An Open-label, Multi-centre, Randomised, Parallel Design Study to Assess the Efficacy of Flash Glucose Monitoring in Adults With Sub-optimally Controlled Type 1 Diabetes.
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Sponsor: Manchester University NHS Foundation Trust

 
 
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Clinical Study Protocol 
 
 
Study Title: 
An open-label, multi-centre, randomised, parallel design study to 
assess the efficacy of flash glucose monitoring in adults with sub-
optimally controlled type 1 diabetes 
                             
 
Short Title:   
Flash-glucose monitoring in sub-optimally controlled type 1 
diabetes (FLASH-UK) 
 
Protocol Version: 
4.0  
29 June 2020 
 
 
 
 
 
 
 
 
IRAS Number: 257593 
 
Clinical Trials.gov Number: NCT03815006 (24th January 2019) 
 
Sponsor’s Number: G64079 / B00373 
 
Funder’s Number: 18/0005836 
 
 
 
 
 
 
 
This protocol has been written in accordance with the current ISO 14155:2011 standard and has regard for 
HRA guidance

 
 
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KEY TRIAL CONTACTS 
 
 
Chief Investigator 
 
Dr Lalantha Leelarathna 
University of Manchester / Manchester University NHS Foundation Trust 
Manchester Diabetes Centre, Manchester Royal Infirmary, 
Hathersage Road, Manchester M13 9WL.  
UK 
Tel: 0161 276 6709 
Fax: 0161 273 6184 
 
Email: Lalantha.leelarathna@mft.nhs.uk 
 
 
Principal 
Clinical 
Investigators  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr Emma Wilmot 
University Hospitals of Derby and Burton NHS Foundation Trust                                
Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE.  
UK 
Phone: +44 1332787696 
E-mail: emma.g.wilmot@gmail.com 
 
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 Iain Cranston 
Academic Department of Diabetes & Endocrinology 
Queen Alexandra Hospital, Cosham, Portsmouth, PO6 3LY 
UK 
Phone: 02392 286044 
Fax:   02392 286791 
E-mail: Iain.cranston@porthosp.nhs.uk 
 
Dr Parth Narendran 
Institute of Immunology and Immunotherapy 
College of Medical and Dental Sciences 
University of Birmingham, Edgbaston, Birmingham B15 2TT 
UK 
Phone: 0121 414 3006 
E-mail: p.narendran@bham.ac.uk 
 
Dr Sankalpa Neupane 
Norfolk and Norwich University Hospitals NHS Foundation Trust 
Colney Lane, Norwich. NR4 7UY  
UK 
Phone: 01603 286312 

 
 
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Fax:   01603 288438 
E-mail: sankalpa.neupane@nnuh.nhs.uk  
 
Prof Gerry Rayman 
Diabetes Research Office (N043)  
East Suffolk and North Essex NHS Foundation Trust 
Ipswich Hospital 
Heath Road  
Ipswich IP4 5PD 
E-mail: Gerry.Rayman@esneft.nhs.uk  
 
Dr Sarah Lumley 
The Adam Practice 
Upton 
Poole, Dorset BH16 5PW 
Phone: 01202 339050 
E-mail: Sarah.lumley@dorsetgp.nhs.uk;  
 
Other Co-
Investigators 
 
 
 
 
 
 
 
 
 
 
Prof Rachel Elliott (Lead Health Economist) 
Division of Population Health, Health Service Research & Primary Care 
University of Manchester 
Oxford Road, Manchester M13 9PL 
UK 
Phone: 0161 275 7639 
E-mail: rachel.a.elliott@manchester.ac.uk 
 
Dr Hood Thabit 
Manchester Diabetes Centre, Manchester Royal Infirmary 
Manchester University NHS Foundation Trust / University of Manchester 
Hathersage Road, Manchester M13 9WL 
UK 
Tel: 0161 276 6709 
Fax: 0161 273 6184 
Email: Hood.Thabit@cmft.nhs.uk 
 
Dr Naresh Kanumilli 
Northenden Group Practice 
489 Palatine Road 
Northernden 
Manchester 
M22 4DH 
Tel: 0161 998 3206 
Email: nkanumilli@nhs.net 
 
Dr Smriti Gaur 
Norfolk and Norwich University Hospitals NHS Foundation Trust 
Colney Lane, Norwich. NR4 7UY  
UK 
E-mail: Smriti.Gaur@nnuh.nhs.uk  
 
Dr Rajna Golubic 

 
 
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Wellcome Trust-MRC Institute of Metabolic Science  
Box 289, Level 4, Addenbrooke's Hospital 
Hills Road, Cambridge CB2 0QQ 
UK 
E-mail: rg380@medschl.cam.ac.uk  
 
Dr Christine Kotonya 
Diabetes Consultant Physician 
University Hospitals of Derby and Burton NHS Foundation Trust 
Burton Hospitals, Belvedere Road, Burton-on-Trent, DE12 0RB 
E-mail: christine.kotonya@nhs.net  
 
Dr Sanjeev Sharma 
Diabetes Research Office (N043)  
East Suffolk and North Essex NHS Foundation Trust 
Ipswich Hospital 
Heath Road  
Ipswich IP4 5PD 
E-mail: Sanjeev.Sharma@esneft.nhs.uk  
 
Dr Christopher Sutton (Lead Statistician and Trials Methodologist) 
Division of Population Health, Health Service Research & Primary Care 
University of Manchester 
Oxford Road, Manchester M13 9PL 
UK 
Phone: 0161 306 8002 
Email: Chris.J.Sutton@manchester.ac.uk 
 
Prof Katharine Barnard (Health Psychologist) 
Barnard Health, BHR Limited 
42 Kilmiston Drive 
Fareham, Hampshire PO16 8EG 
Phone: 01329511971 
E-mail: katharinebarnard@bhrltd.com 
 
Study  
Co-ordinator  
Manchester Clinical Trials Unit (MCTU) 
Jean McFarlane Building 
University of Manchester 
Oxford Road, Manchester M13 9PL 
UK 
Phone: 0161 306 3199 
Email: Flash-uk@manchester.ac.uk 
Study Sponsor  
Manchester University NHS Foundation Trust 
Division of Research & Innovation 
Manchester Royal Infirmary, Oxford Road 
Manchester M13 9WL 
 

 
 
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Study Funder 
 
Diabetes UK 
Wells Lawrence House 
126 Back Church Lane 
London E1 1FH 
 
 
 

 
 
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PROTOCOL SIGNATURE PAGE 
 
The signature below documents the approval of the protocol entitled "An open-label, multi-centre, 
randomised, parallel design study to assess the efficacy of flash glucose monitoring in adults with 
sub-optimally controlled type 1 diabetes" version 4.0 dated 29.06.2020 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………………………. 
 
 
 
Dr Lalantha Leelarathna, Chief Investigator  
 
 

 
 
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SITE SIGNATURE PAGE (Birmingham, UK) 
 
I have read the attached protocol entitled "An open-label, multi-centre, randomised, parallel design 
study to assess the efficacy of flash glucose monitoring in adults with sub-optimally controlled type 1 
diabetes" version 4.0 dated 29.06.2020 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and the GCP Directive 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. 
 
 
 
Principal Clinical Investigator 
 
 
Name: Dr Parth Narendran 
 
 
Signature ……………………………………. Date………………………. 
 
 

 
 
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SITE SIGNATURE PAGE (Cambridge, UK) 
 
I have read the attached protocol entitled "An open-label, multi-centre, randomised, parallel design 
study to assess the efficacy of flash glucose monitoring in adults with sub-optimally controlled type 1 
diabetes" version 4.0 dated 29.06.2020 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and the GCP Directive 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. 
 
 
 
Principal Clinical Investigator 
 
 
Name: Dr Mark Evans 
 
 
Signature ……………………………………. Date………………………. 
 
 

 
 
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SITE SIGNATURE PAGE (Derby, UK) 
 
I have read the attached protocol entitled "An open-label, multi-centre, randomised, parallel design 
study to assess the efficacy of flash glucose monitoring in adults with sub-optimally controlled type 1 
diabetes" version 4.0 dated 209.06.2020 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and the GCP Directive 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. 
 
 
 
Principal Clinical Investigator 
 
 
Name: Dr Emma Wilmot 
 
 
Signature ……………………………………. Date………………………. 
 
 
 
 

 
 
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SITE SIGNATURE PAGE (Norwich, UK) 
 
I have read the attached protocol entitled "An open-label, multi-centre, randomised, parallel design 
study to assess the efficacy of flash glucose monitoring in adults with sub-optimally controlled type 1 
diabetes" version 4.0 dated 29.06.2020 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and the GCP Directive 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. 
 
 
 
Principal Clinical Investigator 
 
 
Name: Dr Sankalpa Neupane 
 
 
Signature ……………………………………. Date………………………. 
 
 

 
 
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SITE SIGNATURE PAGE (Portsmouth, UK) 
 
I have read the attached protocol entitled "An open-label, multi-centre, randomised, parallel design 
study to assess the efficacy of flash glucose monitoring in adults with sub-optimally controlled type 1 
diabetes version 4.0 dated 29.06.2020 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and the GCP Directive 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. 
 
