An Open-label, Multi-centre, Randomised, Two-period, Crossover Study to Assess the Efficacy, Safety and Utility of 16 Week Day and Night Automated Closed-loop Glucose Control Under Free Living Conditions Compared to Sensor Augmented Insulin Pump Therapy in Older Adults With Type 1 Diabetes.
Phase: NA
Conditions: Type 1 Diabetes Mellitus, Hypoglycemia, Arrythmia
Sponsor: University of Cambridge

 
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Clinical Study Protocol 
 
 
 
Study Title: 
An open-label, multi-centre, randomised, two-
period, crossover study to assess the efficacy, 
safety and utility of 16 week day and night 
automated closed-loop glucose control under free 
living conditions compared to sensor augmented 
insulin pump therapy in older adults with type 1 
diabetes 
 
Short Title:   
24/7 closed-loop in older subjects with type 1 
diabetes (Dan06) 
 
Protocol Version: 
5.0   30 July 2020 
 
Protocol ID:  
Dan06  
 
 
Chief 
Investigator 
Professor Roman Hovorka 
Wellcome Trust-MRC Institute of Metabolic Science 
University of Cambridge 
Box 289, Level 4 
Addenbrooke’s Hospital 
Hills Road, Cambridge 
CB2 0QQ 
UK 
Phone: +44 1223 762 862 
Fax:   +44 1223 336 996 
rh347@cam.ac.uk 
 
 
This protocol has been written in accordance with current ISO 14155:2011 
standard 
 
 

 
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Principal Clinical 
Investigators 
 
Dr Mark Evans 
Wellcome Trust-MRC Institute of Metabolic Science  
Box 289, Level 4 
Addenbrooke's Hospital 
Hills Road, Cambridge CB2 0QQ 
UK 
Phone: +44 1223 336 994 
Fax:   +44 1223 330 598 
E-mail: mle24@cam.ac.uk 
 
Dr Lalantha Leelarathna 
Manchester Royal Infirmary 
Central Manchester University Hospitals NHS Foundation Trust 
Manchester Diabetes Centre 
Hathersage Rd, Manchester M13 9WL 
UK 
Phone: +44 161 276 6709 
Fax:   +44 161 273 6184 
E-mail: Lalantha.Leelarathna@cmft.nhs.uk 
 
Dr Parth Narendran 
University Hospitals Birmingham NHS Foundation Trust 
Queen Elizabeth Hospital 
Mindelsohn Way 
Edgbaston, Birmingham  B15 2TH 
UK 
Phone: +44 121 627 8904 
Fax: +44 121 415 8712 
E-mail: P.Narendran@bham.ac.uk 
 
Dr Julia Mader  
Medical University of Graz,  
Dept. of Internal Medicine 
Division of Endocrinology and Diabetology 
Auenbruggerplatz 15 
A- 8036 Graz 
Austria 
Phone: +43 316 385 80254 
Fax: +43 316 385 13428 
julia.mader@medunigraz.at 
 
 
Clinical 
Investigators 
Dr Charlotte Boughton 
Wellcome Trust-MRC Institute of Metabolic Science 
University of Cambridge 
Box 289, Level 4 
Addenbrooke’s Hospital 
Hills Road, Cambridge 

 
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CB2 0QQ 
UK 
Phone +44 1223 769066 
Email: cb2000@medschl.cam.ac.uk 
 
Dr Hood Thabit 
Manchester Royal Infirmary 
Central Manchester University Hospitals NHS Foundation Trust 
Manchester Diabetes Centre 
Hathersage Rd, Manchester M13 9WL 
UK 
Phone: +44 161 276 6709 
Fax:   +44 161 273 6184 
E-mail: Hood.Thabit@cmft.nhs.uk 
 
Other 
Investigators 
 
Dr Malgorzata E Wilinska  
Wellcome Trust-MRC Institute of Metabolic Science 
University of Cambridge 
Box 289, Level 4 
Addenbrooke’s Hospital 
Hills Road, Cambridge 
CB2 0QQ 
UK 
Phone: +44 1223 769 065 
Fax:   +44 1223 336 996 
E-mail: mew37@cam.ac.uk  
 
Stuart Allen, EHRA Certified Cardiac Devices Specialist 
Principal Cardiac Physiologist 
Manchester Heart Centre 
Manchester University Foundation Trust 
Manchester M13 9WL 
UK 
Phone:  (0161 27) x66740 
E-mail: Stuart.Allen@mft.nhs.uk 
 
Study  
Co-ordinator  
Mrs Josephine Hayes 
Wellcome Trust-MRC Institute of Metabolic Science  
Box 289, Level 4 
Addenbrooke's Hospital 
Hills Road, Cambridge CB2 0QQ 
UK 
Tel: +44 (0)1223 769 084 
Fax:   +44 (0)1223 330 598 
E-mail: jfh31@cam.ac.uk 

 
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Human Factor 
Assessment 
Professor Korey K. Hood 
Stanford University School of Medicine 
291 Campus Drive 
Li Ka Shing Building 
Stanford, CA 94305-5101 
USA 
Tel:+1 (650) 497-6899 
E-mail: kkhood@stanford.edu 
 
Dr Eleanor M Scott  
Senior Lecturer in Medicine & Consultant in Diabetes and 
Endocrinology 
Leeds Institute of Cardiovascular and Metabolic Medicine 
University of Leeds  
Leeds, LS2 9JT 
UK 
Tel: +44 (0)113 343 7762 
E-mail: E.M.Scott@leeds.ac.uk 
 
Clinical 
Laboratories 
 
Ms Karen Whitehead 
Chief Research Technician 
University of Cambridge 
Department of Paediatrics 
Level 8 Box 116 
Addenbrooke's Hospital 
Cambridge CB2 0QQ 
UK 
Tel: + 44 (0) 1223 762945 
Fax:+ 44 (0) 1223 336996 
Email kw240@cam.ac.uk 
 
Study Sponsor 
(UK) 
Cambridge University Hospitals NHS Foundation Trust, jointly with 
University of Cambridge  
Ms Carolyn Read 
Research Governance Office 
University of Cambridge 
School of Clinical Medicine 
Box 111, Cambridge Biomedical 
Campus 
Cambridge, CB2 0SP 
UK 
Tel: +44 (0)1223 769 291 
E-mail: 
researchgovernance@medschl.
cam.ac.uk 
Stephen Kelleher 
Cambridge University Hospitals  
NHS Foundation Trust              
Box 277, Addenbrooke's Hospital 
Hills Road, Cambridge, CB2 0QQ,  
UK 
Phone:  +44 (0) 1223 217418 
Fax:  +44 (0) 1223 348494 
r&denquiries@addenbrookes.nhs.u
k  
Funder 
 
National Institute of Diabetes and Digestive and Kidney Diseases 
 

 
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Data Safety and Monitoring Board (DSMB) 
 
DSMB comprises  
 
Independent Chair  
 
Two independent Medical Experts 
 
 
 
 
 

 
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PROTOCOL SIGNATURE PAGE 
 
The signature below documents the approval of the protocol entitled "An open-label, 
multi-centre, randomised, two-period, crossover study to assess the efficacy, 
safety and utility of 16-week day and night automated closed-loop glucose 
control under free living conditions compared to sensor augmented insulin 
pump therapy in older adults with type 1 diabetes" version 5.0 dated 30 July 2020 
and provides the necessary assurances that this study will be conducted according to 
all stipulations of the protocol, the principles of GCP and the appropriate reporting 
requirements. 
 
 
 
Signature ……………………………………. Date…14 October 2020…………. 
Professor Roman Hovorka 
Chief Investigator /Sponsor representative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SITE SIGNATURE PAGE (Cambridge, UK)  
 
I have read the attached protocol entitled “An open-label, multi-centre, randomised, 
two-period, crossover study to assess the efficacy, safety and utility of 16-week 
day and night automated closed-loop glucose control under free living 
conditions compared to sensor augmented insulin pump therapy in older adults 
with type 1 diabetes” version 5.0 dated 30/07/2020, and agree to abide by all 
provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice: The European Clinical Trials Directives 
2001/20/EC and 2005/28/EC. 
 
I agree to ensure that the confidential information contained in this document will not 
be used for any other purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
Signature ……………………………………. Date………………………. 
 
 
Dr Mark Evans  
Principal Clinical Investigator 
 
 
 
 

 
Dan06 protocol   Version 5.0   30 July 2020 
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SITE SIGNATURE PAGE (Manchester, UK) 
 
I have read the attached protocol entitled “An open-label, multi-centre, randomised, 
two-period, crossover study to assess the efficacy, safety and utility of 16-week 
day and night automated closed-loop glucose control under free living 
conditions compared to sensor augmented insulin pump therapy in older adults 
with type 1 diabetes” version 5.0 dated 30/07/2020, and agree to abide by all 
provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice: The European Clinical Trials Directives 
2001/20/EC and 2005/28/EC. 
 
I agree to ensure that the confidential information contained in this document will not 
be used for any other purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
 
 
Signature ……………………………………. Date………………………. 
 
 
 
Dr Lalantha Leelarathna 
Principal Clinical Investigator 
 
 
 
 

 
Dan06 protocol   Version 5.0   30 July 2020 
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SITE SIGNATURE PAGE (Birmingham, UK) 
 
I have read the attached protocol entitled “An open-label, multi-centre, randomised, 
two-period, crossover study to assess the efficacy, safety and utility of 16-week 
day and night automated closed-loop glucose control under free living 
conditions compared to sensor augmented insulin pump therapy in older adults 
with type 1 diabetes” version 5.0 dated 30/07/2020, and agree to abide by all 
provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice: The European Clinical Trials Directives 
2001/20/EC and 2005/28/EC. 
 
I agree to ensure that the confidential information contained in this document will not 
be used for any other purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
 
 
Signature ……………………………………. Date………………………. 
 
 
 
Dr Parth Narendran 
Principal Clinical Investigator 
 
 
 
 
 
 

 
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Table of Contents 
1. 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ....................................... 14 
2. 
STUDY SYNOPSIS .......................................................................................................... 15 
3. 
SUMMARY ....................................................................................................................... 20 
4. 
BACKGROUND ............................................................................................................... 21 
4.1. 
SENSOR-AUGMENTED INSULIN PUMP THERAPY ........................................................... 22 
4.2. 
CLOSED-LOOP INSULIN DELIVERY ................................................................................... 22 
4.3. 
THRESHOLD BASED PUMP INTERRUPTION .................................................................... 23 
4.4. 
PRECLINICAL TESTING OF CAMBRIDGE CLOSED-LOOP ALGORITHM ......................... 23 
4.5. 
STUDIES OF CLOSED-LOOP IN CHILDREN AND ADOLESCENTS WITH TYPE 1 
DIABETES IN THE CLINICAL RESEARCH FACILITY ......................................................... 23 
4.6. 
STUDIES OF CLOSED-LOOP IN ADULTS WITH TYPE 1 DIABETES IN THE CLINICAL 
RESEARCH FACILITY .......................................................................................................... 24 
4.7. 
OVERNIGHT CLOSED-LOOP STUDY IN CHILDREN AND ADOLESCENTS WITH TYPE 1 
DIABETES IN HOME SETTING ............................................................................................ 24 
4.8. 
OVERNIGHT CLOSED-LOOP STUDY IN ADULTS WITH TYPE 1 DIABETES IN HOME 
SETTING ............................................................................................................................... 25 
4.9. 
DAY AND NIGHT CLOSED-LOOP STUDIES IN ADULTS WITH TYPE 1 DIABETES IN 
HOME SETTING ................................................................................................................... 25 
4.10. AUTOMATED CLOSED-LOOP SYSTEM (CAMAPS FX) TO BE USED IN THE PRESENT 
STUDY .................................................................................................................................. 26 
4.11. RATIONALE FOR THE CURRENT STUDY .......................................................................... 27 
5. 
OBJECTIVES .................................................................................................................. 27 
5.1. 
EFFICACY ............................................................................................................................. 27 
5.2. 
SAFETY ................................................................................................................................ 28 
5.3. 
UTILITY ................................................................................................................................. 28 
5.4. 
HUMAN FACTORS ............................................................................................................... 28 
5.5. 
CARDIAC RHYTHM .............................................................................................................. 28 
6. 
STUDY DESIGN .............................................................................................................. 29 
7. 
STUDY SUBJECTS ......................................................................................................... 29 
7.1. 
STUDY POPULATION .......................................................................................................... 29 
7.1.1. 
Inclusion criteria ....................................................................................................... 31 
7.1.2. 
Exclusion criteria for all countries ............................................................................ 31 
7.1.3. 
Additional exclusion criteria specific for Austria ....................................................... 32 
7.2. 
RANDOMISATION ................................................................................................................ 33 
8. 
METHODS UNDER INVESTIGATION ............................................................................ 33 
8.1. 
NAME AND DESCRIPTION OF THE METHOD OF INVESTIGATION ................................. 33 
8.2. 
INTENDED PURPOSE .......................................................................................................... 33 
8.3. 
METHOD OF ADMINISTRATION ......................................................................................... 33 
8.4. 
REQUIRED TRAINING ......................................................................................................... 33 
8.5. 
PRECAUTIONS ..................................................................................................................... 33 
8.6. 
ACCOUNTABILITY OF THE METHOD UNDER INVESTIGATION ....................................... 34 
9. 
STUDY SCHEDULE ........................................................................................................ 34 
9.1. 
OVERVIEW ........................................................................................................................... 34 
9.2. 
RECRUITMENT VISIT (VISIT 1) ........................................................................................... 39 
9.2.1. 
Screening blood sampling ........................................................................................ 39 
9.2.2. 
Human factor assessments ..................................................................................... 39 
9.3. 
TRAINING SESSION ON THE USE OF THE STUDY INSULIN PUMP (VISIT 2) ................. 40 
9.4. 
TRAINING SESSION ON THE CONTINUOUS GLUCOSE MONITORING (VISIT 3) ........... 41 
9.5. 
RUN-IN PERIOD (ENDS AT VISIT 4) ................................................................................... 41 
9.6. 
RANDOMISATION ................................................................................................................ 41 
9.7. 
CLOSED-LOOP VISIT; WITHIN 2 WEEKS OF VISIT 4 (VISIT 5) ......................................... 42 
9.8. 
24-48 HOURS AFTER STARTING STUDY TREATMENT (VISIT 6) .................................... 42 
9.9. 
1 WEEK AFTER STARTING STUDY TREATMENT (VISIT 7) .............................................. 42 
9.10. 2 WEEKS AFTER STARTING STUDY TREATMENT (VISIT 8) ............................................ 43 
9.11. VISITS 9, 10 AND 11 – 4 WEEK, 8 WEEK AND 12 WEEK AFTER STARTING CLOSED-
LOOP THERAPY ................................................................................................................... 43 
9.12. HOLTER MONITOR APPLICATION (VISIT 12) .................................................................... 43 
9.13. END OF CL TREATMENT (VISIT 13) ................................................................................... 43 
9.14. WASHOUT ............................................................................................................................ 44 
9.15. CONTROL THERAPY (VISIT 14) .......................................................................................... 44 
9.16. VISITS 15, 16 AND 17 – 4 WEEK, 8 WEEK AND 12 WEEK AFTER STARTING SENSOR 
AUGMENTED PUMP TREATMENT ..................................................................................... 44 
9.17. HOLTER MONITOR APPLICATION (VISIT 18) .................................................................... 45 
9.18. END OF CONTROL TREATMENT (VISIT 19) ...................................................................... 45 
9.19. PARTICIPANT WITHDRAWAL CRITERIA ............................................................................ 45 

