x 
x 
 
 
Pregnancy test (if applicable) 
x 
 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
 
Questionnaire/s 
x 
 
 
x 
x 
x 
 
Follow-up clinical visits 
 
x 
x 
x 
x 
x 
 
Overnight stay in clinical 
research facility 
 
 
x 
 
 
 
 
Semi-structured interview 
x 
 
 
x 
x 
x 
 
3.0 Statistics  
From our previous published data1,6 we anticipate that the BiAP/ABC4D intervention will 
increase the percentage of time for which plasma glucose concentrations were in the target 
range by a mean of 6% (SD 9.9) compared with the BiAP/fixed bolus artificial pancreas 
system, and by an estimated mean of more than 6% (9.9) compared with the control group. 
We intend to do three pairwise comparisons between the interventions, and therefore have 
conducted a power analysis using the typical sample size formula for the paired t test. We 
estimate, using mean 12% (9.9), that 20 participants would provide 90% power at the 5% 
significance level (corrected for multiple comparisons) to detect differences between the 
three interventions. 
 
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. 
 
Efficacy 
Primary outcome will be: 
• 
% time in target range defined as 3.9-10mmol/l 
 
Secondary outcomes will be: 
• 
% time spent in euglycaemia (3.9-7.8mmol/l) 
• 
% time spent in hypoglycaemia (<3.9mmol/l) 
• 
% time spent in hypoglycaemia (<2.8mmol/l) 

Bio-inspired Artificial Pancreas for the Home Clinical Protocol v1.2 10/11/2017 
 
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• 
% time spent in hyperglycaemia (>10mmol/l) 
• 
% time spent in severe hyperglycaemia (<15mmol/l) 
• 
Mean sensor glucose 
• 
Glycaemic variability  
• 
Glycaemic risk as measured by LBGI and HBGI 
• 
Closed loop error grid analysis 
• 
Glucose area under the curve 
• 
Insulin requirement in units/kg/hr 
• 
Hypoglycaemia awareness (Gold scores) 
• 
Quality of life by mixed quantitative and qualitative methodologies 
• 
Cost-effectiveness 
• 
Device usability and acceptability 
• 
% time in closed loop control 
• 
Severe hypoglycaemia 
• 
Diabetic ketoacidosis 
• 
Sensor MAD% 
 
These are validated, published metrics, which will be assessed at the end of each visit from 
CGM data. There will be an interim analysis of the data after each visit to ensure efficacy 
and safety. 
 
4.0 Data  
During the course of the study visits some data will be stored on laptop computers, not 
connected to the Internet, for later statistical analysis. These data will be coded and non-
identifiable. Any identifiable participant data collected at screening will be stored in a locked 
filing cabinet in a secure room in Imperial College Healthcare NHS Trust. Only the clinical 
research team will have access to the filing cabinet. 
Electronic data will be stored by subject number only on NHS and Imperial College desktop 
computers which are in the same locked room. Laptop computers may be used during the 
visits for portability and convenience. At the end of each visit the anonymised data will be 
transferred immediately to the secure NHS and Imperial College computers and will be 
deleted from the laptop.  
All data will be stored in an anonymised form by using study numbers for identification of 
participants. The NHS code of confidentiality will be followed and all activity will meet the 
requirements of the data protection act. 

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Only members of the clinical research team and those responsible for direct care will have 
access to participants' data during the study. The data generated by the study will be 
analysed by the research team including the engineering team from Imperial College. The 
analysis will be on anonymised data and will take place in Imperial College Healthcare NHS 
Trust and in Imperial College academic buildings, both in the Faculty of Medicine and in the 
Faculty of Engineering. Fully anonymised data may be shared with future collaborators to 
support further development. 
 
Electronic data transmission and storage  
Data security and privacy will be a priority whilst dealing with data obtained throughout the 
study. During the clinical study anonymised clinical data (real-time continuous glucose data 
and insulin doses recommended by the BiAP and ABC4D algorithms) will be automatically 
transmitted between components of the BiAP system and stored locally on the BiAP device. 
In addition, RT-CGM data will be available to the study team using a CE marked smartphone 
application (Dexcom Follow App) to allow remote supervision of the artificial pancreas 
functioning. All data will be stored and protected against non-authorised access; 
transmission of data will be secured; only authorised users will have access to stored data. 
Authorised users will include the clinical and engineering study team members and individual 
participants will have access to their own data.  
 