 
 
Principal Clinical Investigator 
 
 
Name: Dr Iain Cranston 
 
 
Signature ……………………………………. Date………………………. 
 
 
 

 
 
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SITE SIGNATURE PAGE (Ipswich, UK) 
 
I have read the attached protocol entitled "An open-label, multi-centre, randomised, parallel design 
study to assess the efficacy of flash glucose monitoring in adults with sub-optimally controlled type 1 
diabetes version 4.0 dated 29.06.2020 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and the GCP Directive 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. 
 
 
 
Principal Clinical Investigator 
 
 
Name: Prof Gerry Rayman 
 
 
Signature ……………………………………. Date………………………. 
 
 

 
 
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SITE SIGNATURE PAGE (Wareham / Poole, UK) 
 
I have read the attached protocol entitled "An open-label, multi-centre, randomised, parallel design 
study to assess the efficacy of flash glucose monitoring in adults with sub-optimally controlled type 1 
diabetes version 4.0 dated 29.06.2020 and agree to abide by all provisions set forth therein. 
 
I agree to comply with the conditions and principles of Good Clinical Practice as outlined in the 
European Clinical Trials Directives 2001/20/EC and the GCP Directive 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. 
 
 
 
Principal Clinical Investigator 
 
 
Name: Dr Sarah Lumley 
 
 
Signature ……………………………………. Date………………………. 
 
 

 
 
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PROTOCOL SIGNATURE PAGE 
 
The signature below documents the approval of the protocol entitled " An open-label, multi-centre, 
randomised, parallel design study to assess the efficacy of flash glucose monitoring in adults with 
sub-optimally controlled type 1 diabetes" version 4.0 dated 29.063.2020 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………………………. 
 
 
 
Dr Chris Sutton, Lead Statistician 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
 
KEY TRIAL CONTACTS .................................................................................................................................. 2 
1 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS .................................................................... 19 
2 
STUDY SYNOPSIS ............................................................................................................................. 21 
3 
SUMMARY ....................................................................................................................................... 27 
4 
BACKGROUND ................................................................................................................................. 28 
4.1 
ADVANCES IN GLUCOSE MONITORING: ............................................................................. 28 
4.2 
FLASH-GLUCOSE MONITORING WITH FREESTYLE LIBRE DEVICE: ......................................... 29 
4.3 
EVIDENCE FROM RANDOMISED CONTROLLED TRIALS: ........................................................ 29 
4.4 
OBSERVATIONAL STUDIES .............................................................................................. 30 
4.5 
USER SATISFACTION: ..................................................................................................... 32 
4.6 
REAL-WORLD USE OF FSL: ............................................................................................ 33 
4.7 
ADVERSE EVENTS ......................................................................................................... 33 
4.8 
FREESTYLE LIBRE 2 FLASH-GLUCOSE MONITORING SYSTEM TO BE USED IN THE PRESENT STUDY
 ................................................................................................................................... 34 
4.9 
34 
4.9 
RATIONALE FOR THE CURRENT STUDY ............................................................................ 34 
4.9.1 COVID-19 Pandemic: Supporting flexible visit schedules for vulnerable participants ... 35 
5 
OBJECTIVES ...................................................................................................................................... 35 
5.1 
CLINICAL EFFICACY ....................................................................................................... 35 
5.2 
PSYCHOSOCIAL EFFICACY .............................................................................................. 35 
5.3 
COST-EFFECTIVENESS ................................................................................................... 36 
5.4 
SAFETY ........................................................................................................................ 36 
5.5 
PROCESS EVALUATION (UTILITY & ACCEPTABILITY) .......................................................... 36 
6 
STUDY DESIGN ................................................................................................................................. 36 
7 
STUDY PARTICIPANTS ...................................................................................................................... 36 
7.1 
STUDY POPULATION ...................................................................................................... 36 
7.2 
INCLUSION CRITERIA ..................................................................................................... 38 
7.3 
EXCLUSION CRITERIA .................................................................................................... 39 
8 
METHODS UNDER INVESTIGATION .................................................................................................. 41 
8.1 
NAME AND DESCRIPTION OF THE METHOD OF INVESTIGATION ............................................ 41 
8.2 
INTENDED PURPOSE ...................................................................................................... 41 
8.3 
METHOD OF ADMINISTRATION ......................................................................................... 41 
8.4 
REQUIRED TRAINING ..................................................................................................... 41 
8.5 
PRECAUTIONS .............................................................................................................. 41 
8.6 
ACCOUNTABILITY OF THE METHOD UNDER INVESTIGATION ................................................. 41 
9 
STUDY SCHEDULE ............................................................................................................................ 42 
9.1 
OVERVIEW ................................................................................................................... 42 
9.2 
VISIT 1: RECRUITMENT VISIT AND SCREENING ASSESSMENT.............................................. 45 
9.2.1 Screening Blood Sampling .......................................................................................... 45 
9.2.2 Questionnaires at Screening ....................................................................................... 45 
9.3 
VISIT 2: INSERTION OF BLINDED GLUCOSE MONITORING DEVICE .......................................... 46 
9.4 
VISIT 3: ADHERENCE ASSESSMENT, RANDOMISATION AND START OF STUDY TREATMENT ....... 46 
9.4.1 Randomisation scheme .............................................................................................. 46 
9.4.2 Method of implementing the allocation ........................................................................ 46 
9.4.3 Initiation of study treatment ......................................................................................... 47 
9.4.4 Training session (Appendix 9) ..................................................................................... 47 
9.5 
VISIT 4: (+4 WEEKS SINCE RANDOMISATION): REVIEW DATA AND TREATMENT OPTIMISATION .. 48 
9.6 
VISIT 5: (+12 WEEKS SINCE RANDOMISATION): REVIEW DATA AND TREATMENT OPTIMISATION 48 
9.7 
VISIT 6: (+22 WEEKS SINCE RANDOMISATION): FINGER-STICK GLUCOSE MONITORING ARM ONLY48 

 
 
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9.8 
VISIT 7: (+24 WEEKS SINCE RANDOMISATION): END OF RANDOMISED STUDY TREATMENT ...... 48 
9.9 
PARTICIPANT WITHDRAWAL CRITERIA ............................................................................. 49 
9.10 
STUDY STOPPING CRITERIA ........................................................................................... 49 
9.11 
END OF TRIAL ............................................................................................................... 50 
9.12 
SUPPORT TELEPHONE LINE ............................................................................................ 50 
9.13 
PARTICIPANT REIMBURSEMENT ....................................................................................... 50 
10 
ENDPOINTS ...................................................................................................................................... 51 
10.1 
PRIMARY ENDPOINT ...................................................................................................... 51 
10.2 
SECONDARY ENDPOINTS ............................................................................................... 51 
10.2.1 HbA1c based ............................................................................................................ 51 
10.2.2 Sensor based: .......................................................................................................... 51 
10.2.3 Non- sensor based secondary clinical: ...................................................................... 52 
10.2.4 Non-sensor based secondary patient-reported (psychosocial): .................................. 52 
10.2.5 Process evaluation (utility and acceptability) ............................................................. 52 
11 
ASSESSMENT AND REPORTING OF ADVERSE EVENTS ...................................................................... 53 
11.1 
DEFINITIONS ................................................................................................................. 53 
11.1.1 Reportable Adverse Events ...................................................................................... 53 
11.1.2 Adverse Events ........................................................................................................ 53 
11.1.3 Adverse Device Effect .............................................................................................. 53 
11.1.4 Serious Adverse Event ............................................................................................. 53 
11.1.5 Serious Adverse Device Effect .................................................................................. 54 
11.1.6 Unanticipated Serious Adverse Device Effect............................................................ 54 
11.1.7 Device Deficiencies .................................................................................................. 54 
11.1.8 Adverse Event Intensity ............................................................................................ 54 
11.1.9 Adverse Event Causality ........................................................................................... 55 
11.2 
RECORDING AND REPORTING OF ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND DEVICE 
DEFICIENCIES ............................................................................................................... 56 
11.2.1 Monitoring Period of Adverse Events ........................................................................ 56 
11.2.2 Recording and Reporting of Adverse Events ............................................................. 56 
11.2.3 Severe Hypoglycaemia ............................................................................................. 56 
11.2.4 Reporting of Serious Adverse Events and Serious Adverse Device Effects ............... 57 
11.2.5 Recording and Reporting of Device Deficiencies ....................................................... 58 
11.2.6 Reporting Urgent Safety Measures ........................................................................... 58 
11.2.7 Healthcare Arrangements and Compensation for Adverse Events ............................. 59 
11.3 
EXPECTED ADVERSE EVENTS, RISKS AND BENEFITS......................................................... 59 
11.3.1 Risks and expected adverse events .......................................................................... 59 
11.3.2 Hypoglycaemia and Hyperglycaemia ........................................................................ 59 
11.3.3 Blood Sampling ........................................................................................................ 60 
11.3.4 Finger-prick Blood Glucose Measurements ............................................................... 60 
11.3.5 Insulin Pump Therapy ............................................................................................... 60 
11.3.6 Flash Glucose Monitoring ......................................................................................... 60 
11.3.7 Questionnaires ......................................................................................................... 61 
11.4 
BENEFITS ..................................................................................................................... 61 
11.5 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ..................................................... 61 
12 
DATA COLLECTION ........................................................................................................................... 62 
12.1 
PROCEDURES ............................................................................................................... 62 
12.1.1 Height and Weight .................................................................................................... 62 
12.1.2 Subcutaneous Glucose Monitoring............................................................................ 62 
12.1.3 Insulin Pump Data .................................................................................................... 62 
12.2 
QUESTIONNAIRES ......................................................................................................... 62 
12.2.1 Questionnaires ......................................................................................................... 62 
12.3 
LABORATORY METHODS ................................................................................................ 63 
12.3.1 HbA1c ...................................................................................................................... 63 
12.4 
TOTAL BLOOD LOSS ...................................................................................................... 63 
13 
STUDY MATERIALS AND PRODUCTS................................................................................................. 64 
13.1 
FLASH GLUCOSE MONITOR ............................................................................................ 64 