 
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9.20. STUDY STOPPING CRITERIA ............................................................................................. 46 
9.21. SUPPORT TELEPHONE LINE .............................................................................................. 46 
9.22. SUBJECT REIMBURSEMENT .............................................................................................. 46 
10. ENDPOINTS .................................................................................................................... 46 
10.1. EFFICACY ENDPOINTS ....................................................................................................... 46 
10.1.1. 
Primary efficacy endpoint ....................................................................................... 46 
10.1.2. 
Secondary efficacy endpoints ................................................................................ 46 
10.2. SAFETY EVALUATION ......................................................................................................... 47 
10.3. UTILITY EVALUATION ......................................................................................................... 47 
10.4. HUMAN FACTORS EVALUATION ........................................................................................ 47 
10.5. CARDIAC ARRHYTHMIA ANALYSIS ................................................................................... 47 
10.6. SLEEP QUALITY ASSESSMENT ......................................................................................... 47 
11. ASSESSING AND REPORTING OF ADVERSE EVENTS ............................................. 48 
11.1. DEFINITIONS ........................................................................................................................ 48 
11.1.1. 
Reportable Adverse Events .................................................................................... 48 
11.1.2. 
Adverse Events ...................................................................................................... 48 
11.1.3. 
Adverse Device Effect ............................................................................................ 49 
11.1.4. 
Serious Adverse Event ........................................................................................... 49 
11.1.5. 
Serious Adverse Device Effect ............................................................................... 50 
11.1.6. 
Unanticipated Serious Adverse Device Effect ........................................................ 50 
11.1.7. 
Device Deficiencies ................................................................................................ 50 
11.1.8. 
Adverse Event Intensity .......................................................................................... 51 
11.1.9. 
Adverse Event Causality ........................................................................................ 51 
11.2. RECORDING AND REPORTING OF ADVERSE EVENTS, SERIOUS ADVERSE EVENTS 
AND DEVICE DEFICIENCIES ............................................................................................... 52 
11.2.1. 
Monitoring Period of Adverse Events ..................................................................... 52 
11.2.2. 
Recording and reporting of Adverse Events ........................................................... 52 
11.2.3. 
Severe Hypoglycaemia .......................................................................................... 53 
11.2.4. 
Hyperglycaemia, Ketonaemia and Diabetic Ketoacidosis ...................................... 53 
11.2.5. 
Reporting of Serious Adverse Events and Serious Adverse Device Effects ........... 54 
11.2.6. 
Recording and Reporting of Device Deficiencies ................................................... 56 
11.2.7. 
Healthcare Arrangements and Compensation for Adverse Events ........................ 56 
11.3. RISKS AND DISCOMFORTS AND POTENTIAL / ANTICIPATED ADVERSE EVENTS AND 
ADVERSE DEVICE EVENTS/EFFECTS .............................................................................. 56 
11.3.1. 
Risks and anticipated adverse events .................................................................... 56 
11.3.2. 
Hypoglycaemia and hyperglycaemia ...................................................................... 57 
11.3.3. 
Blood sampling ....................................................................................................... 57 
11.3.4. 
12-lead electrocardiogram ...................................................................................... 57 
11.3.5. 
Finger-prick blood glucose measurements ............................................................. 58 
11.3.6. 
Insulin pump therapy .............................................................................................. 58 
11.3.7. 
Continuous glucose monitoring .............................................................................. 58 
11.3.8. 
Holter monitor ......................................................................................................... 58 
11.3.9. 
Actiwatch ................................................................................................................ 59 
11.3.10. 
Human factor assessment .................................................................................... 59 
11.3.11. 
Burdens ................................................................................................................ 59 
11.3.12. 
Risk analysis and residual risk associated with the investigational device ........... 59 
11.4. BENEFITS ............................................................................................................................. 60 
11.5. DATA AND SAFETY MONITORING BOARD ........................................................................ 60 
12. METHODS AND ASSESSMENTS .................................................................................. 60 
12.1. PROCEDURES ..................................................................................................................... 60 
12.1.1. 
Height and weight .................................................................................................. 60 
12.1.2. 
Continuous subcutaneous glucose monitoring ....................................................... 61 
12.1.3. 
Insulin pump data ................................................................................................... 61 
12.1.4. 
12-lead electrocardiogram ...................................................................................... 61 
12.1.5. 
Holter monitor ......................................................................................................... 61 
12.2. SURVEYS AND FOCUS GROUPS ....................................................................................... 61 
12.3. LABORATORY METHODS ................................................................................................... 62 
12.3.1. 
Screening sample .................................................................................................. 62 
12.3.2. 
C-peptide and glucose ........................................................................................... 62 
12.3.3. 
HbA1c .................................................................................................................... 62 
12.4. TOTAL BLOOD LOSS ........................................................................................................... 63 
13. STUDY MATERIALS ....................................................................................................... 63 
13.1. INSULIN ................................................................................................................................ 63 
13.2. INSULIN PUMP ..................................................................................................................... 63 
13.3. CONTINUOUS SUBCUTANEOUS GLUCOSE MONITOR ................................................... 63 
13.4. BLOOD GLUCOSE METER .................................................................................................. 63 
13.5. COMPUTER-BASED ALGORITHM ...................................................................................... 63 
13.6. ACTIWATCH ......................................................................................................................... 64 
13.7. HOLTER MONITOR .............................................................................................................. 64 

 
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14. DATA ANALYSIS ............................................................................................................ 64 
14.1. PRIMARY ANALYSIS ............................................................................................................ 64 
14.2. SECONDARY ANALYSIS ..................................................................................................... 64 
14.2.1. 
Biochemical evaluation ........................................................................................... 64 
14.2.2. 
Analysis of Human Factors Data ............................................................................ 65 
14.2.3. 
Cardiac Arrhythmia Analysis .................................................................................. 65 
14.2.4. 
Quality of Sleep Assessment using Actiwatch ........................................................ 65 
14.3. EXPLORATORY ANALYSIS ................................................................................................. 66 
14.4. INTERIM ANALYSIS ............................................................................................................. 66 
14.5. STATISTICAL METHODS ..................................................................................................... 66 
14.6. SAMPLE SIZE AND POWER CALCULATIONS .................................................................... 67 
14.7. DEVIATIONS FROM THE STATISTICAL PLAN ................................................................... 68 
15. CASE REPORT FORMS ................................................................................................. 68 
16. DATA MANAGEMENT .................................................................................................... 68 
17. STUDY MANAGEMENT .................................................................................................. 69 
17.1. DATA AND SAFETY MONITORING BOARD ........................................................................ 69 
17.2. STUDY MANAGEMENT COMMITTEE ................................................................................. 69 
17.3. STUDY MONITORING .......................................................................................................... 69 
18. RESPONSIBILITIES ........................................................................................................ 70 
18.1. CHIEF INVESTIGATOR ........................................................................................................ 70 
18.2. PRINCIPAL CLINICAL INVESTIGATORS ............................................................................ 70 
18.3. STUDY COORDINATOR ...................................................................................................... 70 
19. ETHICS ............................................................................................................................ 70 
19.1. INDEPENDENT RESEARCH ETHICS COMMITTEES ......................................................... 70 
19.2. INFORMED CONSENT OF STUDY SUBJECTS .................................................................. 70 
20. TIMETABLE ..................................................................................................................... 71 
21. AMENDMENTS TO THE PROTOCOL ............................................................................ 71 
22. DEVIATIONS FROM PROTOCOL .................................................................................. 71 
23. REPORTS AND PUBLICATIONS ................................................................................... 72 
24. RETENTION OF STUDY DOCUMENTATION ................................................................ 72 
25. INDEMNITY STATEMENTS ............................................................................................ 72 
26. REFERENCES ................................................................................................................. 73 
 
 
 
 
 
 
 
 
 
 

 
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1. List of Abbreviations and Relevant Definitions  
ADA 
American Diabetes Association 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AP 
Artificial Pancreas 
AR 
Adverse Reaction 
ASADE Anticipated Serious Adverse Device Effect 
AUC 
Area Under the Curve 
CE 
Conformité Européenne (CE-mark) 
CGM 
Continuous Glucose Monitoring 
CRF 
Case Report Form 
CSII 
Continuous subcutaneous insulin infusion 
DSMB  
Data and Safety Monitoring Board  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
IDE 
US Investigational Device Exemption 
ISPAD 
International Society for Pediatric and Adolescent Diabetes 
i.v. 
Intravenous 
MHRA 
Medicine and Healthcare products Regulatory Agency 
MPC 
Model-Predictive-Control 
NGP 
Next generation insulin pump (Medtronic) 
PSQI 
Pittsburgh Sleep Quality Index 
R & D 
Research and Development 
RCT 
Randomised Control Trial 
REC  
Research Ethics Committee 
s.c. 
Subcutaneous 
SADE 
Serious Adverse Device Effect  
SAE 
Serious Adverse Event  
SAP 
Sensor Augmented Pump Therapy 
SMBG 
Self-Monitoring of Blood Glucose 
T1D 
Type 1 Diabetes Mellitus 
USADE Unanticipated Serious Adverse Device Effect 
WHO 
World Health Organization 
 
 
 
 

 
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2. Study Synopsis 
Title of clinical trial 
An open-label, multi-centre, randomised, two-
period, crossover study to assess the efficacy, 
safety and utility of 16 week day and night 
automated closed-loop glucose control under free 
living conditions compared to sensor augmented 
insulin pump therapy in older adults with type 1 
diabetes 
Short Title 
24/7 closed-loop in older subjects with type 1 diabetes  
Sponsor name 
UK - University of Cambridge and Cambridge 
University Hospitals NHS Foundation Trust, UK 
 
Medical condition or disease 
under investigation 
Type 1 diabetes 
Purpose of clinical trial 
To determine whether day and night automated 
closed-loop glucose control for 16 weeks under free 
living conditions is superior to sensor augmented 
insulin pump therapy in older subjects with type 1 
diabetes  
 
Study objectives 
The study objective is to compare day and night 
automated closed-loop glucose control with sensor 
augmented insulin pump therapy under free living 
conditions. 
1. EFFICACY: The objective is to assess the efficacy 
of day and night automated closed-loop glucose 
control in maintaining CGM glucose levels within the 
target range from 3.9 to 10.0 mmol/l (70 to 180mg/dl), 
as compared to sensor augmented insulin pump 
therapy.  
2. SAFETY: The objective is to evaluate the safety of 
day and night automated closed-loop glucose control 
in terms of episodes of severe hypoglycaemia, 
hyperglycaemia, and other adverse events and 
adverse device effects. 
3. UTILITY: The objective is to determine the 
percentage of time when closed-loop was operational, 
and usability and acceptance of the closed-loop 
system.  
 
4. HUMAN FACTORS: Cognitive, emotional, sleep 
quality, 
and 
behavioural 
characteristics 
of 
participating subjects and their response to the 
closed-loop system and clinical trial will be assessed 
using validated surveys, focus groups, and Actiwatch. 
 
5. CARDIAC RHYTHM: The objective is to evaluate 
cardiac arrhythmic events with concordant CGM 

 
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glucose values during closed-loop system use and 
sensor augmented insulin pump therapy. 
 
Study Design  
An open-label, multi-centre, randomised, two-period 
crossover study, contrasting day and night automated 
closed-loop glucose control, with sensor augmented 
insulin pump therapy.  
Primary Endpoint 
 
Time spent in the target glucose range (3.9 to 
10mmol/l) (70 to 180mg/dl) 
 
Secondary Endpoints 
Key secondary endpoints: 
 
Time spent above target glucose (10.0mmol/l; 
180mg/dl) 
 
Mean of glucose levels 
 
HbA1c at 16 weeks 
 
Time spent below target glucose (3.9mmol/l; 
70mg/dl) 
Secondary efficacy endpoints: 
 
standard deviation and coefficient of variation of 
glucose levels  
 
Time with glucose levels <3.5 mmol/l  (63 mg/dl) 
and <3.0 mmol/l (54mg/dl)  
 
Time with glucose levels in significant 
hyperglycaemia (glucose levels >16.7 mmol/l) 
(300mg/dl) 
 
Total, basal and bolus insulin dose  
Secondary endpoints will be based on sensor 
glucose data. 
Exploratory endpoint(s) 
Day (06:00 to 23:59) vs. night (00:00 to 05:59) 
glucose control. 
Safety Evaluation 
Frequency of severe hypoglycaemic episodes as 
defined by American Diabetes Association, frequency 
of severe hyperglycaemia (>16.7 mmol/l) (>300mg/dl) 
with significant ketosis (plasma ketones >0.6mmol/l) 
and nature and severity of other adverse events. 
 
Utility Evaluation 
Assessment of the frequency and duration of use of 
the closed-loop system.  
Psychosocial evaluation 
Evaluation of participants’ perception in terms of 
cognitive, emotional, and behavioural characteristics 
and responses of participants to closed-loop system 
use. 
Sample Size 
36 adults randomised. Up to 42 subjects will be 
recruited to allow for dropouts.  
Summary of eligibility criteria 
Key inclusion criteria: 
1. 
Age 60 years and above 
2. 
Type 1 diabetes as defined by WHO for at least 
1 year or is confirmed C-peptide negative 
3. 
On insulin pump for at least 3 months, with good 
knowledge of insulin self-adjustment  
4. 
Treated with one of the U-100 rapid acting insulin 
analogues only (insulin Aspart, Lispro, Faster 
Insulin Aspart, but not Glulisine) 
5. 
Willing to perform regular capillary blood glucose 
monitoring 
6. 
HbA1c ≤ 10 % (86mmol/mol)  

 
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7. 
Willingness to wear study devices  
8. 
Literate in English 
9. 
Having a care partner who is aware of the 
subject’s location and is trained to administer 
intramuscular glucagon and able to seek 
emergency assistance 
 
Key exclusion criteria: 
 
1. 
Non-type 1 diabetes mellitus including those 
secondary to chronic disease 
2. 
Use of a closed-loop system within the last 30 
days 
3. 
Any other physical or psychological disease 
likely to interfere with the normal conduct of the 
study and interpretation of the study results as 
judged by the investigator 
4. 
Commencement of any glucose-lowering agent 
(such as Pramlintide, Metformin, GLP-1 analogs) 
in the 3 months prior to enrolment or any use of 
SGLT2 inhibitors 
5. 
Untreated coeliac disease, adrenal insufficiency 
or hypothyroidism 
6. 
Known or suspected allergy to insulin 
7. 
More than one episode of severe 
hypoglycaemia within the last 6 months 
8. 
Random C-peptide >200pmol/l with concomitant 
plasma glucose >4 mmol/l (72 mg/dl) 
9. 
Lack of reliable telephone facility for contact 
10. Total daily insulin dose ≥ 2 IU/kg/day or < 15 
IU/day 
 
Maximum duration of study 
for a subject 
44 weeks (11 months) 
Recruitment 
The subjects will be recruited through the adult 
diabetes outpatient clinics or other established 
methods at participating centres.  
 
Consent 
Participants will be asked to provide written informed 
consent. 
 
Baseline Assessment 
Eligible subjects will undergo a baseline evaluation 
including a 12-lead electrocardiogram and blood 
sample for the measurement of HbA1c, random C-
peptide, glucose, renal, liver functions, full blood 
count, thyroid functions and coeliac antibody screen 
(if not done in the previous 3 months). Additional 
centre specific assessments will also be undertaken. 
Human factors assessment to understand 
expectations, attitudes, and behaviours that 
influence the uptake and response to using a closed-
loop system will be undertaken at baseline.  
 
Study Training 
Training sessions on the use of study CGM, insulin 
pump (and closed-loop system for those randomised 
to the intervention group) will be provided by the 

 
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research team (face to face or remotely). Training 
session on the use of real-time CGM and on how to 
interpret real-time and retrospective stored data will 
be provided to all subjects/carers using written 
material.  
Run-in Period 
During a 4-6 week run-in period, subjects will use 
study CGM and insulin pump. Subjects will be able to 
contact the research team for support as necessary. 
For compliance and to assess the ability of the subject 
to use the CGM and study pump safely, at least 10 
days of CGM data need to be recorded during the last 
14 days, and safe use of study insulin pump 
demonstrated during the last 14 days of run-in period.  
 
Competency Assessment 
Competency on the use of study insulin pump, study 
CGM and closed-loop system will be evaluated using 
a competency assessment tool developed by the 
research team. Further training may be delivered as 
required. 
 