Direct Access to Source Data/Documents 
The investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s), providing direct access to source data/documents. 
 
5.0 Safety  
During intercurrent illness, study visits will be postponed as insulin requirements will be 
altered.  
 
Adverse Event Reporting  
Adverse events will be reported to the Health Research Authority (HRA), the sponsor and 
the Chief Investigator (CI) immediately. Participants will be followed-up after one week 
following an adverse event and thereafter in the diabetes clinic or any other clinically 
indicated follow up. A reporting log form will be kept in the TMF. 
 
A “serious adverse event” is one of which: 
 

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a) led to death, 
b) led to serious deterioration in the health of the subject, that earlier resulted in ; 
1) a life-threating illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threating illness or injury or 
permanent impairment to a body structure or body function, 
     c) led to foetal distress, foetal death or a congenital abnormality or birth defect.   
 
Summary Reports 
In addition to the reporting of individual serious adverse events as detailed above, a 
summary report of all serious adverse events on a 6 monthly basis will be notified to HRA,  
sponsor and CI. A table will be reported including the number of serious adverse events, 
number of participants affected by those events and percentage of the total number or 
enrolled participants affected by those events.  
 
6.0 Regulatory Issues 
  
Ethics Approval  
The Chief Investigator, Professor Nick Oliver, has obtained approval from the National 
Research Ethics Service Committee London-Stanmore.  The study must be submitted for 
Site Specific Assessment (SSA) at each participating NHS Trust.  The Chief Investigator will 
require a copy of the Trust R&D approval letter before accepting participants into the 
study.  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.  Delegated 
research health care professional will obtain signed participant consent.  The right of the 
participant to refuse to participate without giving reasons will be respected.  After the 
participant has entered the study the health care professional remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the participant’s 
best interest, but the reasons for doing so should be recorded.  In these cases the 

Bio-inspired Artificial Pancreas for the Home Clinical Protocol v1.2 10/11/2017 
 
20
participants remain within the study for the purposes of follow-up and data analysis.  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. 
 
Indemnity  
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this study. 
 
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  
The Wellcome Trust is funding this study.  
  
Audits 
The study may be subject 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). 
 
Study Management  
The day-to-day management of the study will be co-ordinated by Professor Nick Oliver and 
the rest multidisciplinary research team. The chief investigator or other senior researchers 
will chair weekly research meetings and monthly data reviews. Annual reports to the funder 
and sponsor will be written and submitted. A data monitoring committee, including statistical 
expertise, a lay member with diabetes and a consultant diabetologist not involved with the 
study, will be established to provide overview of the clinical study. The data monitoring 
committee will meet regularly to review and evaluate the study data for participant safety, 
study conduct and progress. 
 

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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. 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.   
 
 
 
 
References 
 
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based on pancreatic β-cell physiology . Diabetes Sci Technol 2012; 6: 606-615 
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Concept in Closed-Loop Control of Type 1 Diabetes. J Diabetes Sci Technol 
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Technology 2016;10:408-413 
17. Seechurn S, Reddy M, Jugnee N, El Sharkawy M, Pesl P, Herrero P, Godsland I, 
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system impact on post exercise glycaemia? Diabetes Technology and Therapeutics 
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insulin 
pump 
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Bolus Advisor based on Run-To-Run Control and Case-Based Reasoning. IEEE 
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20. Reddy M, Pesl P, Xenou M, Toumazou C, Johnston D, Georgiou P, Herrero P, Oliver 
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Diabetes (ABC4D) based on Casebased Reasoning: a 6-week non-randomised 
single-arm pilot study. Diabetes Technology and Therapeutics 2016 
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Based Reasoning for Insulin Bolus Advice: Evaluation of Case Parameters in a Six-
Week Pilot Study. Journal of Diabetes, Science and Technology 2016 
22. Pesl P, Herrero P, Reddy M, Xenou M, Oliver N, Johnston D, et al. An Advanced 
Bolus Calculator for Type 1 Diabetes: System Architecture and Usability Results. 
IEEE journal of biomedical and health informatics. 2015. 
 
 
 
 
Chief Investigator Signature:  
 
Printed name: Prof Nick Oliver 
Date: 19/05/2018