 
 
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13.2 
STANDARD BLOOD GLUCOSE METERS ............................................................................ 64 
13.3 
INSULIN PUMPS ............................................................................................................. 64 
PARTICIPANTS ALREADY ON INSULIN PUMP THERAPY WILL CONTINUE THEIR USUAL INSULIN PUMP 
THROUGHOUT THE STUDY. ............................................................................................. 64 
13.4 
INSULIN ........................................................................................................................ 64 
PARTICIPANTS WILL CONTINUE THEIR USUAL INSULIN THERAPY THROUGHOUT THE STUDY. ................. 64 
14 
STATISTICS AND DATA ANALYSIS ..................................................................................................... 64 
14.1 
SAMPLE SIZE ................................................................................................................ 64 
14.2 
STATISTICAL ANALYSIS PLAN (SAP) ............................................................................... 65 
14.2.1 Primary Outcome ...................................................................................................... 66 
14.2.2 Secondary Outcomes ............................................................................................... 66 
14.2.3 Subgroup analysis .................................................................................................... 67 
14.2.4 Interim analysis ........................................................................................................ 68 
14.3 
ECONOMIC ANALYSIS ..................................................................................................... 68 
14.3.1 Incremental economic analysis for both economic evaluations .................................. 69 
14.4 
PROCESS EVALUATION ANALYSIS ................................................................................... 70 
15 
CASE REPORT FORMS ...................................................................................................................... 71 
16 
DATA MANAGEMENT ...................................................................................................................... 71 
17 
STUDY MANAGEMENT ..................................................................................................................... 72 
17.1 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ..................................................... 72 
17.2 
TRIAL STEERING COMMITTEE (TSC) ............................................................................... 72 
17.3 
TRIAL MANAGEMENT GROUP (TMG) ............................................................................... 73 
17.4 
STUDY MONITORING ...................................................................................................... 73 
18 
RESPONSIBILITIES ............................................................................................................................ 73 
18.1 
CHIEF INVESTIGATOR .................................................................................................... 73 
18.2 
PRINCIPAL CLINICAL INVESTIGATORS .............................................................................. 74 
18.3 
STUDY COORDINATORS ................................................................................................. 74 
19 
ETHICS ............................................................................................................................................. 74 
19.1 
RESEARCH ETHICS COMMITTEE AND HRA APPROVAL ....................................................... 74 
19.2 
INFORMED CONSENT OF STUDY PARTICIPANTS ................................................................ 74 
20 
AMENDMENTS TO THE PROTOCOL .................................................................................................. 75 
21 
DEVIATIONS FROM THE PROTOCOL ................................................................................................. 75 
22 
TIMETABLE ...................................................................................................................................... 76 
23 
REPORTS AND PUBLICATIONS .......................................................................................................... 76 
24 
RETENTION OF STUDY DOCUMENTATION ....................................................................................... 76 
25 
INDEMNITY STATEMENTS ................................................................................................................ 76 
26 
APPENDICES .................................................................................................................................... 77 
26.1 
APPENDIX 1: EQ-5D-5L QUESTIONNAIRE......................................................................... 77 
26.2 
APPENDIX 2: GLUCOSE MONITORING SATISFACTION SURVEY ............................................ 79 
26.3 
APPENDIX 3: PATIENT HEALTH QUESTIONNAIRE 9 ............................................................ 81 
26.4 
APPENDIX 4: DIABETES TREATMENT SATISFACTION .......................................................... 82 
26.5 
APPENDIX 5: DIABETES FEAR OF INJECTING AND SELF-TESTING (D-FISQ) QUESTIONNAIRE ... 83 
26.6 
APPENDIX 6: DIABETES EATING PROBLEM SURVEY ........................................................... 85 
26.7 
APPENDIX 7: TYPE 1 DIABETES DISTRESS SURVEY ........................................................... 86 
26.8 
APPENDIX 8: CLARKE QUESTIONNAIRE AND GOLD SCORE ................................................. 88 
26.9 
APPENDIX 9: OUTLINE OF EDUCATIONAL CURRICULUM: FLASH-UK STUDY .......................... 90 
26.10 
APPENDIX 10: ASSESSING EXPECTATIONS AND EXPERIENCE OF USING FREESTYLE      LIBRE 2 
DURING FLASH-UK CLINICAL TRIAL ............................................................................... 92 
26.11 
APPENDIX 11: PROCESS EVALUATION, TOPIC GUIDE: PARTICIPANTS................................... 93 

 
 
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26.12 
APPENDIX 12: PROCESS EVALUATION, TOPIC GUIDE: HEALTH PROFESSIONALS AND TRIALLISTS
 ................................................................................................................................... 94 
26.13 
APPENDIX 13: FLASH-UK STUDY: PARTICIPANT DIARY .................................................... 97 
26.14 
APPENDIX 14: PARTICIPANT INFORMATION LEAFLET FREESTYLE LIBRE 2 TREATMENT ARM ... 98 
26.15 
APPENDIX 15: PARTICIPANT INFORMATION LEAFLET SELF-MONITORING BLOOD GLUCOSE 
CONTROL ARM ........................................................................................................... 107 
REFERENCES ............................................................................................................................................ 109 
 
 

 
 
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1 List of Abbreviations and Relevant Definitions  
 
ABCD 
Association of British Diabetologists 
ADE 
Adverse Device Effect 
ASADE 
Anticipated Serious Adverse Device Effect 
AE 
Adverse Event 
AR 
Adverse Reaction 
AUC 
Area Under the Curve 
CE 
Conformité Européenne (CE-mark) 
CEACs 
Cost-effectiveness Acceptability Curves 
CGM 
Continuous Glucose Monitoring 
CRF 
Case Report Form 
CoI 
Conflict of Interest 
CONSORT Consolidated Standards of Reporting Trials 
CTU 
Clinical Trials Unit 
CSII 
Continuous subcutaneous insulin infusion 
DKA 
Diabetic Ketoacidosis 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
FDA 
US Food and Drug Administration 
FSL 
FreeStyle Libre  
FSL2 
FreeStyle Libre 2 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GLP-1 
Glucagon-like peptide-1 
HbA1c 
Glycated haemoglobin (A1c) 
HCG 
Human Chorionic Gonadotropin 
HRA 
Health Research Authority 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intention to Treat 

 
 
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MAO 
Monoamine Oxidase 
MDI 
Multiple Daily Injection 
MHRA 
Medicine and Healthcare products Regulatory Agency 
NIMP 
Non-Investigational Medicinal Product 
PAID 
Problem Areas in Diabetes 
PIC 
Participant Identification Centre 
PPI 
Patient and Public Involvement 
PSS 
Prescribed Specialised Services 
QALYs 
Quality-Adjusted Life Years 
R & D 
Research and Development 
REC  
Research Ethics Committee 
s.c. 
Subcutaneous 
SADE 
Serious Adverse Device Effect  
SAE 
Serious Adverse Event  
SAP 
Sensor Augmented Pump Therapy 
SGLT2 
Sodium-glucose co-transporter-2 
SMBG 
Self-monitoring of blood Glucose 
T1D 
Type 1 Diabetes Mellitus 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
USADE 
Unanticipated Serious Adverse Device Effect 
 

 
 
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2 Study Synopsis  
 
Title of clinical trial 
An open-label, multi-centre, randomised, parallel 
design study to assess the efficacy of flash glucose 
monitoring in adults with sub-optimally controlled type 
1 diabetes  
Short Title 
Flash-glucose monitoring in sub-optimally controlled 
type 1 diabetes (FLASH-UK) 
Sponsor 
Manchester University NHS Foundation Trust 
Medical condition or disease 
under investigation 
Type 1 diabetes 
Clinical trial phase 
Device Trial with CE marked Device 
Purpose of clinical trial 
To determine whether flash glucose monitoring with 
Freestyle Libre 2 (FSL2) device will improve glucose 
control over a 24-week period compared to self-
monitoring of blood glucose in adults and adolescents 
(16 or older) with sub-optimally controlled type 1 
diabetes. 
Study objectives 
The study objective is to compare flash glucose 
monitoring with FSL2 device vs. self-monitoring of 
blood glucose over 24 weeks in adults and adolescents 
(16 or older) with sub-optimally controlled (HbA1c 7.5% 
to 11%) type 1 diabetes 
1. EFFICACY: The objective is to assess the efficacy 
of flash glucose monitoring with FSL2 device 
and self-monitoring of blood glucose on 
glycated haemoglobin A1c (HbA1c) 
2. SAFETY: The objective is to evaluate time spent 
in hypoglycaemia (sensor glucose levels < 3.0 
mmol/l) and episodes of severe hypoglycaemia 
with FSL2 and self-monitoring of blood glucose 
3. UTILITY AND ACCEPTANCE: The objective is to 
determine the frequency of daily scans, 
duration of use of FSL2 device and explore 
participant’s expectations and experience of 
using FSL2 device 
4. PSYCHOSOCIAL: The objective is to evaluate 
participants’ responses in terms of quality of 
life, diabetes distress, low mood, needle 
burden, disordered eating and   diabetes 
treatment satisfaction 
5. COST EFFECTIVENESS: To assess the relative 
cost-effectiveness of the FSL2 device compared 
with self-monitoring in adults and adolescents 

 
 
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(16 
years 
or 
older) 
with 
sub-optimally 
controlled 
type 
1 
diabetes, 
from 
the 
perspective of NHS England. 
Study Design  
An open-label, randomised, parallel design study, for 24 
weeks 
 
Primary endpoint 
 
 
The primary outcome is HbA1c at 24 weeks. 
Key Secondary endpoint(s) 
 
Time spent in the target glucose range between 
3.9 to 10.0 mmol/l (70 to 180mg/dl) based on 
sensor glucose levels. 
 