Randomisation 
Eligible 
subjects 
will 
be 
randomised 
using 
randomisation software to the use of automated 
closed-loop glucose control or to sensor augmented 
insulin pump therapy, with a 4-week washout period 
in between the two interventions. 
 
1.  Automated day and night 
closed-loop insulin delivery 
(interventional period) 
 
 
 
Subjects will be admitted to the Clinical Research 
Facility or clinical area at the agreed time. This can be 
done 
remotely 
if 
required. 
A 
blood 
sample 
(capillary/venous) will be taken for the measurement 
of HbA1c. Training on the use of closed-loop will be 
provided by the research team (face to face or 
remotely). Competency on the use of closed-loop 
system will be evaluated.  Subjects will be advised to 
use automated closed-loop system for the next 16 
weeks. 
Cross-over Assessment 
At the end of the first intervention, a blood sample 
(capillary/venous) for the measurement of HbA1c will 
be taken. Human factor assessment and acceptance 
of the system will be assessed using a validated 
survey. Other questionnaires to assess quality of life 
change, daily diabetes management and fear of 
hypoglycaemia will also be recorded. 
 
Wash-out period 
At the end of the first intervention, subjects will 
undergo a wash-out period of 4 weeks, during which 
they will continue to wear the study insulin pump and 
their standard pump settings will be applied.  
 
2. Sensor augmented insulin 
pump therapy  
(control period) 
Subjects will be admitted to the Clinical Research 
Facility or clinical area at the agreed time. This can be 
done 
remotely 
if 
required. 
A 
blood 
sample 
(capillary/venous) will be taken for the measurement 
of HbA1c. Subjects will use sensor augmented insulin 
pump therapy for 16 weeks. 

 
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End of study assessments 
A blood sample (capillary/venous) will be taken for 
measurement of HbA1c. Human factor assessment 
will be performed to understand expectations, 
attitudes, and behaviours that influence the uptake 
and response to using a closed-loop system. The 
human factor assessments include both quantitative 
and qualitative methods which have been tested in 
adults in the targeted age range. 
Actiwatch application at 2-
month  of each study period  
Subjects will wear an Actiwatch for 7 days for 
objective sleep quality assessment. 
Holter 
monitor 
application 
during the last month of each 
study period 
Subjects will wear a Holter monitor for 5-7 days for 
retrospective analysis of cardiac rhythm during each 
study period. Holter monitor data will be analysed at 
the end of the study. Any incidental finding will be 
referred by the Investigator to the clinical team and be 
managed as per local site policy. 
 
Procedures for safety 
monitoring during trial 
Standard operating procedures for monitoring and 
reporting of all adverse events and adverse device 
events will be in place, including serious adverse 
events (SAE), serious adverse device effects (SADE) 
and specific adverse events (AE) such as severe 
hypoglycaemia.  
 
A Data Safety and Monitoring Board (DSMB) will be 
informed of all serious adverse events and any 
unanticipated adverse device/method effects that 
occur during the study and will review compiled 
adverse event data at periodic intervals. 
 
Criteria for withdrawal of 
patients on safety grounds 
A subject may terminate participation in the study at 
any time without necessarily giving a reason and 
without any personal disadvantage. An investigator 
can stop the participation of a subject after 
consideration of the benefit/risk ratio. Possible 
reasons are: 
 
Serious adverse events 
 
Significant protocol violation or non-
compliance 
 
Failure to satisfy competency assessment 
 
Decision by the investigator, or the sponsor, 
that termination is in the subject’s best 
medical interest 
 
Allergic reaction to insulin  
 
Technical grounds (e.g. subject relocates) 
 
 
 

 
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3. Summary 
The main objective of this study is to determine whether automated day and night 
closed-loop insulin delivery for 16 weeks under free living conditions is safer and more 
efficacious compared to sensor augmented insulin pump therapy in older adults with 
type 1 diabetes.  
 
This is an open-label, multi-centre, randomised, crossover design study, involving a 4-
6 week run-in period, followed by two 4 month study periods during which glucose 
levels will be controlled either by an automated closed-loop system or by sensor-
augmented pump therapy in random order. A total of up to 42 adults (aiming for 36 
completed subjects) aged 60 years and older with T1D on insulin pump therapy will 
be recruited through diabetes clinics and other established methods in participating 
centres. Subjects who drop out of the study within the first 6 weeks of the first 
intervention period will be replaced.   
 
Subjects will receive appropriate training (face to face or remotely) in the safe use of 
closed-loop insulin delivery system. Subjects will have regular contact with the study 
team during the home study phase including 24/7 telephone support.  
 
The primary outcome is time spent in target range between 3.9 and 10.0 mmol/L (70 
and 180mg/dl) as recorded by CGM. Secondary outcomes are the HbA1c, time spent 
with glucose levels above and below target, as recorded by CGM, and other CGM-
based metrics. Measures of human factor assessment, cardiac arrhythmia and 
objective sleep quality assessment will also be evaluated in this study. 
 
 
 
 
 
 
 
 
 
 
 

 
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4. Background  
Type 1 diabetes mellitus (T1D) is characterised by an absolute deficiency of insulin 
caused by immunologically-mediated damage to the beta cells in the pancreas and 
raised blood glucose levels. It is one of the commonest endocrine and metabolic 
conditions in both children and adults. It is estimated that approximately 285 million 
adults (5-15% type 1 diabetes) and 480,000 children (95% type 1 diabetes) worldwide 
suffer from diabetes (1). Recent reports suggest that incidence and prevalence of T1D 
is increasing in many countries, at least in the under 15 year age group with the 
predicted number of new cases of childhood diabetes in Europe increasing to 24,400 
in 2020 from 15,000 in 2005 (2; 3). The number of older people living with T1D is also 
increasing due to increasing life expectancy (4). This population faces unique 
challenges related to diabetes self-management due to long disease duration and 
burden of other co-morbidities compared to the younger age group (5). Hypoglycaemia 
(too low blood sugar) unawareness is common in the older T1D population (6) and is 
a recognized risk factor for severe hypoglycaemia (7; 8), predisposing to cardiac 
arrhythmias and cardiovascular mortality (9; 10).  
 
Until the introduction of insulin replacement therapy in early 1920s T1D was a 
uniformly fatal condition. While significant advancements have been made in insulin 
therapy since, major limitations still exist, hypoglycaemia (low blood glucose) being 
the most significant. Despite the availability of therapeutic options such as self-
monitoring of blood glucose, structured patient education, rapid-acting insulin 
analogues and insulin pump therapy, glycaemic control in the majority of patients with 
type 1 diabetes remains suboptimal and they are prone to get complications 
associated with poor control such as kidney failure and blindness. Risk of these 
complications can be reduced by intensive insulin therapy(11) but for most patients 
this is associated with hypoglycaemia limiting the intensification of treatment (12; 13).  
 
Recommended treatment goals specific for various age groups of people with T1D 
have been published (14), but achieving it in clinical practice is still challenging due to 
hypoglycaemia risk associated with insulin therapy (15). This is pertinent in the older 
patient group, due to multiple burden of co-morbidities. The average patient with T1D 
suffers two symptomatic episodes of hypoglycaemia per week, and one episode of 
severe hypoglycaemia, defined as an event requiring assistance of another person to 
administer rescue treatment in the form of carbohydrate and/or glucagon, per year 
(16). Even in patients with good control, as judged by average HbA1c, significant 

 
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glucose excursions occur with periods of silent hyper- and hypoglycaemia (17; 18). 
Further older patients with T1D have impaired defence mechanisms (counter-
regulatory responses) to low glucose, thus impairing recovery and increasing the 
threat of future episodes (19). In addition to the physical morbidity, hypoglycaemia also 
has significant psychological consequences, including fear of future episodes with 
resulting maladaptive coping behaviours such as excessive eating or under-
insulinising that may negatively impact glycaemic control (20). 
 
Despite the rapid advancements in insulin pump technology and the ongoing 
development of more physiological insulin preparations, the currently available 
therapeutic regimens are still unable to achieve optimal glycaemic control. The 
emergence of continuous glucose monitoring (CGM) over the last decade, which 
enables users to view real-time interstitial glucose readings and receive alarms for 
impending hypo- or hyperglycaemia, thus facilitating appropriate changes in insulin 
therapy, is a major step towards improved diabetes monitoring. Several recent studies 
have shown a clinical benefit of CGM on reduction in HbA1c in those patients that are 
compliant with using the device.(21-24).    
4.1. Sensor-Augmented Insulin Pump Therapy  
Sensor-augmented pumps (SAP) combine real-time CGM with insulin pump therapy. 
In the first major study (485 patients, 329 adults and 156 children) comparing SAP with 
MDI, SAP treatment showed superior HbA1c reduction (at 1 year, from 8.3% to 7.5% 
in SAP vs. from 8.3% to 8.1% in MDI group, between-group difference in the SAP 
group of -0.6% (95% CI, -0.7 to -0.4; P < 0.001), but showed no difference in 
hypoglycaemia or severe hypoglycaemia rates between groups (25). Patients with 
more than one severe hypoglycaemic event in the preceding year were excluded from 
this study. A smaller multi-centre study in Europe (86 patients) has also shown 
improvements in HbA1c with SAPs (mean difference in change in HbA1c after 26 
weeks was -1.21% (95% CI -1.52 to -0.90, P < 0.001), but there was no difference in 
biochemical or severe hypoglycaemia between groups (26). 
4.2.  Closed-Loop Insulin Delivery  
The development of a closed-loop system that combines glucose monitoring with 
computer-based algorithm informed insulin delivery may provide further improvements 
in glycaemic control while reducing hypoglycaemia and ultimately represent a realistic 
treatment option for people with type 1 diabetes. The vital component of such a 
system, also known as an artificial pancreas (AP), is a computer-based algorithm. The 
role of the control algorithm is to translate, in real-time, the information it receives from 

 
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the CGM and to compute the amount of insulin to be delivered by the pump. The other 
components include a real-time continuous glucose monitor and an infusion pump to 
titrate and deliver insulin (27). 
4.3.  Threshold Based Pump Interruption  
Automatic suspension of insulin delivery by the pump when a predefined glucose level 
is reached represents the simplest form of closed-loop insulin delivery. Such a system 
(Veo (non-US) or Medtronic 530G (US) insulin pump coupled with Minilink sensor, 
Medtronic Minimed, Northridge, CA, USA) which stops insulin delivery for up to 2 hours 
is currently commercially available. This approach aims to reduce the severity of 
hypoglycaemia. Since insulin is not delivered in an automated fashion there is no risk 
of system-induced hypoglycaemia. In an in-clinic study, following a period of exercise, 
the threshold based pump interruption feature has been shown to reduce the duration 
of hypoglycaemia (28). Two relatively small out-patient studies of short duration (21 
children for 6 weeks (29) and 31 adults (30) for 3 weeks) have also shown that 
threshold based pump interruption may reduce the time spent in hypoglycaemia 
without leading to rebound hyperglycaemia or ketosis. A recent large RCT (247 
patients with type 1 diabetes; age range 16 to 70 years; threshold based pump 
interruption group, 121 patients), has confirmed these findings with a 37% lower mean 
area under the curve (AUC) for nocturnal hypoglycaemic events in the threshold based 
pump interruption group than in the control group (54.4 ± 66.6 vs. 87.0 ± 110.7 mmol/l 
× minutes, P < 0.001) without any rise in HbA1c after 3 months (31).  
4.4.  Preclinical Testing of Cambridge Closed-loop Algorithm 
The research we are conducting at the University of Cambridge has been focused on 
developing a closed-loop system for overnight glucose control in patients with T1D. 
The studies that have been performed so far employ model predictive control (MPC) 
– this algorithm estimates patient-specific parameters from CGM measurements taken 
every 1 to 15 minutes and makes predictions of glucose excursions, which are then 
used to calculate basal insulin infusion rates (32).  
 
The closed-loop model predictive control (MPC) algorithm has been studied 
extensively using in silico testing utilising a simulator developed by members of the 
study team (33). The simulations suggested a reduced risk of nocturnal 
hypoglycaemia and hyperglycaemia with the use of the MPC algorithm (34). 
4.5.  Studies of Closed-Loop in Children and Adolescents 
with Type 1 Diabetes in the Clinical Research Facility 

 
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To date around sixty children and adolescents with type 1 diabetes have been studied 
at the clinical research facility. Closed-loop insulin delivery was maintained on more 
than 100 nights. No episodes of significant hypoglycaemia (plasma glucose 
concentration less than 2.8 mmol/l) have been observed thus far during closed-loop 
blood glucose control. Results from these studies were published in The Lancet (35) 
and showed that overnight closed-loop therapy increased the time spent euglycaemic 
by 37% and reduced the risk of overnight hypoglycaemia eight-fold, as compared to 
conventional pump treatment. Different real-life scenarios predisposing to nocturnal 
hypoglycaemia, such as afternoon exercise, were explored and closed-loop therapy 
reduced the risk of overnight hypoglycaemia as compared to conventional insulin 
pump therapy in a randomised, cross-over design.   
4.6.  Studies of Closed-Loop in Adults with Type 1 Diabetes in 
the Clinical Research Facility 
We have completed two randomised overnight closed-loop studies in 24 adults with 
T1D, testing a similar closed-loop system comprising “off the shelf” CGM and pump 
devices and a MPC algorithm.  The first study (n=12) assessed the feasibility and 
efficacy of overnight closed-loop insulin delivery following a moderate-sized (60g 
carbohydrate) evening meal compared with conventional pump therapy.  We 
demonstrated that overnight closed-loop insulin delivery, compared with usual CSII, 
significantly increased time in target plasma glucose range (3.9-8 mmol/l) by 24% and 
reduced glycaemic variability as measured by standard deviation of plasma glucose.  
The improvements in glucose control seen on closed-loop were even greater after 
midnight, when time in target increased by 41%.  In the second study we tested the 
efficacy of overnight closed-loop following a common situation such as consuming a 
large (100g carbohydrate) evening meal and drinking alcohol (0.75g ethanol/kg body 
weight of 13%abv white wine).  We showed that overnight closed-loop insulin delivery, 
compared with conventional CSII, similarly increased time in target plasma glucose 
between 3.9 and 8.0 mmol/l by 24% and reduced time spent above target by 11%, 
even following such challenges. Importantly these improvements during closed-loop 
were achieved with no increased requirement in the average rate of insulin infusion 
overnight. These results have been published in the British Medical Journal (36).     
4.7.  Overnight 
Closed-Loop 
study 
in 
Children 
and 
Adolescents with Type 1 Diabetes in Home Setting 
Following successful demonstration of safety and efficacy of closed-loop insulin 
delivery in the research facility, overnight closed-loop studies under free living 
conditions were commenced in July 2012. The first study compared the efficacy and 

 
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safety of closed-loop with sensor augmented pump therapy in 16 adolescents (37). 
Closed-loop was activated over at least 4 hours on 269 nights (80%); sensor data were 
collected over at least 4 hours on 282 control nights (84%). Closed-loop increased the 
time when glucose was in target range by a median 15% (interquartile range −9 to 
+43), P<0.001. Mean overnight glucose was reduced by a mean 0.8±3.2mmol/l, 
P<0.001. Time when glucose was below 3.9mmol/l was low in both groups but nights 
with glucose below 3.5mmol/l for at least 20min were less frequent during closed-loop 
(10% vs. 17%, P=0.01). Despite lower total daily insulin doses by a median 2.3 
(interquartile range -4.7 to +9.3) units, P=0.009, overall 24h glucose was reduced by 
a mean 0.5 (standard deviation 2.3)mmol/l (P=0.006) during closed-loop. 
4.8.  Overnight Closed-Loop Study in Adults with Type 1 
Diabetes in Home Setting 
We completed a four week overnight closed-loop study under free living conditions in 
24 adults with type 1 diabetes on insulin pump therapy in a multicentre crossover study 
design (38). Closed-loop was utilised over median 8.3 (interquartile range 6.0, 9.6) 
hours on 555 nights (86%). The proportion of time when overnight glucose was in 
target range between 3.9 and 8.0mmol/l from midnight to 07:00 was significantly higher 
during closed-loop compared to sensor augmented pump therapy (52.6%±10.6 vs. 
39.1%±12.8, 
mean±SD; 
p<0.001). 
Mean 
overnight 
glucose 
(8.2±0.9 
vs. 
9.0±1.3mmol/l, p=0.005) and time spent above target (44.3%±11.9 vs. 57.1%±15.6, 
p=0.001) were significantly lower during closed-loop. Time spent below target was low 
and comparable between interventions [1.8%( 0.6, 3.6) vs. 2.1%(0.7, 3.9), p=0.28].  
 