Time spent below target glucose (<3.9mmol/l) 
(<70mg/dl) 
 
Time spent above target glucose (10.0 mmol/l) 
(180 mg/dl)  
 
Average and standard deviation glucose levels 
 
Coefficient of variation glucose levels  
 
The time with sensor glucose levels < 3.5 
mmol/l  (63 mg/dl), <3.0 (54mg/dl) and <2.8 
mmol/l (50 mg/dl) 
 
The time with sensor glucose levels in the 
significant hyperglycaemia (glucose levels > 
16.7 mmol/l) (300mg/dl) 
 
AUC of glucose below 3.0mmol/l (54mg/dl) 
 
Average total daily insulin dose, basal and bolus 
dose 
 
Average number of boluses of rapid acting 
insulin administered per day 
 
HbA1c at 12 weeks 
 
HbA1c ≤ 53 mmol/mol (7.0%) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 
HbA1c ≤ 59 mmol/mol (7.5%) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 
Reduction in HbA1c ≥5.5 mmol/mol (0.5%) from 
baseline (screening) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 
Reduction in HbA1c ≥ 11 mmol/mol (1.0%) from 
baseline (screening) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 

 
 
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Safety Evaluation 
 
Frequency of severe hypoglycaemic episodes as 
defined by American Diabetes Association 
 
Frequency of significant ketosis events (plasma 
ketones >3mmol/l) 
 
Nature and severity of other adverse events. 
Psychosocial and usability 
evaluation 
 
Evaluation of participants’ responses in terms 
of quality of life, diabetes distress, depression, 
needle burden, disordered eating and diabetes 
treatment satisfaction using EQ-5D-5L 
questionnaire, Type 1 Diabetes Distress Scale 
(T1-DDS), Diabetes fear of injecting and self-
testing (D-FISQ) questionnaire, Diabetes Eating 
Problem Survey (DEPS-R), Diabetes Treatment 
Satisfaction Questionnaire (DTSQ), Patient 
Health Questionnaire (PHQ-9) and The Glucose 
Monitoring Satisfaction Survey (GMSS). An 
additional questionnaire will explore 
participant’s expectations and experience of 
using FSL2 device for those in the FSL2 arm 
Sample size 
Assuming a standard deviation of 0.8% and treatment 
difference of 0.4% - 128 participants (64 per each arm) 
with primary outcome will give 80% power to detect 
the difference between treatment groups at 2-sided 
type 1 error = 5%.  Recruitment target is 180 
participants (25 to 30 per centre) aiming for 150 to be 
randomised following the adherence run-in period, and 
allowing for 15% post-randomisation attrition. 
Summary of eligibility criteria 
Key inclusion criteria: 
1. The participant is ≥16 years old 
2. The participant has type 1 diabetes, as defined 
by WHO for at least 1 year or is confirmed C-
peptide negative if duration of diabetes is < 1 
years 
3. Participant is treated with insulin pump or 
multiple daily injection for at least 12 weeks 
and no plans to change treatment modality 
during next 28 weeks  
4. The participant is literate in English for safe 
study conduct 
5. Screening HbA1c  ≥ 7.5% (58.5mmol/mol) and 
≤ 11% (97 mmol/mol) based on analysis from 
local, central or third party external laboratory  
6. The participant is literate in English 
7. The participant is willing to wear study glucose 
sensor and scan for glucose levels at regular 
intervals,  
8. The participant is willing to follow study 
specific instructions and improve glucose 
control 
9. Female participants of child bearing age 

 
 
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should be on effective contraception or not 
sexually active / no plans for pregnancy  
 
Key exclusion criteria: 
1. Non-type 1 diabetes mellitus including those 
secondary to chronic disease 
2. Any other physical disease or people with 
known severe mental illness (psychotic 
disorder, bipolar disorder, dementia, substance 
and alcohol dependence, learning disabilities, 
depression with active suicidal ideation) which 
are likely to interfere with the normal conduct 
of the study and interpretation of the study 
results as judged by the investigator  
3. Current users of real-time glucose monitoring 
sensors or flash-glucose monitoring for more 
than 4 weeks within last 12 weeks 
4. Initiation of medications/treatments known to 
interfere with glucose metabolism (e.g: 
metformin, SGLT2 inhibitors, GLP-1 agonists, 
Pramlinatide) within the last 6 weeks or 
planning to start these medications within the 
next 6 months (patients on stable treatment is 
not an exclusion) or current or planned 
glucocorticoid use other than inhaled/ topical 
use 
5. Known or suspected allergy against insulin 
6. Severe visual impairment  
7. Complete loss of hypoglycaemia awareness 
8.  Patient receiving dialysis / pre-dialysis based on 
history  
9. More than one episode of severe 
hypoglycaemia as defined by American 
Diabetes Association (30) in preceding 24 weeks 
10. Pregnancy, Planned Pregnancy in the next 8 
months or breast feeding 
 
 
Recruitment 
Participants will be recruited through diabetes clinics at 
participating centres as well as throughout the nation of 
England through social and other local / national media. 
Each centre may also utilise participant identifying 
centres to help recruitment. The Study may be 
advertised  within GP practices.  . This will facilitate self-
referral from interested candidates for screening and 
optimise trial recruitment across centres. 
  
1. Manchester University Foundation Trust 
2. University Hospitals of Derby and Burton NHS 
Foundation Trust  
3. University 
Hospitals 
Birmingham 
NHS 

 
 
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Foundation Trust 
4. Addenbrookes Hospital, Cambridge 
5. Norfolk and Norwich University Hospital, 
Norwich 
6. Queen Alexandra Hospital, Portsmouth 
7. Ipswich Hospital, East Suffolk and North Essex 
NHS Foundation Trust, Ipswich 
8. Wareham Surgery (Wareham) and The Adam 
Practice (Poole), NHS England Primary Care GP 
Practices 
 
Each centre will aim to recruit up to 30 participants. 
If participants are outside the catchment area of the 
clinic, we will contact the clinical team responsible for 
the participant to confirm type 1 diabetes status and 
any other contraindications for study participation. 
Maximum duration of study for a 
participant 
30 weeks  
Consent 
Participants will provide written informed consent 
before any study procedures. Eligible participants who 
choose to join the trial through virtual consultation 
because of Covid-19 will receive a consent form at 
home which can be signed and returned to the research 
team before scheduling the first virtual visit.   
Baseline assessment 
Eligible participants will undergo a baseline evaluation 
of  HbA1c using the local laboratory (face to face clinic) 
or a home HbA1c where the participant will collect a 
blood sample using a self-test kit and send in a pre-paid 
envelope to a central or third party external laboratory.  
Questionnaires as mentioned above will also be 
completed either during face to face clinics or by postal 
delivery for virtual consultations.  
Run-in Period 
During the 2-week run-in period, blinded FSL2 will be 
worn by participants to ensure that participants are 
able to wear and tolerate subcutaneous glucose 
sensors, and for glucose data collections. Eligible 
participants who join the trial by virtual consultation 
will receive a Blinded FSL2 pro sensor and reader by 
post for self-insertion with relevant advice. 
 
Randomisation 
Eligible 
participants 
will 
be 
randomised 
using 
randomisation software to the use of flash glucose 
monitoring with FSL2 or self-monitoring of blood 
glucose. Randomisation, using minimisation (with a 
random component) will take into account among other 
factors, centre, baseline HbA1c, treatment modality 
(MDI vs. Continuous Subcutaneous insulin Infusion 
(CSII), previous participation of structured education 
course & current use of bolus calculator. 
1. Flash glucose monitoring 
Training and education on the use of FSL2 will be 
provided by the research team either in person or 

 
 
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during a remote video consultation supported by online 
education material developed by Diabetes Technology 
Network. Participants will be advised to use flash 
glucose monitoring continuously for the next 24 weeks.  
  
2. Self-monitoring of blood 
glucose 
Masked FSL2 will be applied for two weeks, during the 
last two weeks of control period. Education will focus 
on using finger-stick measurement for treatment 
optimisation with education provided either in person 
or during a remote video consultation supported by 
online 
educational 
material 
such 
as 
Bertie 
Online(www.bertieonline.org.uk). Blinded FSL2 will be 
posted to participants where necessary for self-
insertion with relevant advice. 
 
End of 24 week assessments 
- A blood sample will be taken for measurement of 
HbA1c using the local laboratory (face to face clinic) or a 
home HbA1c where the participant will collect a blood 
sample using a self-test kit and send in a pre-paid 
envelope to a central or third party external laboratory. 
- Validated questionnaires as described before 
evaluating quality of life, mood, needle burden, 
disordered eating, diabetes distress and diabetes 
treatment satisfaction will be completed either during 
face to face clinics or by postal delivery for virtual 
consultations. 
Additional questionnaire for those in the FSL2 arm 
exploring expectations and experience of using FSL2 
during the study will also be administered. 
 
Procedures for safety monitoring 
during trial 
Standard operating procedures for reporting all adverse 
events will be in place.  
 
 
 

 
 
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3 Summary 
 
 
FreeStyle Libre 2 (FSL2) is a novel glucose monitoring device (Flash glucose) in the form of a disc 
worn on the arm for 14 days and a hand-held reader which is designed to largely replace the 
recommended 4-10 painful finger-stick blood glucose tests required each day for the self-
management of type1diabetes. The purpose of this study is to determine whether flash glucose 
monitoring with FSL2 device will improve HbA1c over a 24-week period compared to self-monitoring 
of blood glucose in adults and adolescents (16 years or older) with sub-optimally controlled (HbA1c 
7.5% to 11%) type 1 diabetes.  
 
This is an open-label, multi-centre, randomised, parallel design study, involving a 2-week run-in 
period, followed by a 24-week study period during which participants will use either FSL2 or 
continue usual finger-stick glucose monitoring in random order. A total of up to 180 participants 
(aiming for 150 randomised and 128 completed participants) aged 16 years and older with T1D on 
insulin pump therapy or multiple daily injection therapy will be recruited through diabetes clinics or 
via online advertisement in participating centres.  
 
Participants will receive appropriate training to maximise benefits of FSL2 in self-management. The 
primary outcome is difference in HbA1c between the two groups at 24 weeks. Secondary outcomes 
are time spent with glucose levels above and below target, as recorded by FSL2, and other flash 
glucose-based metrics. Impact on quality of life, diabetes distress, mood, needle burden, disordered 
eating and treatment satisfaction will also be undertaken. Relative cost-effectiveness of FSL2 device 
compared with self-monitoring will also be assessed from a UK NHS perspective.  

 
 
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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 
(1). It is one of the commonest endocrine and metabolic conditions in both children and adults. It is 
estimated that approximately 415 million adults (5-15% type 1 diabetes) and 520,000 children (95% 
type 1 diabetes) worldwide suffer from diabetes (2) . 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).  
 
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 (4) and they are prone to get 
complications associated with poor control such as kidney failure and blindness (5). In England less 
than one third of patients with type 1 diabetes achieve a HbA1c level <7.5% (6) . 
 
Studies have shown strong relationship with number of finger-stick glucose tests and HbA1c (7). 
However due to pain, inconvenience and accumulated trauma finger-stick glucose monitoring 
remains a key barrier in achieving near normal glucose levels.  
 
4.1 Advances in glucose monitoring: 
 
In contract to finger-stick glucose monitoring, continuous glucose monitors (CGM) can provide 
continuous real-time glucose information as well as glucose trend information (8). In 1999 MiniMed 
received FDA approval for the first retrospective continuous glucose monitor (CGM) device in the 
USA (9). Since then, a number of CGM options have been introduced including MiniMed iPro, Enlite 
2, Enlite Enhanced, Enlite 3 (Medtronic Inc, Northridge, CA, USA), DexCom STS (Short Term Sensor), 
Dexcom 3, 7, Gen 4 and 5 (Dexcom Inc, San Diego, CA, USA), and Navigator I and II (Abbott Diabetes 
Care, Alameda, CA, USA). These devices have been evaluated in a range of studies in a variety of 
patient groups, using both multiple daily injections (MDI)(10; 11) and continuous subcutaneous 
insulin infusion (CSII)(12; 13) which have  demonstrated the consistent use of CGM is associated with 
improvements in HbA1c and reductions in hypoglycaemia. However, widespread adoption of these 

 
 
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devices has been hampered by several factors including cost, accuracy of earlier devices and user 
acceptability.  
 
4.2 Flash-glucose monitoring with FreeStyle Libre device: 
 
Three years ago, in 2014 a new category of device was born: the FreeStyle Libre Flash Glucose 
Monitoring System (FSL) (Abbott Diabetes Care, Oxon, UK). This device is different to earlier CGM 
systems. Although it does produce real-time on-demand continuous glucose data, it does not alarm 
to alert users of rising or falling glucose levels. Hence the label: ‘flash glucose monitoring’. The FSL 
device is a replaceable white disc, worn on the arm for 14 days. The sensor utilises wired enzyme 
technology (14) (osmium mediator and glucose oxidase enzyme co-immobilised on electrochemical 
sensor) to continuously measure interstitial glucose levels. It is factory calibrated and does not need 
calibration during use. Abbott provided potential users with the option of direct on-line purchase of 
FSL, without prior approval from health care providers. The Freestyle Libre (FSL) flash glucose 
monitor became available on prescription (subject to local health authority approval) in all four 
nations of the United Kingdom from November 2017, a watershed moment in the history of diabetes 
care. Freestyle Libre 2 (which is CE marked) has been produced by the manufacturer. This is identical 
to FSL but with the optional additional functionality of alarm alerts for users who fall outside of 
adequately controlled glucose levels. This model has yet to be assigned an official release date for 
the United Kingdom.  
 
4.3 Evidence from randomised controlled trials: 
 
The largest study to evaluate FSL is the IMPACT randomised controlled multicentre European trial 
(15). This study included 328 participants with well controlled (HbA1c <= 7.5%, 59 mmol/mol) Type 1 
diabetes, a third of which used CSII therapy. FSL use was associated with improvement in a range of 
glucose related outcomes: a 38% reduction in time spent in hypoglycaemia (<3.9 mmol/l) with no 
change in total daily insulin dose.  The reduction in hypoglycaemia was achieved within 2 weeks, 
despite no training on glucose data interpretation and no health care professional contact during 
this initial period, suggesting that users intuitively understood how to react to the data (Figure 1). 
There was an increase in glucose time in range combined with a reduction in glycaemic variability. 
The HbA1c was unchanged.  

 
 
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FSL users in the IMPACT study were scanning an average of 15 times/ day, a behaviour sustained 
over the 6 month follow up period. FSL utilisation was high and sustained at >90%, a reflection of the 
high treatment satisfaction described. Users performed 0.5 blood glucose tests per day or one blood 
glucose tests every 2-5 days. Despite this, there was a reduction in hypoglycaemia, providing support 
for the non-adjunctive use of flash glucose monitoring, in line with the product label. It is important 
to highlight that those with impaired awareness of hypoglycaemia (IAH) were not included in 
IMPACT and the study results are not generalisable to this high-risk group, who are likely to be 
reliant on alarms to alert them to impending hypoglycaemia. 
 
Reddy et al from London have assessed FSL in a randomised parallel group study compared to real 
time CGM (Dexcom G5) in patients with Type 1 diabetes and IAH (16). After a 2-week run in, 32 
participants using intensified multiple daily injections were randomised to either Dexcom G5 CGM or 
FSL for 8 weeks (Preliminary analysis, conference abstract). The reduction in percentage time spent 
in hypoglycaemia was significantly greater in those using the Dexcom G5 compared to FSL (D=3.6, 
p=0.034). The difference in the reduction in the Gold score was greater with the G5 compared to FSL 
(D=1.1, p=0.029). The percentage of time in target was significantly greater for both devices. They 
concluded that real-time CGM has significantly greater benefit in those with IAH than FSL. These 
findings lend support to the current NICE recommendations for CGM use in Type 1 diabetes (17). 
 
The impact of FSL was assessed in those with Type 2 diabetes on intensive insulin therapy in a large 
multi-centre European study of 224 participants (18). Despite less frequent senor scans than was 
seen in IMPACT (8 vs 15 per day), time in hypoglycaemia (<3.9mmol/l) reduced by 0.47±0.13 h/day 
compared with controls, representing a 43% reduction in hypoglycaemia. HbA1c was unchanged. 
Treatment satisfaction was higher in users and no device related serious adverse events were 
reported, suggesting that flash glucose monitoring also offers a suitable replacement to SMBG in 
those with Type 2 diabetes who are on intensive insulin therapy. 
 