A multicentre crossover RCT comparing 12 week overnight closed-loop with 12 week 
sensor augmented pump therapy in 24 children and adolescents aged 6 to 18 years 
has been completed recently; data analysis is underway.  
4.9.  Day and Night Closed-Loop Studies in Adults with Type 
1 Diabetes in Home Setting 
We completed a seven day, day and night home study in 17 suboptimally controlled 
(HbA1c>7.5%) adults with type 1 diabetes in a multicentre, multi-national crossover 
study design (39). During the home phase, the percentage time when glucose was in 
target range was significantly higher during closed-loop compared to sensor 
augmented pump therapy (75 [61, 79] vs. 62 [53, 70]%, median [IQR], p=0.005). Mean 
glucose (8.1 vs. 8.8 mmol/l, p=0.027) and time spent above target (p=0.013) were 
lower during closed-loop while time spent below target was comparable (p=0.339). 

 
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Increased time in target was observed during both day-time (p=0.017) and night-time 
(p=0.013). A two centre multinational crossover study comparing day and night closed-
loop with usual pump therapy during free-living settings was completed in 29 adults 
with well-controlled (HbA1c<7.5%) type 1 diabetes (40). The proportion of time when 
sensor glucose concentration was in target range was significantly increased during 
closed-loop delivery compared with usual pump therapy (65·6±8.1 vs 76·2±6·4%, 
p<0.0001). Compared with usual pump therapy, closed-loop delivery also reduced the 
proportion of time spent in hypoglycaemia: the proportion of time with glucose 
concentration below 3·5 mmol/L was reduced by 65% (53 to 74, p<0·0001) and below 
2·8 mmol/L by 76% (59 to 86, p<0·0001). No episodes of serious hypoglycaemia or 
other serious adverse events occurred. 
 
We completed a 12-week day and night multicentre, multi-national crossover design 
home study in 33 adults with T1D (18 male, age 40.0±9.4years, duration of diabetes 
20.9±9.3years)(41). The proportion of time when sensor glucose was in target range 
between 3.9 and 10.0mmol/l was significantly increased during closed-loop compared 
to sensor augmented pump therapy (67.7±10.6 vs. 56.8±14.2%, p<0.001). Mean 
glucose (8.7 vs. 9.3 mmol/l, p<0.001) and time spent above (p<0.001) and below target 
range (p=0.02) were significantly reduced during closed-loop. Hypoglycaemia 
exposure measured by AUC <3.5 mmol/l was reduced during closed-loop (p<0.001). 
Reduction in mean glucose and time spent above target range during closed-loop was 
brought about without changing the total daily insulin delivery (p=0.57). 
 
4.10. Automated Closed-Loop System (CamAPS FX) to be used 
in the Present Study  
The automated closed-loop system (CamAPS FX) will consist of: 
 
Dexcom G6 (Dexcom, San Diego, CA, USA) or similar Continuous Glucose 
Monitoring (CGM) System  
 
Dana R Diabecare (Sooil Corp. Seoul, South Korea) or similar subcutaneous 
insulin infusion pump 
 
An Android smartphone hosting CamAPS FX Application with the Cambridge 
model predictive control algorithm and communicating wirelessly with the 
insulin pump  
 
An overview of this proposed automated closed-loop system is given in Figure 1. 
 

 
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Figure 1. CamAPS FX comprises Samsung Galaxy phone (or similar) running 
Cambridge control algorithm, Dana insulin pump (Sooil), G6 real-time CGM sensor 
(Dexcom).      
                                      
 
 
4.11. Rationale for the Current Study 
No study thus far has specifically evaluated use of closed-loop insulin delivery in older 
adults with type 1 diabetes. The current study will provide further evidence on the effect 
of consecutive closed-loop day and nights over 4 months in a group of older subjects 
with type 1 diabetes in a multicentre and multi-national setting to demonstrate the 
generalisability of results.  
5. Objectives 
5.1. Efficacy  
To assess efficacy of day and night automated closed-loop glucose control in 
maintaining glucose levels within the target range from 3.9 to 10.0 mmol/l based on 
subcutaneous continuous glucose monitoring (CGM) as compared to sensor 
augmented insulin pump therapy alone.  

 
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5.2. Safety 
To evaluate the safety of automated closed-loop glucose control in terms of episodes 
and severity of hypoglycaemia and nature and severity of other adverse events. 
5.3. Utility   
To determine the percentage of time when closed-loop was operational.  
5.4. Human Factors 
To evaluate the expectations, attitudes and behaviours that influence the uptake and 
response to using a closed-loop system, and sleep quality. 
5.5. Cardiac Rhythm 
To evaluate cardiac arrhythmic events with concordant CGM sensor glucose values 
during closed-loop system use and sensor-augmented pump therapy. 
 
 

 
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6. Study Design 
An open-label, multi-centre randomised, two-period crossover study comparing day 
and night automated closed-loop glucose control with sensor-augmented pump 
therapy.  
 
It is expected that up to 42 older subjects with type 1 diabetes with T1D will be 
recruited, aiming for 36 randomised subjects. Subjects who drop out within the first six 
weeks of the intervention may be replaced.  The study flow chart is outlined in Figure 
2.  
. 
7. Study Subjects 
7.1. Study population 
This is a multicentre and multinational study and recruitment will take place at the 
following centres: 
1. Addenbrooke’s Hospital, Cambridge, UK 
2. Manchester Royal Infirmary, Manchester, UK 
3. Queen Elizabeth Hospital, Birmingham, UK 
4. Medical University of Graz, Graz, Austria 
 
Adults aged 60 years or over with type 1 diabetes on insulin pump therapy will be 
recruited. The study will aim for 36 completed subjects. Recruitment will target up to 
42 subjects (8 - 20 subjects per centre) to allow for drop-outs. Methods of patient 
recruitment will follow well established practice at each centre. 
 
Potential participants will be identified by their treating clinicians and invited to contact 
the research team. They will be sent the study information leaflets and an invitation to 
join the study by the research team at least one day before the recruitment visit. 
 
 
 
 
 

 
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Figure 2. Study flow chart. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training Session(s): Study pump and CGM 
Competency Assessment 
Baseline Blood Sample(s), ECG and Human Factor 
Assessment 
4 months Day-and-Night Closed-loop (CL) 
 
CL training & competency assessment at 
clinical facility 
 
Actiwatch at 2 month 
 
Holter monitor at 4 month  
4 months Sensor-Augmented Pump (Control) 
 
Pump & CGM  refresher training at clinical 
facility 
 
Actiwatch at 2 month 
 
Holter monitor at 4 month 
 
 
HbA1c 
 
Human factor assessment  
4 Weeks WASHOUT 
Randomisation 
Recruitment & Consent 
 HbA1c 
End of the study 
 
Human factor assessment 
 
Subjects resume normal care 
 
CGM, Holter monitor and Actiwatch data analysis 
 HbA1c 
 HbA1c 
4-6 weeks CGM & study pump run-in 
Compliance assessment 
4 months Sensor-Augmented Pump (Control) 
 
Pump & CGM  refresher training at clinical 
facility 
 
Actiwatch at 2 month 
 
Holter monitor at 4 month 
 
4 months Day-and-Night Closed-loop (CL) 
 
CL training & competency assessment at 
clinical facility 
 
Actiwatch at 2 month 
 
Holter monitor at 4 month 

 
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7.1.1. Inclusion criteria 
1. Age 60 years and above  
2. Type 1 diabetes as defined by WHO for at least 1 year or is confirmed C-
peptide negative 
3. On insulin pump for at least 3 months with good knowledge of insulin self-
adjustment  
4. Treated with one of the U-100 rapid acting insulin analogues only (insulin 
Aspart, Lispro, Faster insulin Aspart but not Glulisine) 
5. Willing to perform regular capillary blood glucose monitoring 
6. HbA1c ≤ 10% (86 mmol/mmol) based on analysis from central laboratory or 
equivalent  
7. Literate in English 
8. Having a care partner who is aware of the subject’s location and is trained to 
administer intramuscular glucagon and able to seek emergency assistance 
9. Willing to wear closed-loop system at home and at work place 
10. Willing to follow study specific instructions 
11. Willing to upload pump and CGM data at regular intervals 
12. Has access to WiFi  
 
7.1.2. Exclusion criteria for all countries 
1. Non-type 1 diabetes mellitus 
2. Use of a closed-loop system within the last 30 days 
3. Any other physical or psychological disease or condition likely to interfere with 
the normal conduct of the study and interpretation of the study results  
4. Commencement of any glucose-lowering agent (such as Pramlintide, 
Metformin, GLP-1 analogs) in the 3 months prior to enrolment or any use of 
SGLT2 inhibitors 
5. Untreated coeliac disease, adrenal insufficiency or hypothyroidism 
6. Known or suspected allergy against insulin 
7. More than one episodes of severe hypoglycaemia as defined by American 
Diabetes Association (42) in preceding 6 months 
8. Random C-peptide > 200pmol/l with concomitant plasma glucose >4 mmol/l 
(72 mg/dl) 
9. Lack of reliable telephone facility for contact 
10. Total daily insulin dose  2 IU/kg/day 

 
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11. Total daily insulin dose < 15 IU/day 
12. Severe visual impairment  
13. Severe hearing impairment 
14. Medically documented allergy towards the adhesive (glue) of plasters or 
unable to tolerate tape adhesive in the area of sensor placement 
15. Serious skin diseases (e.g. psoriasis vulgaris, bacterial skin diseases) located 
at places of the body, which could potentially be used for localisation of the 
glucose sensor) 
16. Subject is currently abusing illicit drugs 
17. Subject is currently abusing prescription drugs 
18. Subject is currently abusing alcohol 
19. Subject has elective surgery planned that requires general anaesthesia during 
the course of the study 
20. Subject is a shift worker with working hours between 10pm and 8am 
21. Subject has a sickle cell disease, haemoglobinopathy; or has received red 
blood cell transfusion or erythropoietin within 3 months prior to time of 
screening  
22. Subject plans to receive red blood cell transfusion or erythropoietin over the 
course of study participation 
23. Subject diagnosed with current eating disorder such as anorexia or bulimia 
24. Subject plans to use significant quantity of herbal preparations (use of over the 
counter herbal preparation for 30 consecutive days or longer period during the 
study) or significant quantity of vitamin supplements (four times the 
recommended daily allowance used for 30 consecutive days or longer period 
during the study) known to affect glucose metabolism and/or blood glucose 
levels during the course of their participation in the study 
25. Subject not proficient in English (UK), or German (Austria) 
7.1.3. Additional exclusion criteria specific for Austria  
1. Positive results on urine drug screen (amphetamines/metamphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates).  
2. Positive alcohol breath test. 
3. Positive reaction to any of the following tests: hepatitis B surface (HBs) 
antigen, anti-hepatitis C virus (anti-HCV) antibodies, anti-human 
immunodeficiency virus (HIV) 1 antibodies, anti-HIV2 antibodies. 
 
 
 

 
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7.2. Randomisation 
The order of closed-loop or sensor-augmented pump therapy will be randomly 
allocated using block randomisation within a centrally administered randomisation 
programme. Randomisation will take place within 1 week before the start of first home 
study phase.    
 
8. Methods under Investigation 
8.1. Name and description of the method of investigation  
The investigational treatment is the CamAPS FX, see section 4.10, or follow up 
prototypes of the automated day and night closed-loop system manufactured by the 
Cambridge University Hospitals NHS Foundation Trust.  Component versions will be 
identified during regulatory submission to the MHRA and relevant authority in Austria. 
8.2. Intended purpose 
The intended purpose of the investigational treatment is automated day and night 
closed-loop insulin delivery.  
8.3. Method of administration 
The closed-loop system consists of components directly attached to the patient, which 
are the CGM transmitter and the insulin pump. The component not directly attached 
to the patient is the handheld smartphone containing closed-loop algorithm and 
communicating wirelessly with the insulin pump.  
8.4.  Required training 
Prior to commencement of the study, the research team nurses/clinicians at each of 
the investigation centres will be trained to use the closed-loop system and its 
components. Prior to the use of study devices, participants will be trained to use the 
study CGM device, the study pump and where appropriate the closed-loop system. 
This can be done face to face or remotely as required. Competency assessments of 
the participants’ capability to use study devices and the closed-loop system will be 
made.  
8.5. Precautions 
During treatment with insulin there is a risk of hypoglycaemia and hyperglycaemia. In-
hospital testing and Hazard Analysis both documented reduced risk of hypoglycaemia 

 
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and hyperglycaemia during day and night closed-loop compared to sensor-augmented 
pump treatment. 
8.6. Accountability of the method under investigation 
The local Investigator will provide training for the study participants and will make every 
effort, through regular contact, to ascertain that the closed-loop system is used for the 
study purposes only.  Devices will be identified using batch/lot/serial numbers and the 
location of investigational devices and their dates of use by subjects will be 
documented throughout the study. 
9. Study Schedule 
9.1. Overview  
The study will be coordinated from the Institute of Metabolic Science, University of 
Cambridge, and performed at the following sites 
 
1. Addenbrooke’s Hospital, Cambridge, UK 
2. Manchester Royal Infirmary, Manchester, UK 
3. Queen Elizabeth Hospital, Birmingham, UK 
4. Medical University of Graz, Graz, Austria 
 
The study will consist of up to 19 visits or pre-planned telephone/email contacts 
including two study periods (closed-loop vs. sensor-augmented pump therapy). The 
study periods will last 4 months each. The order of the two interventions will be in 
random order.  
 
The visit to set up automated closed-loop for the first time may take place in the study 
or clinical facility or can be done remotely.  All other visits can take place at the hospital 
clinic, home or other suitable meeting place or remotely, according to participants’ 
convenience. Two 16-week study periods will be performed within four weeks of each 
other. Maximum time in study is 12 months. 
 
Table 1 outlines study activities when CL intervention precedes sensor-augmented 
pump therapy. 
Table 2 outlines study activities when sensor-augmented pump therapy precedes CL 
intervention. 
 
 
 

 
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Table 1. Schedule of study visits when closed-loop intervention precedes sensor-
augmented pump therapy. 
 