4.4 Observational studies 
 
A range of observational studies have evaluated the FSL. Dover et al prospectively assessed the FSL 
in 25 participants and described improved glucose control, reduced hypoglycaemia and improved 
quality of life (19). The mean HbA1c of 8.0±0.14% reduced to 7.5%±0.14% after 16 weeks. Those 
with a baseline HbA1c >7.5% (58 mmol/mol) experienced a greater -0.59±0.15% reduction. There 
was a significant reduction in hypoglycaemia and diabetes distress. A key behavioural change 

 
 
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associated with FSL use was an increase in those delivering the insulin bolus 15-20 minutes pre-meal 
as per recommendations.  McKnight and Gibb, subsequently reported FSL use in approximately 3% 
of their Type 1 diabetes clinic population in Edinburgh (20). FSL use was associated with a significant 
change in HbA1c versus non users (-0.2% versus +0.1%, respectively). Of those with a HbA1c >7.5% 
(>58mmol/mol), 32% of FSL reached target HbA1c compared to only 9.8% of non-users (p<0.001).  
 
A study in Israel of 31 patients with poorly controlled Type 1 or Type 2 diabetes noted an HbA1c 
decrease of 1.33±0.29% after 8 weeks of FSL (21). For those who continued using the device (n=27), 
the change was maintained for 24 weeks (1.21±0.42%; p = 0.009).  
 
Holcombe et al (conference abstract) assessed the FSL in a small group of 13 patients with Type 1 
diabetes (22). Mean HbA1c reduced from 75 (9.0%) to 65 (8.1%) mmol/mol, with increased time in 
target (29 vs 24%) and reduced hypoglycaemia (82 vs 95 minutes). All subjects demonstrated a 
reduction in their PAID (Problem Areas in Diabetes) scores. Glucose monitoring increased from 3 
finger-stick tests per day to 11 scans per day. They also commented in their abstract that the device 
facilitated virtual contact and support.  
 
Campbell et al. evaluated the use of FSL as a replacement for SMBG in young people (4-17 years) 
(n=76, 58% CSII users, 46% males age 10.3±4.0 years, baseline HbA1c 7.9±1.0% (63 mmol/mol), T1D 
duration 5.4±3.7 years) with Type 1 diabetes in a single arm European multi-centre trial (23). After 2 
weeks’ baseline masked (blinded) wear, participants used FSL for 8 weeks. Time in range (70-180 
mg/dL) significantly improved vs. baseline by 1.0±2.8 hours/day (mean±SD), p=0.0056. HbA1c 
significantly improved vs. baseline, -0.4±0.6%, p<0.0001. Scan frequency of FSL was on average 12.9 
times daily, whereas SMBG tests dropped from a median of 8.0 (baseline) to 1.0/day during open 
use. Diabetes Treatment Satisfaction Questionnaire showed increased overall treatment satisfaction 
for parents (n=70), 21.7±6.6 (mean change score±SD), p<0.0001 and teens (13+years) (n=23), 
18.7±5.6, p<0.0001. 
 
These studies add to the growing clinical perception that FSL is desirable and beneficial for people 
living with Type 1 diabetes. This echoes the authors own clinical experience, having observed striking 
reductions in HbA1c with FSL use in those with very poorly controlled diabetes (HbA1c 
>86mmol/mol, 10%) who are doing little or no glucose monitoring. Unfortunately, these are often 
not patients who are included in clinical studies.   
 

 
 
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4.5 User satisfaction: 
 
Patient feedback on FSL is generally very positive. Olafsdottir et al. explored treatment experience in 
58 adults with Type 1 diabetes (24). FSL scored favourably with scores of 9/10 for ‘My experience of 
the FSL was very positive’ and 9.4/10 for ‘I would like to use FSL in my daily life’. They reported it 
was easy to use (9.8/10), easy and trouble free insertion (9.1/10) and importantly they felt it was 
easy to interpret information on the FSL screen (9.6/10). Authors also compared their findings for 
FSL user satisfaction (overall score 8.22 to 9.8 out of 10) with their earlier studies of Dexcom G4 and 
Enlite sensor which used the same questions (overall score 72.5 to 90 out of 100 for Dexcom G4 and 
42.1 to 86.1 out of 100 for Enlite). This may, in part, account for the >90% utilisation reported in the 
IMPACT study which is higher than previous CGM studies. 
 
Ish-Shalom reported their experience in Israel with the FSL (21). All patients (n = 31) were highly 
satisfied and stated that they would like to use flash glucose in the future. In addition, the patients 
unanimously stated that it was easy to use and painless. Health care professionals reported that the 
data presentation, particularly the ambulatory glucose profile (AGP), was an outstanding tool, 
enabling better and easier control of glucose levels. (21). 
 
Families of paediatric patients who have used the device are generally satisfied. McPhater et al 
contacted the families of 19 FSL users. They reported that the sensor was easy to insert and was an 
easier method of checking glucose than SMBG (25). The majority found the sensor lasted 14 days. 
Most perceived that glucose control had improved during use due to improved awareness of glucose 
levels, and changes in self-management behaviour, particularly around hypoglycaemia. Although 
trend data was useful most users did not alter self-management as a result. Confidence in nocturnal 
glucose control was improved. One quarter did not continue to use the sensors due to limited sensor 
duration and blood glucose discrepancies compared to SMBG. 
 
Another user evaluation in the paediatric population also described high user satisfaction with the 
majority rating the device favourably for sensor application (84.3–92.1%),sensor wear and use 
(87.2–100%), comparing use to SMBG (85.4–97.5%) and the device itself (68.3–96.3%) (26) . 
 
 

 
 
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4.6 Real-world use of FSL: 
 
The manufacturer has evaluated the association of the real-world scanning with FSL and glucose 
control measures.  A large number of readers (n=50,831) with 279,446 sensors (86.4 million 
monitoring hours by 63.8 million scans) were analysed (27) (Figure 2). Users performed an average 
of 16.3 scans per day (median:14, interquartile range: 10-20).  Estimated HbA1c reduced (p<0.001) 
as scan rate increased, from 8.0% (64 mmol/mol)  to 6.7% (50 mmol/mol) from the lowest (mean 4.4 
scans/day) to highest (mean 48.1 scans/day) groups, while time below 3.9, 3.0 and 2.5 mmol/l 
decreased by 15%, 40% and 49%, respectively (all p<0.001). 
 
4.7 Adverse events 
 
As one would expect, most adverse events are related to the medical grade adhesives used to secure 
the sensor for 14 days. Sensor-wear-related symptoms were recorded as adverse events in the 
IMPACT trial if the effects were severe and lasted for >7 days, or if the patient required prescription 
medication for the event to resolve (15). Adverse event severities were recorded on the basis of a 
health-care professional’s assessment of mild, moderate, or severe events. IMPACT reported 13 
cutaneous adverse events in 10 patients, and were categorised as mild (three cases), moderate (four 
cases), and severe (six cases).  Seven participants withdrew from the study due to device-related 
adverse events or repetitive occurrences of sensor insertion-related symptoms.  For participants 
with adverse events involving skin symptoms during this trial, symptoms (including severe) were 
resolved by use of barrier products (eg, Cavilon spray) or drug therapy (eg, zinc ointment, Fenistil 
gel, or hydrocortisone cream) as prescribed, or simply by relocating the device to another area of the 
skin such that the effects were maintained at a tolerable, background level (28). In other cases, 
although the adverse events were generally mild or moderate, the longevity of the symptoms, 
despite use of treatment, contributed to the participant's decision to withdraw from the trial. 
Investigations have since identified isobornyl acrylate as the likely agent causing contact dermatitis 
(29) 
Since completion of the IMPACT trial, minor design changes have been made to FSL. These changes 
are expected to improve breathability of the skin that is in contact with the sensor and to facilitate 
the exclusion of moisture between the sensor–skin interface (28). During the children’s study, five 
device related adverse events were reported in five (6%) participants, aged 6, 9, 10, 12 and 15 years: 
allergic reaction, blister, pink mark/scabbing and abrasion on sensor removal (n=2). Four were mild, 
one was moderate, all were resolved at study completion.(26) 

 
 
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4.8 FreeStyle Libre 2 flash-glucose monitoring system to be used in the 
present study  
 
Flash-glucose monitoring system will consist of a body worn disc (about the size of £2 coin and) a 
hand held reader or a smart mobile phone with an app for flash glucose monitoring (Figure 1). 
Reader can display current glucose level as well as direction of glucose change and last 8 hours of 
glucose data.  In contrast to the first generation FreeStyle Libre device, Libre 2 has the additional 
functionality of optional alarms, vibratory alerts or both when glucose levels become low and high.  
The “low glucose value” is factory set at 3.9 mmol/L and the “high glucose value” at 13.3 mmol/L. 
Users can adjust these values within a permitted range so they are tailored to their Type 1 diabetes 
management requirements. 
 
 
Figure 1: FreeStyle Libre 2 flash glucose monitoring system (Abbott Diabetes Care, Oxon, UK): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.9  
4.9 Rationale for the Current Study 
 
Use of FSL device in people with well controlled T1D has shown reduction in hypoglycemia burden. 
However, to date no randomised study with FSL2 has been undertaken in people with T1D and high 
HbA1c. Without randomised study evidence, there is a reluctance of payers to fund this device to 
wider group of T1D, potentially restricting its use in large number of people who could benefit. The 
purpose of this study is to determine whether use of flash glucose monitoring with FSL2 device will 
Front & Side Profile of Sensor. The 
sensor probe (inserted into skin) is 
0.4 mm wide and 5mm in length 
The Sensor is applied to the back 
of the upper arm with a disposable 
applicator. The reader can scan 
through clothing 
Hand held reader 
(Communicates wirelessly 
with Sensor and shows 
blood glucose reading 

 
 
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improve HbA1c over a 24-week randomised period compared to self-monitoring of blood glucose in 
adults with sub-optimally controlled type 1 diabetes. 
 