 
Visit/ 
contact 
Description 
Start relative to 
previous / next 
Visit / Activity 
Duration 
 
*Visit 1 
Recruitment visit: Consent  
HbA1c, baseline bloods, 12-
lead ECG, human factor 
assessment 
- 
1-3 hours 
Study Pump & CGM 
Training /Run-In 
*Visit 2 
Insulin pump training and 
initiation of study pump 
Competency assessment 
Can be combined 
with Visit 1, or 
within 1 to 
3  weeks of Visit 
1  
3-4 hours 
*Visit 3 
CGM training 
Initiation of CGM 
Competency assessment 
Within  7 days of 
Visit 2. Can 
coincide with 
Visit 2 
1 hour 
 
*Visit 4 
Review pump and CGM 
data & compliance 
assessment & 
Randomisation 
After 3 - 4 weeks 
of Visit 3 
1-2 hours 
CL 
Intervention 
(4 months) 
*Visit 5 
CL initiation at CRC or 
remotely 
- CL training & competency 
assessment 
- HbA1c 
Can be combined 
with Visit 4, or 
within 2 week of 
Visit 4 
Up to 6 
hours 
* Visit 6 
Review use of study 
devices 
After 24-48 hours 
of Visit 5 
<1 hour 
*Visit 7 
Review use of study 
devices 
After 1 week of 
Visit 5 
<1 hour 
*Visit 8 
Review pump and CGM 
data 
After 1 week of 
Visit 7 
<1 hour 
*Visit 9 
End of first month;  
Review pump and CGM 
data.  
After 4 weeks of 
Visit 5 
<1 hour 
*Visit 10 
End of second month; 
Review pump and CGM 
data. Actiwatch sleep 
monitor 
After 4 weeks of 
Visit 9 
<1 hour 
*Visit 11 
End of third month;  
Review pump and CGM 
data.  
After 4 weeks of 
Visit 10 
<1 hour 
*Visit 12 
12-lead Holter monitor 
applied for 5-7 days.  
Within 14 days 
after Visit 11. 
<1 hour 

 
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Can coincide with 
Visit 11 
*Visit 13 
End of closed-loop 
treatment period (4 
months). HbA1c. 
Collect algorithm device. 
Revert back to usual 
diabetes therapy. Human 
factor assessment. 
After 4 weeks of 
Visit 11 
1-2 hours 
 
- 
Washout period  
Immediately after 
Visit 13 
 4 weeks 
Control  
Intervention 
(4 months) 
*Visit 14 
Control therapy initiation at 
CRC or remotely 
- Sensor-augmented pump 
refresher training & 
competency assessment 
- HbA1c 
After 4 weeks of 
end of Visit 13 
Up to 6 
hours 
*Visit 15 
End of first month.  
Review of home data.  
After 4 weeks of 
Visit 14 
<1 hour 
*Visit 16 
End of second month. 
Review of home data. 
Actiwatch sleep monitor 
After 4 weeks of 
Visit 15 
<1 hour 
*Visit 17 
End of third month. 
Review of home data.  
After 4 weeks of 
Visit 16 
<1 hour 
*Visit 18 
12-lead Holter monitor 
applied for 5-7 days.  
Within 14 days 
after Visit 17. 
Can coincide with 
Visit 17 
<1 hour 
*Visit 19 
End of open-loop treatment 
period (4 months) HbA1c. 
Human factor assessment 
After 4 weeks of 
Visit 17 
1-2 hours 
*Could be done via phone / e-mail in UK.  
 
 

 
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Table 2. Schedule of study visits when sensor-augmented pump therapy precedes 
closed-loop intervention. 
 
 
Visit/ 
contact 
Description 
Start relative to 
previous / next 
Visit / Activity 
Duration 
 
*Visit 1 
Recruitment visit: Consent  
HbA1c, baseline bloods, 12-
lead ECG, human factor 
assessment 
- 
1-3 hours 
Study Pump & CGM 
Training /Run-In 
*Visit 2 
Insulin pump training and 
initiation of study pump 
Competency assessment 
Can be combined 
with Visit 1, or 
within 1 to 
3  weeks of Visit 
1 
3-4 hours 
*Visit 3 
CGM training 
Initiation of CGM 
Competency assessment 
Within 7 days of 
Visit 2. Can 
coincide with 
Visit 2 
1 hour 
 
*Visit 4 
Review pump and CGM 
data & compliance 
assessment & 
Randomisation 
After 4 weeks of 
Visit 3 
1-2 hours 
Control  
Intervention 
(4 months) 
*Visit 14 
Control therapy initiation at 
CRC or remotely 
- Sensor-augmented pump 
refresher training & 
competency assessment 
- HbA1c 
After 8 week of 
end of Visit 13 
Up to 6 
hours 
*Visit 15 
End of first month.  
Review of home data.  
After 4 weeks of 
Visit 14 
<1 hour 
*Visit 16 
End of second month; 
Review of home data. 
Actiwatch sleep monitor 
After 4 weeks of 
Visit 15 
<1 hour 
*Visit 17 
End of third month. 
Review of home data.  
After 4 weeks of 
Visit 16 
<1 hour 
*Visit 18 
12-lead Holter monitor 
applied for 5 days.  
Within 14 days 
after Visit 17. 
Can coincide with 
Visit 17 
<1 hour 
*Visit 19 
End of open-loop treatment 
period (4 months) HbA1c. 
Revert back to usual pump 
therapy. Human factor 
assessment 
After 4 weeks of 
Visit 17 
1-2 hours 
 
- 
Washout period  
Immediately after 
Visit 19 
 4 weeks 

 
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CL 
Intervention 
(4 months) 
*Visit 5 
CL initiation at CRC or 
remotely 
- CL training & competency 
assessment 
- HbA1c 
After 4 weeks of 
end of Visit 19 
Up to 6 
hours 
* Visit 6 
Review use of study 
devices 
After 24-48 hours 
of Visit 5 
<1 hour 
*Visit 7 
Review use of study 
devices 
After 1 week of 
Visit 5 
<1 hour 
*Visit 8 
Review pump and CGM 
data 
After 1 week of 
Visit 7 
<1 hour 
*Visit 9 
End of first month;  
Review pump and CGM 
data.  
After 4 weeks of 
Visit 8 
<1 hour 
*Visit 10 
End of second month; 
Review pump and CGM 
data. Actiwatch sleep 
monitor 
After 4 weeks of 
Visit 9 
<1 hour 
*Visit 11 
End of third month;  
Review pump and CGM 
data.  
After 4 weeks of 
Visit 10 
<1 hour 
*Visit 12 
12-lead Holter monitor 
applied for 5 days.  
Within 14 days 
after Visit 11. 
Can coincide with 
Visit 11 
<1 hour 
*Visit 13 
End of closed-loop 
treatment period (4 
months). HbA1c. Collect 
algorithm device. Revert 
back to usual pump 
therapy. Human factor 
assessment.  
After 4 weeks of 
Visit 11 
1-2 hours 
 
*Could be done via phone / e-mail in UK.   
 
 
 

 
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9.2. Recruitment Visit (Visit 1) 
Once the subjects have agreed to participate in the study, they will be invited for the 
recruitment visit, when the following activities will be performed by the research team: 
 
 
written informed consent/assent  
 
checking inclusion and exclusion criteria  
 
medical (diabetes) history 
 
body weight and height measurement; calculation of BMI 
 
blood pressure measurement 
 
12-lead electrocardiogram recording 
 
record of current insulin therapy  
 
record of occupation and educational attainment  
 
Austria only - At the recruitment visit, the subject will have a breath alcohol test, a 
urine drug screen, and blood test for serology (HIV/Hepatitis B, C).  
 
9.2.1. Screening blood sampling 
Blood samples will be taken for the screening measurement of random C-peptide, 
glucose, and HbA1c. Liver, renal, thyroid function, full blood count, anti-
tranglutaminase antibodies and IgA will also be evaluated (if not done in previous 3 
months). Less than 15 ml of whole blood will be taken from each participant.    
 
9.2.2. Human factor assessments 
Human factors assessment to understand expectations, attitudes, and behaviours that 
influence the uptake and response to using a closed-loop system will be undertaken 
at baseline. This will include surveys listed in Table 3.  It is estimated that participants 
will take 20-25 minutes to complete surveys. 
 
Table 3. Human Factors Assessment Battery. 
Measure 
Construct Measured / Relevant Points 
WHO-5 quality of life 
measure* 
All participants complete this 5 item measure from the World Health Organization 
(WHO) that assesses health related quality of life. (5 items; 3 mins) 

 
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Diabetes Distress 
Scale* 
Gold standard measure for understanding distress symptoms related to diabetes. 
A recently validated version for adults with T1D includes 28 items and takes 6 
minutes to complete. 
Glucose Monitoring 
Satisfaction Survey* 
This recently validated survey is an outgrowth of DirecNet and JDRF CGM 
surveys. It has been reduced to 15 items and evaluates treatment satisfaction 
and burden. (4 mins) 
Hypoglycemia 
Confidence* 
Includes 8 different common situations where hypoglycemia occurs (e.g., 
physical activity, driving) and evaluates level of confidence it can be managed in 
those situations. (8 items; 3 mins) 
 INSPIRE Survey 
 Newly developed measure of the psychosocial impact of closed-loop. Include 31 
items and takes 5 - 7 minutes to complete. 
Pittsburgh Sleep 
Quality Index (PSQI) 
The PSQI is a validated 19 item questionnaire that holistically assesses sleep 
quality and sleep duration. 
Cognitive Functioning 
Computerised assessment of attention, executive functioning, and processing 
speed using standardised tools from CogState (10 – 12 minutes) 
 
 
9.3. Training session on the use of the study insulin pump 
(Visit 2) 
This session will cover key aspects of insulin pump use and particular attention will be 
paid to the following areas:  
 
Importance of carbohydrate counting and refresher on carbohydrate counting 
skills 
 
Understanding insulin to carb ratios and correction factors 
 
Correct use of bolus calculator - subjects will be required to use this bolus 
calculator for all insulin boluses during the study period. 
 
Insulin cartridge and Infusion set changes and correct priming procedure 
 
Sick day rules 
 
Dealing with hypo and hyperglycaemia 
 
Uploading pump data  
 
Written easy to use guidelines for the operation of insulin pump will be provided.  
 
This session will be conducted by a member of the study team and/or a professional 
pump educator following a written curriculum. Competency in the use of study pump 
will be assessed. 
 

 
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9.4. Training session on the continuous glucose monitoring 
(Visit 3)  
This session will cover key aspects of the study CGM and particular attention will be 
paid to the following areas:  
 
Insertion and initiation of sensor session 
 
Use of handheld CGM receiver & sensor calibrations 
 
Use of software to analyse CGM data 
 
Use of CGM data to optimise treatment 
 
Uploading CGM data using software 
 
Written guidelines for the operation and use of CGM device will be provided. If 
necessary, training sessions may be repeated. 
 
This session will be conducted by a member of the study team. Competency in the 
use of CGM will be assessed.  
 
9.5. Run-in period (ends at Visit 4)  
The subject will use study insulin pump and study CGM over the run-in period. The 
subject will be invited to attend the research centre or contacted via e-mail / telephone 
at the end of the run-in period. Study insulin pump and CGM device will be downloaded 
and data may be used for treatment optimisations. There should be a minimum of 
three weeks run-in period for all subjects (end of Visit 3 to end of Visit 4). Subjects will 
be able to contact the research team during the run-in period via phone/email to 
troubleshoot any problems and to ask for any additional training on the devices if 
required.  
 
At the end of the run-in period (Visit 4), the subject’s compliance in using the study 
CGM and study pump over preceding 14 days will be assessed. To proceed with the 
study subject needs to demonstrate correct use of study insulin pump including use of 
bolus calculator over 75% of meal boluses and at least 10 days’ worth of CGM data 
during last 14 days of run-in period. 
 
9.6. Randomisation 
Subject will be randomised in Visit 4 if no extension of the run-in period is needed. 
Eligible subjects will be randomised centrally using a randomisation based on a 

 
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computer-generated random code.  Randomisation will take place centrally. Subjects 
will be allocated to either closed-loop intervention preceding sensor augmented insulin 
pump therapy, or vice versa. 
 
The next section describes the situation when closed-loop precedes the sensor 
augmented insulin pump therapy. 
 
9.7. Closed-loop visit; within 2 weeks of Visit 4 (Visit 5) 
Subject will arrive at the clinical research facility or clinical area at the agreed time. If 
required this visit can be done remotely by telephone. A blood sample for HbA1c 
(capillary/venous) will be taken. Subjects will receive training required for safe and 
effective use of the closed-loop system. This will include training on connection and 
disconnection of the closed-loop system, and switching between closed-loop and 
usual pump therapy. Subjects will be advised to use closed-loop 24/7 for the next 4 
months with bolus wizard integrated with control algorithm adapted insulin carb ratio 
for prandial insulin delivery. Written step by step guidance will also be provided, 
including how to deal with low and high glucose at home. Subjects will be provided 
with 24 hour telephone helpline and information on when to contact study team. 
Competency in the use of closed-loop system will be assessed by the study team. 
Only subjects who demonstrate competency in use of the system will be allowed to 
continue to the home study phase.  
 
The subject is allowed to drive while adhering to usual precautions and country specific 
rules and regulations. Subjects will be warned about hypoglycaemia if they start 
regular exercise during study period.   
9.8. 24-48 hours after Starting Study Treatment (Visit 6) 
 
The subject will be contacted via telephone/e-mail or invited to attend the research 
centre approximately 24-48 hours after Visit 5 once study treatment has begun. The 
purpose of this visit will be to review the use of study devices and to provide any 
additional training required. 
 
9.9. 1 Week after Starting Study Treatment (Visit 7) 
 

 
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The subject will be invited to attend the research centre approximately 1 week after 
Visit 5. The purpose of this visit will be to review the use of study devices and to provide 
any additional training required.  
 
In the UK, the visit could be done via phone / e-mail.  
9.10. 2 Weeks after Starting Study Treatment (Visit 8) 
 
The subject will either be contacted via telephone/e-mail or seen in the clinic 1 week 
after Visit 7. The purpose of this visit would be to troubleshoot any problems.  The 
subject is free to optimise further treatment but no active treatment optimisation will be 
undertaken by the study team.  
 
9.11. Visits 9, 10 and 11 – 4 week, 8 week and 12 week after 
starting closed-loop therapy  
The subject will be invited to attend the research centre approximately 4 (Visit 9), 8 
(Visit 10) and 12 (Visit 11) weeks after Visit 5. These visits could be done via 
telephone/e-mail. The purpose of these visits will be to review the use of study devices 
and data from study devices will be downloaded. The subject is free to adjust further 
treatment but no active treatment optimisation will be undertaken by the study team. 
An Actiwatch sleep monitor will be applied at Visit 10 and worn for 7 days at home. 
Participants will be asked to complete a sleep diary while they wear the Actiwatch and 
will be provided with a stamped addressed envelope to return/post the Actiwatch and 
sleep diary to investigators for further analysis. 
9.12. Holter monitor application (Visit 12) 
The subject will be invited to attend the research centre within 7 days after Visit 11 to 
have a Holter monitor applied by the investigator. This procedure may also coincide 
with Visit 11. If required this visit can be done remotely by telephone once the Holter 
monitor has been delivered to the participant. The Holter monitor device will be 
collected at Visit 13, or at an agreed time and place with the investigator or returned 
via post/courier. Holter monitor data will be retrospectively evaluated and analysed at 
the end of the study. Any incidental finding will be referred by the Investigator to the 
clinical team and be managed as per local site policy for incidental findings. 
9.13. End of CL treatment (Visit 13) 

 
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The subject will be invited to attend the research centre approximately 4 weeks after 
visit 11. If required this visit can be done remotely by telephone. This would be the end 
of 4 month home study period and subjects will return to their normal diabetes care. 
Insulin pump and CGM device data will be downloaded. The subject will have a blood 
test (capillary/venous) for the HbA1c. Human factors survey assessment (Table 3) will 
be performed. Subjects will be asked to return the CGM and control algorithm devices, 
and will revert to their usual diabetes care with their usual home devices during the 1-
month washout period. 
9.14. Washout 
A minimum washout period of four weeks must be ensured between treatment periods. 
Duration of the wash out period has been chosen to minimise any carry over effect 
between the two interventions. This duration was decided pragmatically based on 
experience of the study team as there are no published studies investigating an 
optimal washout period for closed-loop studies.  The subject may continue to use the 
study CGM and study insulin pump during the washout period if he or she wishes. 
Otherwise the subject will continue to use their usual diabetes care with their usual 
home devices during the washout period. Then the subject will cross over to alternative 
intervention.  
9.15. Control therapy (Visit 14) 
The order of Visit 5 and Visit 14 will be in random order. Visit 14 is similar to Visit 5 
except that in Visit 14 there is no closed-loop insulin training and application, and 
subjects will initiate sensor augmented insulin pump therapy. If required this visit can 
be done remotely by telephone. Subjects will follow usual treatment guidelines for 
driving, exercise, hyperglycaemia and hypoglycaemia. 
9.16. Visits 15, 16 and 17 – 4 week, 8 week and 12 week after 
starting sensor augmented pump treatment 
The subject will be invited to attend the research centre approximately 4 (Visit 15), 8 
(Visit 16) and 12 (Visit 17) weeks after Visit 14. If required these visits can be done 
remotely via telephone/e-mail. The purpose of this visit will be to review the use of 
study devices and data from study devices will be downloaded. The subject is free to 
adjust further treatment but no active treatment optimisation will be undertaken by the 
study team. At Visit 16, an Actiwatch sleep monitor will be applied and worn for 7 days 
at home. Participants will be asked to complete a sleep diary and will be provided with 
a stamped addressed envelope to return/post the Actiwatch to investigators for further 
analysis. 

 
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9.17. Holter monitor application (Visit 18) 
The subject will be invited to attend the research centre within 14 days after Visit 17 to 
have a Holter monitor applied by the investigator. If required this visit can be done 
remotely by telephone once the Holter monitor has been delivered to the participant. 
This procedure may also coincide with Visit 17. The Holter monitor device will be 
collected at Visit 19, or at an agreed time and place with the investigator or returned 
via post/courier. Holter monitor data will be retrospectively evaluated and analysed at 
the end of the study. Any incidental finding will be referred by the Investigator to the 
clinical team, to be managed as per local site policy for incidental findings. 
9.18. End of control treatment (Visit 19) 
The subject will be invited to attend the research centre approximately 4 weeks after 
Visit 17. If required this visit can be done remotely by telephone. This would be the 
end of the study period and subjects will return to their normal diabetes care. Insulin 
pump will be downloaded. The subject will have a blood test (capillary/venous) for the 
HbA1c. A human factors survey assessment (Table 3) will be performed. Participants 
will be invited to a focus group for investigators to gather feedback and reactions to 
the closed-loop system, the clinical trial, and quality of life changes. 
9.19.  Participant withdrawal criteria 
The following pre-randomisation withdrawal criteria will apply: 
1. Subject is unable to demonstrate safe use of study insulin pump and / or CGM 
during run-in period as judged by the investigator 
2. Subject fails to demonstrate compliance as mentioned in section 9.5 with study 
insulin pump and / or CGM during run-in period   
 
The following pre- and post-randomisation withdrawal criteria will apply: 
 
3. Subjects may terminate participation in the study at any time without 
necessarily giving a reason and without any personal disadvantage 
4. Significant protocol violation or non-compliance 
5. Any severe hypoglycaemia event related to use of the closed-loop system 
6. Two severe hypoglycaemia events unrelated to the use of the closed-loop 
system 
7. DKA unrelated to infusion site failure and related to the use of the closed-loop 
system 
8. Decision by the investigator or the sponsor that termination is in the subject's 
best medical interest 

 
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9. Allergic reaction to insulin  
10. Severe allergic reaction to adhesive surface of infusion set or glucose sensor 
 
Subjects who are withdrawn for reasons stated in (4) to (10) will be invited to provide 
a blood sample at the end of the planned study intervention for the assessment of 
HbA1c. 
  
9.20. Study Stopping Criteria 
The study may be stopped if three consecutive participants withdraw on safety 
grounds or on the advice of an independent Data Safety and Monitoring Board 
(DSMB). 
 
9.21. Support telephone line 
There will be a 24-hour telephone helpline to the research team for subjects in case of 
any technical device or problems related to diabetes management such as hypo- or 
hyperglycaemia.         
                     
9.22. Subject reimbursement 
The study will provide the CGM device, insulin pump, closed-loop components, related 
consumables, and glucose test strips. A recompense payment to participants will be 
paid to reflect local practice. The amount paid will be specified in the participant 
information sheet and REC application form. Reasonable travel expenses will also be 
reimbursed. After completing the study, subjects will not keep the study devices. They 
will revert to their conventional insulin pump therapy. 
10.  Endpoints 
10.1.  Efficacy endpoints 
10.1.1. 
Primary efficacy endpoint 
The primary outcome is the time spent in the target glucose range from 3.9 to 
10.0 mmol/l (70 to 180mg/dl) throughout the 16 week study periods based on 
continuous glucose monitoring (CGM).  
10.1.2. 
Secondary efficacy endpoints 
Key secondary outcomes include: 

 
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 
Time spent above target glucose (10.0 mmol/l) (180 mg/dl) 
 
Average of glucose levels  
 
HbA1c at 16 weeks  
 
Time spent below target glucose (3.9mmol/l) (70mg/dl) 
Other secondary endpoints 
 
standard deviation and coefficient of variation of glucose levels 
 
The time with glucose levels <3.5 mmol/l  (63mg/dl), and <3.0 mmol/l (54mg/dl)  
 
The time with glucose levels in the significant hyperglycaemia (glucose levels 
>16.7 mmol/l) (300mg/dl) 
 
Total, basal and bolus insulin dose  
 
Glucose endpoints will be based on sensor glucose.  
 
10.2. Safety evaluation 
Safety evaluation will comprise number of episodes of severe hypoglycaemia as well 
as 
the 
number 
of 
subjects 
experiencing 
severe 
hypoglycaemia, 
severe 
hyperglycaemia (fingerprick glucose >16.7 mmol/l) (>300mg/dl) and plasma ketones 
>0.6mmol/l), diabetic ketoacidosis, and other adverse events.   
 
All subjects including those who withdraw will be included in the safety evaluation. 
10.3.  Utility evaluation 
Utility evaluation is the frequency and duration of use of the closed-loop system at 
home.  
10.4. Human factors evaluation  
Cognitive, emotional, and behavioural characteristics of participating subjects and 
family members and their response to the closed-loop system and clinical trial will be 
assessed using validated surveys and focus groups. 
10.5. Cardiac arrhythmia analysis 
Holter monitor data at the fourth month in the two treatment groups will be 
retrospectively evaluated by a cardiologist masked to other study data at the end of 
the study. Any incidental finding will be referred by the Investigator to the clinical team 
and be managed as per local incidental findings site policy. 
10.6. Sleep quality assessment  

 
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Quality, duration and fragmentation of sleep will be assessed subjectively (using the 
Pittsburgh Sleep Quality Index (PSQI), and a daily sleep diary) and objectively (by 
actigraphy) in participants.  
 
The PSQI is a validated 19 item questionnaire that holistically assesses sleep quality 
and sleep duration. The sleep diary will record time of going to bed and waking, plus 
time of, and reason for any nocturnal awakenings. 
 
An Actiwatch (Philips Respironics, Bend, Oregon, USA) worn on the non-dominant 
wrist will provide objective measures of sleep and wakefulness based on motor activity 
- a low cost, non-invasive and objective method for evaluating sleep in free-living 
participants. Actiwatches will record time in bed and actual sleep time, as well as 
changes in sleep quality from measures of sleep maintenance, sleep efficiency, sleep 
latency, fragmentation index, total nocturnal activity, and percentage moving time. 
Light exposure will be measured by the Actiwatch’s photovoltaic sensor. 
 
11. Assessing and Reporting of Adverse Events 
11.1. Definitions 
11.1.1. 
Reportable Adverse Events 
A reportable Adverse Event is any untoward medical occurrence that meets criteria for 
a serious adverse event or any unanticipated medical occurrence in a study subject 
that is study or device-related. Device deficiencies that could have led to a serious 
adverse device effect will also be reported. 
11.1.2. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory findings) in a subject 
who has received an investigational device, whether or not related to the 
investigational medical device.  This definition includes events related to the device 
under investigation or the comparator or to the study procedures 
 
The following anticipated adverse events will not be recorded: 
 
Non clinically significant skin reactions as judged by investigator 
 
Pre-existing medical conditions 

 
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 
New illnesses or conditions not requiring concomitant medication or medical 
intervention/procedures 
 
Non severe hypoglycaemia 
 
Hyperglycaemia without significant ketonaemia (>0.6mmol/l) 
11.1.3. 
Adverse Device Effect   
An Adverse Device Effect (ADE) is an adverse event related to the use of an 
investigational medical device. This includes adverse events resulting from insufficient 
or inadequate instructions for use, deployment, implantation, installation, or operation, 
or any malfunction of the investigational medical device.  This definition also includes 
any event resulting from use error or from intentional misuse of the device under 
investigation. 
11.1.4. 
Serious Adverse Event 
A serious adverse event (SAE) is an adverse event that: 
 
Led to a death  
 
Led to a serious deterioration in the health of the subject, that either resulted 
in: 
o a life threatening illness or injury  
o a permanent impairment of a body structure or function    
o in-patient hospitalisation or prolonged hospitalization 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function 
 
Led to foetal distress, foetal death or a congenital abnormality or birth defect 
 
A planned hospitalisation for pre-existing condition, or a procedure required by the 
study protocol, without a serious deterioration in health, is not considered to be a 
serious adverse event. 
 
More than one of the above criteria can be applicable to one event.  Life-threatening 
in the definition of a serious adverse event or serious adverse reaction refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it were more severe.  
Medical judgement should be exercised in deciding whether an adverse event or 
reaction is serious in other situations.  
 
Important adverse events or reactions that are not immediately life-threatening or do 
not result in death or hospitalisation but may jeopardise the subject or may require 

 
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intervention to prevent one of the other outcomes listed in the definition above, should 
also be considered serious. 
 
The following serious adverse events, should they occur, will be classified as 
anticipated: 
 
Severe hypoglycaemia 
 
DKA 
 
11.1.5. 
Serious Adverse Device Effect   
A Serious Adverse Device Effect (SADE) is an adverse device effect that has resulted 
in any of the consequences characteristic of a serious adverse event. 
11.1.6. 
Unanticipated Serious Adverse Device Effect 
An Unanticipated Serious Adverse Device Effect (USADE) is a serious adverse device 
effect which by its nature, incidence, severity or outcome has not been identified in the 
current version of the protocol. 
 
This includes unanticipated procedure related serious adverse events; that is, serious 
adverse events occurring during the study procedure that are unrelated to any 
malfunction or misuse of the investigational medical device. 
 
An Anticipated Serious Adverse Device Effect (ASADE) is a serious adverse device 
effect which by its nature, incidence, severity or outcome has been identified in the 
current protocol. 
11.1.7. 
Device Deficiencies 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance.  A device deficiency may lead to 
an Adverse Device Effect or Serious Adverse Device Effect. The following anticipated 
device deficiencies and device-related issues will not be recorded: 
 
Infusion set occlusion/leakage not leading to ketonaemia 
 
Sensor failure due to miscalibration/detachment 
 
Premature interruption of sensor-life  
 
Battery lifespan deficiency due to inadequate charging or extensive 
wireless communication 
 
CAD error messages not needing system replacement 

 
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 
Intermittent device communication failure not leading to system 
replacement 
 
11.1.8. 
Adverse Event Intensity 
 
Intensity 
Definition 
 
Mild 
 
Patient is aware of signs and symptoms but they are easily tolerated.  
 
Moderate 
 
Signs / symptoms cause sufficient discomfort to interfere with usual 
activities. 
 
Severe 
 
Patient is incapable of working or performing usual activities. 
 
NB. The term “severe” is often used to describe the intensity (severity) of a specific 
event. This is not the same as ‘serious’, which is based on patient/event outcome or 
action criteria (see definition 11.1.4). For example, itching for several days may be 
rated as severe, but may not be clinically serious. 
11.1.9. 
Adverse Event Causality 
 
Intensity 
Definition 
 
Not 
assessable  
A report suggesting an adverse event, which cannot be judged because 
information is insufficient or contradictory, and which cannot be 
supplemented or verified.  
 
Unlikely  
A clinical event, including laboratory test abnormality, with a temporal 
relationship, which makes a causal relationship improbable, and in 
which other drugs/treatments, chemicals or underlying disease(s) 
provide plausible explanations. 
  
Possible  
 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment/use of investigational 
treatment/device, but which also could be explained by concomitant 
diseases or other drugs/treatments or chemicals.  

 
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Probable  
 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the treatment/use of medical 
method/device, unlikely to be attributable to concomitant disease(s) or 
other drugs/treatments or chemicals, and which follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfil this definition. 
  
Certain  
 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to study treatment/use of medical 
method/device and which cannot be explained by concomitant 
disease(s), other drugs/treatments or chemicals. The response to 
withdrawal of the treatment (dechallenge) should be clinically plausible. 
The event must be unambiguous, either pharmacologically or as 
phenomenon, using satisfactory rechallenge procedures if necessary.  
 
 
(Reference: WHO-UMC Causality Categories)  
 
11.2.  Recording and Reporting of Adverse Events, Serious 
Adverse Events and Device Deficiencies 
11.2.1. 
Monitoring Period of Adverse Events  
The period during which adverse events will be reported is defined as the period from 
the beginning of the study (obtaining informed consent) until 3 weeks after the end of 
the second intervention. Adverse events that continue after the subject’s 
discontinuation or completion of the study will be followed until their medical outcome 
is determined or until no further change in the condition is expected. The follow up of 
AEs may therefore extend after the end of the clinical investigation; however no new 
AEs will be reported after the trial reporting period.   
11.2.2. 
Recording and reporting of Adverse Events 
Throughout the course of the study, all efforts will be made to remain alert to possible 
adverse events or untoward findings. The first concern will be the safety of the subject, 
and appropriate medical intervention will be taken.  The investigator will elicit reports 
of adverse events from the subject at each visit and complete adverse event forms. 
All AEs, including those the subject reports spontaneously, those the investigators 

 
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observe, and those the subject reports in response to questions will be recorded on 
paper or electronic AE forms at each site within seven days of discovering the event.   
 
The study investigator will assess the relationship of any adverse event to be device-
related or unrelated by determining if there is a reasonable possibility that the adverse 
event may have been caused by the study device or study procedures. The individual 
investigator at each site will be responsible for managing all adverse events according 
to local protocols, and decide if reporting is required. 
11.2.3. 
Severe Hypoglycaemia  
Severe hypoglycaemia will be defined as an event requiring assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. 
These episodes may be associated with sufficient neuroglycopaenia to induce seizure 
or coma. If plasma glucose measurements are not available during such an event, 
neurological recovery attributable to the restoration of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.  
 
Severe hypoglycaemia will be regarded as a foreseeable serious adverse event and 
a serious adverse event form will be completed. Non-severe hypoglycaemia will not 
be reported or considered an adverse event.  
 
11.2.4. 
Hyperglycaemia, Ketonaemia and Diabetic 
Ketoacidosis  
  
Diabetic Ketoacidosis (DKA) is defined as: hyperglycemia (blood glucose >250 mg/dl 
or >13.9 mmol/l) with low serum bicarbonate (<15 mEq/l) and/or low pH (<7.24), anion 
gap (> 12) and either ketonemia or ketonuria and requiring treatment within a health-
care facility (American Diabetes Association Workgroup on Hypoglycemia, Diabetes 
Care 28:1245-1249, 2005). 
 
DKA will be regarded as a foreseeable serious adverse event and a severe adverse 
event form will be completed.  
 
Severe hyperglycaemic events (fingerprick glucose >300 mg/dl/16.7mmol/l and blood 
ketones >0.6mmol/l) will be recorded as Adverse Events. Non-severe hyperglycaemia 
events will not be reported or considered as adverse events.  

 
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11.2.5. 
Reporting of Serious Adverse Events and 
Serious Adverse Device Effects 
When reporting adverse events, all pertinent data protection legislation must be 
adhered to. 
 
The serious adverse event report should contain the following information*: 
1. 
Study identifier (EudraCT number if applicable) 
2. 
Participant’s unique study number 
3. 
Date of birth 
4. 
Event description 
5. 
Start date of event 
6. 
Laboratory tests used and medical interventions used to treat the SAE 
7. 
Planned actions relating to the event, including whether the study device was 
discontinued 
8. 
Statement on the patient’s current state of health 
9. 
Reason 
for 
seriousness 
(i.e. 
death, 
life 
threatening, 
hospitalisation, 
disability/incapacity or other) 
10. Evaluation of causality (including grade of relatedness) with the following (more 
than one may apply): 
a. the investigational treatment/medical device 
b. the clinical study/a study specific procedure 
c. other: e. g. concomitant treatment, underlying disease  
11. Reporter’s name, date and signature 
*In the case of incomplete information at the time of initial reporting, all appropriate 
information should be provided as soon as this becomes available.   
 