4.9.1 COVID-19 Pandemic: Supporting flexible visit schedules for vulnerable participants 
 
In March 2020the Covid-19 pandemic led to the suspension of research activity in the UK. In light of 
the ongoing and future risks and challenges  Covid-19 presents, in May 2020 we updated our 
protocol to facilitate social distancing and protection of the people with diabetes who remain 
eligible and would like to participate in this trial. People with diabetes are categorised as ‘vulnerable’ 
due to the greater risks of adverse outcomes if they contract Covid-19. As such we have integrated 
flexibility to how sites and participants choose to progress through the schedule of assessments 
given the unknowns around Covid-19 transmission across England during 2020 / 2021. As is 
increasingly being adopted for routine diabetic clinics, participants will be able to join the trial 
through virtual consultation supported by video conferencing and telephone (when appropriate) or 
if available at individual sites through face to face clinics or a mixture of both. For those who choose 
to enter the trial by virtual means, any required devices, study documents and kits for HbA1c 
collections will be provided to participants free of charge with pre-paid return postage. 
 
5 Objectives 
 
The study’s primary objective is to compare flash glucose monitoring with Freestyle Libre 2 (FSL2) 
device with self-monitoring of blood glucose over 24 weeks in adults & adolescents (16 years or 
older) with sub-optimally controlled (HbA1c 7.5% to 11%) type 1 diabetes.  
5.1 Clinical Efficacy  
The objective is to assess the clinical efficacy of flash glucose monitoring with FSL2 device relative to 
that with self-monitoring of blood glucose on glycated haemoglobin A1c (HbA1c) (primary clinical 
objective) and sensor-based glucose metrics (secondary clinical objectives; e.g. time spent in target 
glucose range 3.9 to 10 mmol/L).  
5.2 Psychosocial efficacy 
Evaluation of participants’ responses in terms of quality of life, diabetes related distress, diabetes 
treatment satisfaction, low mood, needle burden and disordered eating behaviours will be assessed 
using validated questionnaires. 

 
 
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5.3 Cost-effectiveness  
The objective is to assess the relative cost-effectiveness of the FSL2 device compared with self-
monitoring in adults and adolescents with sub-optimally controlled type 1 diabetes, from the 
perspective of NHS England 
 
5.4 Safety 
The objective is to evaluate time spent in hypoglycaemia (sensor glucose levels < 3.0 mmol/l and 
other sensor based biochemical hypoglycaemia) and number of episodes of severe hypoglycaemia 
with FSL2 and self-monitoring of blood glucose 
5.5 Process Evaluation (Utility & Acceptability)   
The objectives are to explore the frequency and patterns of daily scans, duration of use of FSL2 
device and explore participants’ expectations and experiences  
 
6 Study Design 
 
An open-label, multi-centre, randomised, parallel study, in adults and adolescents (16 years and 
older) with type 1 diabetes and sub-optimal glycaemic control (HbA1c 7.5% to 11%), either on insulin 
pump treatment or multiple daily injections, contrasting flash glucose monitoring using FreeStyle 
Libre 2 device with traditional finger-stick glucose monitoring for 24 weeks. The study flow chart is 
outlined in Figure 2.   
 
 
7 Study Participants 
7.1 Study Population 
 
This is a UK multi-centre and recruitment will take place at the following centres: 
1. Diabetes Centres within Manchester University NHS Foundation Trust 
2. Diabetes Centres within University Hospitals of Derby and Burton NHS Foundation Trust  
3. University Hospitals Birmingham NHS Foundation Trust, Birmingham 
4. Addenbrookes Hospital, Cambridge  
5. Norfolk and Norwich University Hospital, Norwich 
6. Queen Alexandra Hospital, Portsmouth  
7. Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Ipswich 

 
 
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8. Wareham Surgery (Wareham) and The Adam Practice (Poole), NHS England Primary Care GP 
Practices 
 
Each centre will aim to recruit between 25 to 30 participants up to a total of 180 participants. 
Additional diabetes centres surrounding above hospitals may act as participant identification 
centres. In addition, the study may be advertised via social media and other local media so people 
who don’t usually attend above diabetes centres could also join the study providing unique 
opportunity for a wider group of people with sub-optimally controlled type 1 diabetes to join the 
study. If participants are outside the catchment area of the clinic, we will contact the clinical team 
responsible for the participant to confirm type 1 diabetes status and any other contraindications for 
study participation. 
 
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 by post or in-person to join 
the study by the research team at least one day before the recruitment visit. The study may also be 
advertised via social media or posters displayed in clinic. Additionally, the study will be advertised in 
GP practices.  . This will facilitate self-referral from interested candidates for screening purposes and 
optimise trial recruitment across centres.  
 

 
 
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2-week run-in period 
Blinded FreeStyle Libre use 
Baseline Blood Sample(s) including HbA1c and 
Questionnaires 
24 weeks flash-glucose monitoring with Freestyle 
Libre (FSL)  
 
 
Freestyle Libre training including education package to 
optimise treatment with FSL 
 
Visit after 3 weeks for optimisation 
 
12 week visit for optimisation, data collection and 
HbA1c 
24 weeks self-monitoring blood glucose (Control) 
 
 
 
Education to optimise use of SMBG 
 
Visit after 3 weeks for optimisation 
 
12 week visit for optimisation, data collection and 
HbA1c.  
 
2 weeks before end of study blinded sensor insertion 
 
Randomisation (n=150) 
Recruitment & Consent (n=180) 
Final Assessment  
 
 
Final HbA1c measurement 
 
Psychosocial & Usability Questionnaires 
 
Study device collection  
End of the Study (n=128) 
Final Assessment  
 
 
Final HbA1c measurement 
 
Psychosocial Questionnaires 
 
Study device collection  
Figure 2. Study flow chart 
 
 
 
7.2 Inclusion Criteria 
1. The participant is ≥16 years old 
2. The participant has type 1 diabetes, as defined by WHO for at least 1 year or is confirmed 
C-peptide negative if duration of diabetes is < 1 years 
3. Participant is treated with insulin pump or multiple daily injection for at least 12 weeks and 
no plans to change treatment modality during next 28 weeks  
4. The participant is literate in English for safe study conduct 
5. Screening HbA1c  ≥ 7.5% (58.5mmol/mol) and ≤ 11% (97 mmol/mol) based on analysis 
from local, central or third party external laboratory 

 
 
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6. The participant is willing to wear study glucose sensor and scan for glucose levels at 
frequent intervals 
7. The participant is willing to follow study specific instructions to improve glucose control 
8. Female participants of child bearing age should be on effective contraception or not 
sexually active/no plans for pregnancy in the next 8 months.  
9. The participant adopting a virtual pathway through the trial is able and willing to post study 
devices, questionnaires and blood collection kits back to the research team or to the 
laboratory using pre-paid postal services 
10. The participant adopting a virtual pathway through the trial has internet connection, 
appropriate videoconferencing software and supporting devices to undertake video 
consultations where necessary. 
 
7.3 Exclusion Criteria 
1. Non-type 1 diabetes mellitus including those secondary to chronic disease 
2. Any other physical disease or people with known severe mental illness (psychotic disorder, 
bipolar disorder, dementia, substance and alcohol dependence, learning disabilities, 
depression with active suicidal ideation) which are likely to interfere with the normal 
conduct of the study and interpretation of the study results as judged by the investigator  
3. Current users of real-time glucose monitoring sensors or flash-glucose monitoring for more 
than 4 weeks within last 12 weeks 
4. Initiation of medications/treatments known to interfere with glucose metabolism (e.g: 
metformin, SGLT2 inhibitors, GLP-1 agonists, Pramlinatide) within the last 6 weeks or 
planning to start these medications within the next 6 months (patients on stable treatment 
is not an exclusion) or current or planned glucocorticoid use other than inhaled/ topical use. 
5. Known or suspected allergy against insulin 
6. Severe visual impairment  
7. Complete loss of hypoglycaemia awareness 
 
8.  Patient receiving dialysis / pre-dialysis based on history 
9. More than one episode of severe hypoglycaemia as defined by American Diabetes 
Association (30) in preceding 24 weeks as confirmed by clinical history or hospital notes; 
(severe hypoglycaemia is defined as an event requiring assistance of another person to 
actively administer carbohydrates, glucagon, or take other corrective actions including 
episodes of hypoglycaemia severe enough to cause unconsciousness, seizures or attendance 

 
 
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at hospital; children: severe hypoglycaemia is defined as an event associated with a seizure 
or loss of consciousness);  
10. Total daily insulin dose ≥ 2 IU/kg/day 
11. Pregnancy, planned pregnancy in the next 8 months, or breast feeding  
12. Participant is using implanted internal pace-maker 
13. Participants with medically documented allergy towards the adhesive (glue) of plasters or 
participant is unable to tolerate tape adhesive around sensor placement area 
14. Serious skin diseases (e.g. psoriasis vulgaris, bacterial skin diseases) located at places of the 
body, which potentially are possible to be used for localisation of the glucose sensor) 
15. Participant is currently abusing illicit drugs as judged by the investigator 
16. Participant is currently abusing prescription drugs as judged by the investigator 
17. Participant is currently abusing alcohol as judged by the investigator 
18. Participant has elective surgery planned that requires general anaesthesia during the course 
of the study 
19. Participant has a sickle cell disease, haemoglobinopathy; or has received or plan to receive 
red blood cell transfusion or erythropoietin within 12 weeks prior to time of screening or 
during study duration 
 