The relationship of the SAE to the investigational treatment / medical device should 
be assessed by the investigator at site, as should the anticipated or unanticipated 
nature of any SAEs and SADEs. 
 

 
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All SAEs whether or not deemed investigational method/device related and whether  
anticipated or unanticipated must be reported to the Sponsor by email or fax within 24 
hours (one working day) of the Investigator learning of its occurrence.   
 
UK specific reporting instructions: 
SAEs should be reported to:  
Stephen Kelleher 
Cambridge University Hospitals  
NHS Foundation Trust              
Box 277, Addenbrooke's Hospital 
Hills Road, Cambridge, CB2 0QQ, UK 
Phone:  +44 (0) 1223 217418 
Fax:  +44 (0) 1223 348494 
E-mail: r&denquiries@addenbrookes.nhs.uk 
 
A written report must follow within five working days and is to include a full description 
of the event and sequelae, in the format detailed on the Serious Adverse Event 
reporting form.  If applicable, the Sponsor will notify the competent authority of all 
Serious Adverse Events in line with pertinent legal requirements.  
 
The Investigator will notify the Research Ethics Committee (REC) in UK of all Serious 
Adverse Events in line with pertinent legal requirements. The Investigator will inform 
the Sponsor about all reports sent to the reporting organisation including follow-up 
information and answers by the reporting organisation.  The local investigator is 
responsible for informing other site principal investigators and the CI of all SAEs. 
 
The regulatory authority (MHRA will be notified of all SAEs as soon as possible within 
ten days of the event occurring during the study.  The main REC will be notified of all 
unexpected and related SAEs within 15 days of the occurrence of the event.  
 
Austria specific reporting instructions:  
All SAEs have to be documented by the sponsor and immediately reported according 
to § 42 (8) of the Austrian Medical Device Directive (StF: BGBl. Nr. 657/1996, BGBl. I 
Nr. 143/2009) to the competent authority (AGES) and the competent authorities of 
other countries within the European Union where the study is conducted. All SAEs 
must be reported using the templates provided by AGES. 
 

 
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It is the responsibility of the local investigator to follow the SAE and SADE reporting 
requirements stipulated by the Investigational Centre’s reviewing REC and the 
Sponsor. 
11.2.6. 
Recording 
and 
Reporting 
of 
Device 
Deficiencies 
All device deficiencies will be documented throughout the study.  The investigator at 
each site will be responsible for managing all device deficiencies and determine and 
document in writing whether they could have led to a serious adverse device effect.   
 
All device deficiencies that might have led to a serious adverse device effect(s) if: 
suitable action had not been taken; intervention had not been made; or if 
circumstances had been less fortunate, must be reported to the Sponsor as for 
SAEs/SADEs.  
11.2.7. 
Healthcare Arrangements and Compensation 
for Adverse Events  
Healthcare arrangements for subjects who suffer an adverse event as a result of 
participating in the study may include advice from clinical members of the study team 
or the patient’s treating diabetes team, or use of emergency health services.  
 
If an adverse event occurs, there are no special compensation arrangements unless 
this was due to the negligence of one of the clinical investigators or due to harm 
resulting from study protocol design. In this case subjects may have grounds for legal 
action for compensation. The normal national complaints mechanism will be available.  
In addition, any harm arising due to study design (both negligent and non-negligent) 
will be covered under Sponsor’s insurance policy as applicable. 
 
11.3.  Risks and discomforts and potential / anticipated 
adverse events and adverse device events/effects 
11.3.1. 
Risks and anticipated adverse events  
Known risks represent hazardous situations which may result in anticipated adverse 
events. In the following text, where appropriate, the term “risk” and “anticipated 
adverse events” are used interchangeably without affecting meaning. 
 

 
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11.3.2. 
Hypoglycaemia and hyperglycaemia 
Subjects with type 1 diabetes have a pre-existing risk for hypoglycaemia and 
hyperglycaemia. Potential risks are: 
 
Risk of mild to moderate hypoglycaemia and associated symptoms such as 
sweating, trembling, difficulty thinking and dizziness. There is also a rare risk 
of severe hypoglycaemia when conscious level is altered, needing help from a 
third party to correct the hypoglycaemia. These risks are pre-existent in any 
patient with type 1 diabetes and the study objective is to develop systems to 
minimise these risks 
 
Risk of possible mild to moderate hyperglycaemia similar to the risk that a 
subject with type 1 diabetes experiences on a daily basis  
 
Risk of hyperglycaemia leading to diabetic ketoacidosis (DKA). This risk is pre-
existent in any patient with type 1 diabetes. 
11.3.3. 
Blood sampling 
Subjects will be required to have screening blood tests at baseline (venepuncture). 
Venepuncture is required annually as part of the annual review for people with 
diabetes, and in some places venepuncture is required every 3 to 6 months for 
assessment of HbA1c. HbA1c samples collected during the study can be capillary 
(NOT point of care) or venous samples. Capillary samples can be collected by the 
participant using their own blood glucose testing apparatus and delivered to the local 
investigator if required. 
 
Potential risks of venepuncture include: 
 
Localised infection – an infection in the tissue around the site 
 
Phlebitis – inflammation of the wall of the vein 
 
Haematoma – an accumulation of blood within the tissues that clots to form a 
solid swelling 
 
Local anaesthetic cream or spray may be used to minimise the discomfort. 
11.3.4. 
12-lead electrocardiogram 
Potential risks and adverse device effects associated with electrocardiogram 
recording: 
 
Slight discomfort at the time of electrode adhesives placement (rare) 
 
Mild skin irritation to electrode adhesives (rare) 

 
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If an incidental finding is found during the electrocardiogram recording at the 
Recruitment Visit, this will be referred by the Investigator to the clinical team, to be 
managed as per local site policy. 
11.3.5. 
Finger-prick blood glucose measurements 
Finger-prick tests may produce pain and/or bruising at the site. 
11.3.6. 
Insulin pump therapy 
Subjects participating in this study are already using an insulin pump. Potential risks 
and adverse device effects associated with insulin pump therapy include: 
 
Slight discomfort at the time of insertion of the insulin delivery cannula 
(common) 
 
Slight bruising at the site of insertion (common) 
 
Bleeding at insertion site (rare) 
 
Infection at the site of insertion (rare) 
 
Allergy to the insulin delivery cannula or adhesive (rare) 
 
Infusion set and cannula occlusions (rare) 
 
Insulin pump malfunction and mechanical problems (rare) 
 
Allergy to insulin (very rare) 
 
Lipodystrophy / lypoatrophy (very rare) 
 
Priming mechanism failure  
 
Pump screen damage 
 
Fast battery drainage 
 
11.3.7. 
Continuous glucose monitoring 
Potential risks and adverse device effects associated with CGM: 
 
Slight discomfort at the time of insertion of CGM (common) 
 
Slight bruising at the site of insertion (unlikely) 
 
Bleeding at insertion site (rare) 
 
Infection at the site of insertion (very rare) 
 
Intermittent CGM failure (common) 
 
If a skin reaction is classified as severe (the observation is noticeable and bothersome 
to the subject and may indicate infection or risk of infection or potentially life-
threatening allergic reaction); an adverse event form will be completed. 
 
11.3.8. 
Holter monitor 

 
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Potential risks and adverse device effects associated with Holter monitor: 
 
Slight discomfort at the time of  electrode adhesives placement (rare) 
 
Mild skin irritation to electrode adhesives (rare)  
If an incidental finding is found during analysis of the Holter monitor data at the end of 
the study period, this will be referred by the Investigator to the clinical team, to be 
managed as per local site policy. 
 
11.3.9. 
Actiwatch 
Potential risks and adverse device effects associated with Actiwatch include: 
 
Mild irritation at skin surface in contact with Actiwatch (rare)  
 
11.3.10. 
Human factor assessment 
As part of the study, subjects will complete surveys and participate in focus groups 
which include questions about their private attitudes, feelings and behaviour related to 
diabetes. It is possible that some people may find these surveys and focus groups to 
be mildly upsetting. Similar methods have been used in previous research and these 
reactions are uncommon. 
 
11.3.11. 
Burdens 
The study will involve up to 19 visits but all of these visits could be done via e-mail/ 
telephone. The study also includes two up to 6 hour visits to the clinical research facility 
(which can be done via telephone if required) and four months home study period.   
 
At home, subjects will wear the closed-loop system for a 4 month period. The subject 
is required to carry the closed-loop system for work and when going outside home. 
During the night, the closed-loop system will be located on a bedside table. 
 
The subjects will be required to perform regular finger stick measurements (4 - 6 
hourly) during day time. 
11.3.12. 
Risk analysis and residual risk associated 
with the investigational device 
After in-depth analysis and consideration of all the potential hazards in relation to use 
of the CamAPS FX system in the home environment, it is concluded that the CamAPS 
FX system is safe, if used as intended. 
 

 
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Risk Assessment of the CamAPS FX system has been carried out in accordance with 
ISO 14971:2012. A preliminary Hazard Determination has been carried out including 
consideration of the questions in Annex C of ISO 14971:2012. 
 
One hazard ‘Hazard S7: Incorrect Calibration of Blood Glucose Sensor due to error of 
reading resulting in overestimation of blood glucose’ is the only hazard identified that 
could not be reduced to an acceptable risk level, post mitigation. Our in-detail 
risk/benefit assessment concluded that the benefits of the system outweigh the risk 
with respect to this specific hazard. 
 
As per our risk management process, further risk analysis shall be undertaken post 
production and release as to ensure any issues raised are acted upon to ensure the 
CamAPS FX system continues to improve and develop. 
 
11.4. Benefits 
It is expected that day and night closed-loop system or sensor-augmented pump 
therapy may have an important role in the management of diabetes. Therefore, the 
results of this study are likely to be beneficial for subjects with diabetes. 
 
It is possible that subjects will not directly benefit from being a part of this study. 
However, it is also possible that the blood sugar information from the CGM devices 
along with the information about insulin dosing during day and night closed-loop will 
be useful for subjects’ diabetes self-management. 
11.5. Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board (DSMB) will be informed of all 
serious adverse events and any unanticipated adverse device effects that occur during 
the study and will review compiled adverse event data at periodic intervals.  
12. Methods and Assessments 
12.1.  Procedures 
12.1.1. 
Height and weight 
These will be recorded at the study initiation visit at baseline. Height will be measured 
in centimetres using calibrated measuring devices. Weight will be measured in 
kilograms using a calibrated electronic scale. 

 
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12.1.2. 
Continuous 
subcutaneous 
glucose 
monitoring 
At least 10 days of CGM data will be collected before visit 4. During the study subject 
is required to upload the CGM data via internet using secure website. 
12.1.3. 
Insulin pump data  
During the study subject is required to upload insulin pump data via internet using 
secure website. 
12.1.4. 
12-lead electrocardiogram 
During the Recruitment Visit, a 12-lead electrocardiogram recording will be collected.  
Any incidental finding will be referred by the Investigator to the clinical team and be 
managed as per local site policy. 
12.1.5. 
Holter monitor 
At least 5 days of Holter monitor data will be collected during the fourth month in the 
two treatment groups and analysed at the end of the study period. Any incidental 
finding will be referred by the Investigator to the clinical team and be managed as per 
local site policy. 
 
An incidental finding may be defined as ‘a finding that has potential health or 
reproductive importance, unknown to the participant, which is discovered 
unexpectedly in the course of conducting research, but is unrelated to the purpose and 
beyond the aims of the study’. This study will adopt the following framework for 
handling incidental findings:  
 To respect the research participant's right to know or, alternatively, their right not to know 
about incidental findings. Explicit consent must have always been given by the participant 
for incidental findings to be returned.  
 Incidental findings should only be returned where they are of significant clinical 
importance.  
 Incidental findings should be clinically and analytically validated before being returned to 
participants by their treating clinician.  
 Feedback to individual participants should be conducted by a trained professional.  
 
12.2. Surveys and focus groups 

 
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Human factors assessments in closed-loop trials are made up of tests and procedures 
that taps in to the “human side” of these systems. Human factor assessments cut 
across the acceptability, usability, and efficacy of the system from the perspective of 
the user. Further, human factor assessments help to understand expectations, 
attitudes, and behaviours that influence the uptake and response to using a closed-
loop system. The human factor assessments in research include both quantitative and 
qualitative methods and have been tested in adults in the targeted age range. They 
reflect the most methodologically sound and clinically informed tools available. 
Surveys are listed in Table 3 and all surveys will be administered in-person. It is 
estimated that participants will take 20-25 minutes to complete surveys. Surveys will 
be completed at the time of major assessments in the trial – baseline (after run-in, but 
prior to randomisation) and at the end of each study period. 
 
In addition, focus groups will be convened during the study trial. Focus groups will 
meet when each study group completes each study period. We will aim to conduct 
focus groups in-person and will utilise local facilitators who have worked with the 
research team on similar projects. Focus groups will include 3-6 participants and a 
script of open-ended questions will be used to gather feedback and reactions to the 
closed-loop system, the clinical trial, and quality of life changes. There will also be time 
for discussion of content raised by participants. Use of a moderator with advanced 
training (PhD level) will ensure consistency across groups. Sessions will be audio- and 
video-taped and transcribed by a professional transcription service. 
12.3.  Laboratory methods  
12.3.1. 
Screening sample 
Renal, liver and thyroid function and anti-transglutaminase antibodies with IgA levels 
(to exclude diagnosis of coeliac disease) and full blood count will be measured locally 
if not done within the previous 3 months.  
12.3.2. 
C-peptide and glucose 
A random blood sample for the measurement of C-peptide with simultaneous 
exclusion of biochemical hypoglycaemia (plasma glucose <4.0 mmol/l (72mg/dl)) by 
laboratory glucose analysis on a sample at the same time point, will be taken at 
screening.   
 
Plasma C-peptide will be measured at a local laboratory. 
12.3.3. 
HbA1c 

 
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HbA1c will be measured at a local laboratory compliant with IFCC reference HbA1c 
method. This sample can be capillary or venous. 
12.4. Total Blood Loss 
The total blood loss will be approximately 50 to 100 ml. 
13. Study Materials 
13.1. Insulin 
U-100 rapid acting insulin analogue will be used in the insulin pumps.  This includes 
either Aspart (Novorapid; Novo Nordisk, Bagsvaerd, Denmark), Faster Insulin Aspart 
(Fiasp; Novo Nordisk, Bagsvaerd, Denmark), or Lispro (Humalog; Eli Lily, Indianapolis, 
USA) but not Glulisine (Apidra; Sanofi-Aventis, Paris, France). 
13.2. Insulin Pump  
During the run-in period and both study arms, the Dana insulin pump (SOOIL) will be 
used. Glooko/Diasend software or similar will be used to download insulin pump data 
at regular intervals. 
13.3. Continuous Subcutaneous Glucose Monitor 
The Dexcom G6 real-time sensor with sensor applicator (Dexcom, Northridge, CA, 
USA) will be the study CGM. The sensor will be calibrated according to manufacturer’s 
instructions.  
13.4. Blood Glucose Meter  
Study participants will use their own approved glucose meter for self-monitoring of 
capillary blood glucose (SMBG) during the study. The capillary glucose meter readings 
may be used to calibrate the sensor according to manufacturer’s instructions.  
 
13.5. Computer-based Algorithm 
 
The model predictive computer-based controller will be used. The controller has been 
used safely and effectively in the closed-loop studies in both children and adults with 
T1D (studies REC Ref. 06/Q0108/350, REC Ref. 07/H0306/116, REC Ref. 
08/H0304/75, REC Ref. 08/H0308/297, REC Ref. 09/H0306/44, REC Ref. 
10/H0304/87, REC Ref. 12/EE/0155, REC Ref. 12/EE/0034, and REC Ref. 
12/EE/0424). 

 
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13.6. Actiwatch 
An Actiwatch (Philips Respironics, Bend, Oregon, USA), worn on the non-dominant 
wrist, will be used to measure sleep. 
13.7. Holter Monitor 
A Holter monitor (Lifecard 12; Spacelabs Healthcare, Hertford, UK, or similar) will be 
applied. 
14. Data Analysis  
14.1. Primary Analysis 
The primary analysis will evaluate the time (midnight to midnight) spent in the target 
glucose range from 3.9 to 10 mmol/l (70 to 180mg/dl) based on CGM glucose levels 
during the 16 week interventions. 
 
14.2. Secondary Analysis 
14.2.1. 
Biochemical evaluation 
Key secondary endpoints include the between group differences in time spent above 
target glucose (>10.0 mmol/l) (>180mg/dl), average glucose levels, HbA1c levels at 
the end of treatment period and time spent below target glucose (<3.9mmol/l) 
(<70mg/dl), Other secondary efficacy endpoints include the between group differences 
in standard deviation, and the coefficient of variation of glucose levels, the time with 
glucose levels < 3.5 mmol/l (63mg/dl) and <3.0 mmol/l (54mg/dl), the time with glucose 
levels in the significant hyperglycaemia (glucose levels > 16.7 mmol/l) (300mg/dl), 
total, basal and bolus insulin dose.   
 
All analyses will be by intention to treat. 
 
Summary statistics for the following outcome metrics will also be tabulated separately 
for daytime (defined as 6am to less than 12am) and nighttime (defined as 12am to less 
than 6am) over the four month period:  
• 
Percent time with glucose levels spent in the target range (3.9 to 10.0 mmol/L) 
• 
Mean of glucose levels 
• 
Standard deviation of glucose levels 
• 
Percent time with glucose levels below 3.9 mmol/L 
• 
Total insulin dose 

 
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Per-protocol analysis will also be performed which will evaluate glucose sensor based 
outcomes with a minimum of 60% of available CGM readings during the control period 
and 60% CL system use during the CL period. Descriptive tabulations of 
questionnaires will be carried out. 
 
14.2.2. 
Analysis of Human Factors Data 
Quantitative data on usability and satisfaction will be analysed using simple descriptive 
statistics. In addition, we will analyse scores from the measures in the human factors 
assessment battery to determine if changes occur over time and between groups. 
Using SAS v9.4, we will construct predictive models in the general linear framework to 
examine each set of human factors (e.g., QOL, fear of hypoglycaemia) and its 
association with our outcomes. Group assignment will be the primary covariate. 
 
Qualitative data will be analysed using Atlas.ti (release 6.0; Scientific Software 
Development GmbH, Berlin, Germany) to organise and manage the entire corpus of 
focus group data. Analysis begins with an initial coding procedure to capture and 
describe the range of responses to the intervention. A second, more focused and 
detailed level of coding will be applied to major categories of findings in the initial 
review to determine themes in response to the clinical trial, use of the closed-loop 
system, and quality of life changes. 
14.2.3. 
Cardiac Arrhythmia Analysis 
Holter monitor data at the fourth month in the two treatment groups will be analysed at 
the end of the study period. Arrhythmic events analysed will include atrial fibrillation, 
atrial ectopic beats, bradycardia, ventricular premature beats, complex ventricular 
premature beats, non-sustained ventricular tachycardia and measures of heart rate 
variability and QT interval. All identified arrhythmic events will be manually verified for 
accuracy. 
Investigators will be blinded to glucose values during arrhythmia analysis. The 
frequency of arrhythmic events during periods of hypoglycaemia (sensor glucose ≤3.9 
mmol/L and 3.0 mmol/L), will be compared to the frequency of arrhythmic events 
during normoglycaemia (3.9-10 mmol/L) within each study arm. Analyses will be 
calculated for daytime and night-time periods to take into account diurnal variation.  
Any incidental finding will be referred by the Investigator to the clinical team and be 
managed as per local site policy. 
14.2.4. 
Quality of Sleep Assessment using Actiwatch 

 
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Sleep will be automatically scored by Actiware software using previously described 
and validated algorithms. Sleep duration will be calculated as the sum of all epochs 
scored as sleep during the time in bed. Variability across nights in a participant’s sleep 
duration will be summarised using the coefficient of variation. Sleep data will be 
averaged across nights in each participant for each study period. 
 
14.3. Exploratory Analysis  
No exploratory analyses will be performed. 
 
14.4. Interim Analysis 
No interim analysis will be performed. 
 
14.5. Statistical Methods 
The respective values obtained during the 4 month randomised interventions 
contrasting the closed-loop system against the sensor augmented insulin pump 
therapy will be compared using a linear mixed model adjusting for period as a fixed 
effect and site as a random effect. The analysis dataset will be three records per 
subject (one for baseline and one for each period). Inclusion of the pre-randomization 
baseline value as a third observation for each subject in the model gives a variance 
reduction analogous to adjusting for it as a covariate. Residual values from the 
regression model will be examined for an approximate normal distribution. If values 
are highly skewed a transformation or nonparametric analyses will be used. The 
statistical analysis will include the assessment of the period effect.  
 
The primary analysis will follow the intention-to-treat principle and will be a single 
comparison. No attempt will be formally made to control the overall type I error rate for 
the secondary outcomes. A 5% significance level will be used to declare statistical 
significance for the primary comparison.  
 
For the primary endpoint and key secondary endpoints, the familywise type I error rate 
(FWER) will be controlled at two-sided α = 0.05. A gatekeeping strategy will be used, 
where the primary endpoint will be tested first, if passing the significance testing, other 
key endpoints will be tested in the order listed below using the fixed-sequence method 
at α = 0.05: 
• 
Time spent with sensor glucose levels between 3.9 to 10.0 mmol/l  

 
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• 
Time spent above target glucose (10.0 mmol/l) 
• 
Average of glucose levels 
• 
HbA1c 
• 
Time spent below target glucose (3.9 mmol/l) 
This process continues iteratively moving to the next variable down on the list until a 
non-significant result (p ≥ 0.05) is observed, or all five variables have been tested.  If 
a non-significant result is encountered, then formal statistical hypothesis testing is 
terminated and any variables below on the list are not formally tested and analysis of 
these variables becomes exploratory. 
 
A per protocol analysis will be performed to replicate the primary analysis limited to 
subjects who meet the following criteria: 
 
Intervention period: Closed loop active for at least 60% of the time 
 
Control period: Sensor used for at least 60% of the time 
Consistency of treatment effect across sites will be investigated by testing for 
interaction between study intervention and study site. 
 
Severe hypoglycaemic events and ketone-positive hyperglycaemia will be tabulated 
in each treatment group, which will be compared (if enough events) using repeated 
measures logistic regression adjusting for period and whether the subject has ever 
had a prior event. We will also apply a repeated measures regression model as for the 
primary analysis to assess treatment differences in absolute terms.  
 
Safety 
data 
including 
severe 
hypoglycaemia 
events 
and 
ketone-positive 
hyperglycaemia will be tabulated for all subjects, including drop-outs and withdrawals, 
irrespective of whether CGM data are available and irrespective of whether closed-
loop was operational.  
 
14.6. Sample Size and Power Calculations 
Power calculation is based on improvements in time in target. Assuming a standard 
deviation of 18% at baseline and average improvement of time in target of 10% (41), 
31 subjects are required at the desired 80% power and an alpha level of 0.05 (two-
tailed).  
 
Up to 40 subjects could be recruited aiming for 36 completed subjects to allow for 
drop-outs.  Subjects who drop out of the study during optimisation period and within 
the first 4 weeks of the first intervention period may be replaced. 

 
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14.7. Deviations from the statistical plan 
Any deviations from the original statistical plan will be recorded and agreed by the 
Investigators.  
15. Case Report Forms 
The Case Report Form (CRF) is the printed, optical, or electronic document designed 
to record all the protocol required information to be reported to the Chief Investigator 
for each study participant. 
 
CRFs will be completed in accordance with GCP and ISO 15197;2013 Guidelines. 
Corrections to the CRF will be performed by striking through the incorrect entry and 
by writing the correct value next to the data that has been crossed out; each correction 
will be initialled and explained (if necessary) by the Investigator or the Investigator’s 
authorised staff. 
 
The electronic CRF system provides an edit feature that records the identity of the 
person making the change and retains a record of the before and after values of the 
data field(s) in question.  In addition, all eCRF changes require electronic review and 
signoff by the investigator associated with the visit. 
 
If any amendments to the protocol or other study documents are made, CRFs will be 
reviewed to determine if an amendment to these forms is also necessary. 
16. Data Management 
Confidentiality of subject data shall be observed at all times during the study.  Personal 
details for each subject taking part in the research study and linking them to a unique 
identification number will be held locally on a study screening log in the Trial Master 
File at each of the investigation centres. These details will not be revealed at any other 
stage during the study, and all results will remain anonymous. The study identification 
number will be used on the case report forms and on all the blood and serum samples 
that are collected throughout the study. Names and addresses will not be used.  
 
Electronic data will be stored on password-protected computers.  All paper records will 
be kept in locked filing cabinets, in a secure office at each of the investigation centres. 
Only members of the research team and collaborating institutions will have password 

 
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access to the anonymised electronic data. Only members of the research teams will 
have access to the filing cabinet.  Paper copies of the data will be stored for 15 years 
in line with the General Data Protection Regulation (GDPR) (EU) 2016/679. 
 
Direct access to the source data will be provided for monitoring, audits, REC review 
and regulatory authority inspections during and after the study. The fully anonymised 
data may be shared with third parties (EU or non-EU based) for the purposes of 
advancing management and treatment of diabetes.  
 
Appropriate procedures agreed by the Chief Investigator and Clinical Principal 
Investigators will be put in place for data review, database cleaning and issuing and 
resolving data queries. 
17.  Study Management 
The study will be undertaken in accordance with Good Clinical Practice (GCP). All staff 
will receive appropriate Good Clinical Practice Training. A Study Management 
Committee, and Data and Safety and Monitoring Board will be appointed for the study. 
Each recruiting site will have a designated Principal Investigator. Obtaining consent 
and recruitment to the study, CGM training, insulin pump training and closed-loop 
system training will be undertaken by appropriately trained members of the local 
teams.  A delegation log will be held at each site listing the responsibilities of staff 
members. 
17.1. Data and Safety Monitoring Board  
An independent Data Safety Monitoring Board (DSMB) will comprise a chairperson 
and two experts. The DSMB will be informed of all serious adverse events and any 
unanticipated adverse device effects/events that occur during the study. The DSMB 
will review compiled adverse event data at periodic intervals. The DSMB will report to 
the Study Management Committee any safety concerns and recommendations for 
suspension or early termination of the investigation.  
17.2. Study Management Committee  
A study management committee consisting of the Chief Investigator, Study 
Coordinator, and Study Data Manager will be responsible for the day to day 
management of the trial. The Principal Clinical Investigators may also participate. 
17.3. Study Monitoring  

 
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The Study Coordinator will ensure that the study is conducted in accordance with ICH 
GCP standards through site monitoring visits. A monitoring plan will be written and 
agreed prior to randomisation. 
18.  Responsibilities 
18.1. Chief Investigator 
The Chief Investigator (CI) is the person with overall responsibility for the research and 
all ethical applications will be submitted by the CI. The CI is accountable for the 
conduct of the study and will ensure that all study personnel are adequately qualified 
and informed about the protocol, any amendments to the protocol, the study 
treatments and procedures and their study related duties.  The CI should maintain a 
list of appropriately qualified persons to whom he/she has delegated specified 
significant study-related duties.  
18.2. Principal Clinical Investigators 
The Principal Clinical Investigators at each investigation centre will be responsible for 
the day-to-day conduct of the clinical aspects of the study.  
18.3. Study Coordinator 
The Study Coordinator will provide day-to-day support for the sites and provide training 
through Principal Investigator meetings, site initiation and routine monitoring visits. 
19.  Ethics 
The study will be conducted in accordance with the Declaration of Helsinki Ethical 
Principles for Medical Research involving Human Subjects (64th WMA General 
Assembly, Fortaleza, Brazil, October 2013).  
19.1.  Independent Research Ethics Committees  
Prior to commencement of the study, the protocol, any amendments, subject 
information and informed consent and assent forms, any other written information to 
be provided to the subject, subject recruitment procedures, current investigator CVs, 
and any other documents as required by the Research Ethics Committee will be 
submitted. Written approval will be obtained from the REC prior to the commencement 
of the study.  Any additional requirements imposed by the REC or regulatory authority 
shall be followed. 
19.2.  Informed consent of study subjects 

 
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In obtaining and documenting informed consent, the investigator will comply with the 
applicable regulatory requirements and will adhere to GCP standards and to the ethical 
principles that have their origin in the Declaration of Helsinki. Prior to the start of the 
study, the Investigator will obtain favourable ethical opinion of the written informed 
consent form, assent form and any other written information to be provided to subjects. 
 
Subjects will be given full verbal and written information regarding the objectives and 
procedures of the study and the possible risks involved. The study team will avoid any 
coercion or undue improper inducement of the subject to participate and subjects will 
be given ample time to consider participation in the study.  Subjects will be informed 
about their right to withdraw from the study at any time. 
 
The subject will be informed in a timely manner should any new information become 
available during the course of the study that may affect their well-being, safety and 
willingness to participate in the study. 
 
Written consent will be obtained from participants according to REC requirements. The 
signed informed consent forms will be photocopied, originals filed in the Investigator’s 
Site File, and a copy placed in the patient’s notes and a copy given to the subjects.  
 
20. Timetable 
Inclusion of the first subject in the study is planned to take place in Q2 2019. The 
expected completion of the last subject is Q4 2020 and the planned completion of the 
Clinical Study Report is Q1 2021. 
21. Amendments to the Protocol 
Any substantial amendments to the protocol and other documents shall be notified to, 
and approved by, the Research Ethics Committee, and the regulatory authority, prior 
to implementation as per nationally agreed guidelines. 
22. Deviations from Protocol 
Deviations from the protocol should not occur without prior approval of the REC or 
Sponsor except under emergency circumstances, to protect the rights, safety and well-
being of subjects. If deviations do occur, they will be documented, stating the reason 
and the date, the action taken, and the impact for the subject and for the study. The 
documentation will be kept in the Investigator’s Site File.  Deviations will be logged 

 
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electronically and will require chief investigator or local principal investigator 
acknowledgement and sign-off. 
 
Deviations affecting the subject’s rights, safety and well-being or the scientific integrity 
of the study will be reported to the REC and Sponsor as soon as possible/ in a timely 
manner, following nationally agreed guidelines. 
23. Reports and Publications 
Data will be published in internationally peer-reviewed scientific journals; members of 
the investigator group will all be co-authors. The privacy of each subject and 
confidentiality of their information shall be preserved in reports and publication of data. 
24. Retention of Study Documentation 
Subject notes must be kept for the maximum of time period as permitted by relevant 
institutions. Other source documents and the Investigator’s Site File must be retained 
for at least 15 years in line with the General Data Protection Regulation (GDPR) (EU) 
2016/679. The Principal Investigator will archive the documentation pertaining to the 
study in an archive after completion or discontinuation of the study. 
25. Indemnity Statements 
 Cambridge University Hospitals NHS Foundation Trust, as a member of the NHS 
Clinical Negligence Scheme for Trusts, will accept full financial liability for harm caused 
to participants in the clinical trial caused through the negligence of its employees and 
honorary contract holders. There are no specific arrangements for compensation 
should a participant be harmed through participation in the trial, but no-one has acted 
negligently. 
 
The University of Cambridge will arrange insurance for negligent harm caused as a 
result of protocol design and for non-negligent harm arising through participation in the 
clinical trial. 
 
 

 
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