 
 

 
 
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8 Methods under Investigation 
8.1 Name and Description of the Method of Investigation  
The investigational treatment the CE marked FreeStyle Libre 2 (FSL2) flash glucose monitoring device 
(Abbott Diabetes Care, Oxon, UK).   
8.2 Intended Purpose  
The intended purpose of the investigational treatment is flash-glucose monitoring intended at 
replacing finger-stick glucose levels.  
8.3 Method of Administration 
The FSL2 glucose sensor is directly attached to the patient. Each sensor is intended to last for 14 
days. The component not directly attached to the patient is the handheld reader and/or mobile 
phone app  which display current and historical glucose data (Figure). 
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 FSL2 system and its components. This will be 
documented on each site’s training log. Prior to the use of study devices, participants will be trained 
to use the FSL2..  
8.5 Precautions 
During treatment with insulin there is a risk of hypoglycaemia and hyperglycaemia. Participants will 
be educated in minimising this risk during the study. 
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 study is conducted according to protocol. Devices will be 
identified using batch/lot/serial numbers and the location of investigational devices and their dates 
of use by participants will be documented throughout the study. 

 
 
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9 Study Schedule 
9.1 Overview  
The study will be co-ordinated from Manchester Clinical Trials Unit and performed at following sites:  
 
1. Diabetes Centres within Manchester University Foundation Trust  
2. Diabetes Centres within University Hospitals of Derby and Burton NHS Foundation Trust  
3. University Hospitals Birmingham NHS Foundation Trust 
4. Addenbrookes Hospital, Cambridge  
5. Norfolk and Norwich University Hospital, Norwich 
6. Queen Alexandra Hospital, Portsmouth  
7. Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Ipswich 
8. Wareham Surgery (Wareham) and The Adam Practice (Poole), NHS England Primary Care GP 
Practices 
 
 
After recruitment, consent, participants will be randomised for 24-weeks home use of flash-glucose 
monitoring or 24-weeks use finger-stick glucose monitoring.  
 
The study includes up to 7 visits for participants completing the study. Maximum time in study is 30 
weeks. Each study visit can be scheduled with +/-  2 weeks of the planned visit date. 
 
Study visits will be conducted through virtual consultation supported by video conferencing and 
telephone (when appropriate) or if available at individual sites through face to face clinics or a 
mixture of both. For those who choose to enter the trial by virtual means, any required devices, 
study documents and kits for HbA1c collections will be provided to participants free of charge with 
pre-paid return postage. All study visits conducted remotely will use Video/ Audio consultation tools 
approved by the local NHS organisation. 
  
Table 1 outlines study activities when participant is randomised to flash glucose monitoring 
intervention (intervention group).  
 
Table 2 outlines study activities when participant is randomised to finger-stick glucose monitoring 
(control group).  
 
 

 
 
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Table 1. Schedule of study visits when participant is randomised to flash glucose monitoring 
intervention (intervention group).  All study visits could be done remotely. 
 
Visit/ 
contact 
Description 
Time since 
randomisation 
Start relative to 
previous / next 
Visit / Activity** 
Duration 
Visit 1 
Recruitment & Screening 
visit: Consent  
HbA1c, baseline bloods, 
questionnaires 
-2 to -3 weeks 
- 
2 hours 
Visit 2 
Blinded flash glucose 
monitor insertion 
-2 weeks 
Within 1 to 2 
weeks of Visit 1. 
Can coincide with 
Visit 1 
0.5 hour 
Visit 3 
Adherence assessment & 
Randomisation 
Flash-glucose monitoring 
initiation  
- Training, education & 
competency assessment 
0 weeks 
After 2 weeks of 
Visit 2 
 2 hours 
Visit 4 
Review data /optimisation 
and use of study devices. 
Data download & collect 
participant diary 
+4 weeks 
After 4 weeks of 
Visit 3 
1 hour 
Visit 5 
Review data /optimisation. 
Data download  
- HbA1c. 
- Collect participant diary 
+12 weeks 
After 8 weeks of 
Visit 4 
2 hours 
Visit 6 
Not applicable in this arm 
 
 
 
Visit 7 
End of Flash-glucose 
monitoring intervention 
arm 
- HbA1c 
- Questionnaires  
- Data download 
- Collect participant diary  
 
+24 weeks 
12 weeks after 
Visit 5 
2 hours 
**Each study visit can be scheduled with +/-  2 weeks of the planned visit date. 
 
 
 

 
 
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Table 2.  Schedule of study visits when participant is randomised self-monitoring of blood glucose  
All study visits could be done remotely. 
 
  
Visit/ 
contact 
Description 
Time since 
randomisation 
Start relative 
to previous / 
next Visit / 
Activity** 
Duration 
Visit 1 
Recruitment & Screening 
visit: Consent  
HbA1c, baseline bloods, 
questionnaires 
-2 to -3 weeks 
- 
2 hours 
Visit 2 
Blinded flash glucose 
monitor insertion 
-2 weeks 
Within 1 to 2 
weeks of Visit 
1. Can coincide 
with Visit 1 
0.5 hour 
Visit 3 
Adherence assessment & 
Randomisation 
Self- monitoring of glucose 
initiation  
- Education 
 
0 weeks 
After 2 weeks 
of Visit 2 
2 hours 
 Visit 4 
Review data /optimisation 
Collect participant diary  
+4 weeks 
After 4 weeks 
of Visit 3 
1 hour 
Visit 5 
Review data /optimisation. 
Data download  
- HbA1c 
- Collect participant diary 
 
+12 weeks 
After 8 weeks 
of Visit 5 
2 hour 
Visit 6 
Blinded flash glucose 
monitor insertion (Extra visit 
in this arm) 
+22 weeks 
After 10 weeks 
of Visit 5 
 
Visit 7 
End of self-monitoring 
intervention arm 
- HbA1c. 
- Questionnaires 
- Collect participant diary 
 
+24 weeks 
2 weeks after 
Visit 6 
2 hour 
**Each study visit can be scheduled with +/-  2 weeks of the planned visit date. 
 
 
  

 
 
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9.2 Visit 1: Recruitment Visit and Screening Assessment 
 
Once the participants have agreed to participate in the study, they will be invited for the recruitment 
visit, and given a participant ID, when the following activities will be performed by the research 
team: Due to the current COVID-19 pandemic all study visits can be provided by virtual consultation 
supported by video conferencing and telephone (when appropriate). 
 
 
written informed consent/assent (Signed consent form can be returned to the research team 
with pre-paid postage for those following the virtual pathway).   
 
checking inclusion and exclusion criteria  
 
medical and diabetes history including presence of diabetes complications and hypoglycaemia 
burden 
 
ethnicity, body weight and height measurement; calculation of BMI 
 
Demographic data (Date of Birth, Gender registered at birth, Full Postcode) 
 
record of current insulin therapy  
 
record of occupation and educational attainment  
 
any history of disordered eating or needle phobia 
 
previous participation in structured education, status of carb counting, use of bolus calculator 
9.2.1 Screening Blood Sampling 
Blood samples will be taken to measure HbA1c. This will be done using a local laboratory (face to 
face clinic) or a home HbA1c where the participant will collect a blood sample using a self-test kit 
and send in a pre-paid envelope to a central or third party external laboratory.    . Less than 15 ml of 
whole blood will be taken from each participant.    
9.2.2 Questionnaires at Screening 
Evaluation of participants’ responses in terms of quality of life, diabetes distress, needle burden, 
disordered eating, depression and diabetes treatment satisfaction using EQ-5DL-5L questionnaire, 
Type 1 Diabetes Distress Scale (DDS), Diabetes fear of injecting and self-testing (D-FISQ) 
questionnaire, Diabetes Eating Problem Survey (DEPS-R), Diabetes Treatment Satisfaction 
Questionnaire (DTSQ), Patient Health Questionnaire (PHQ-9) and The Glucose Monitoring 
Satisfaction Survey (GMSS). Hypoglycaemia burden will be assessed using Clarke questionnaire and 
Gold score. Where necessary questionnaires will be provided by postal delivery for participants who 
choose to join the virtual pathway. 

 
 
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9.3 Visit 2: Insertion of blinded glucose monitoring device 
 
Purpose of visit 2 is to insert a blinded glucose monitor (FreeStyle Libre Pro device). Participant will 
be provided with instructions about using this device for next 2 weeks. Visit 2 may be combined with 
visit 1.  Eligible participants who join the trial by virtual consultation will receive a Blinded FSL2 pro 
sensor and reader by post for self-insertion with relevant advice. At the end of the two weeks the 
participant can return the items to the research team by pre-paid postal services. 
 
 
9.4 Visit 3: Adherence assessment, randomisation and start of study 
treatment  
 
During Visit 3, participant’s adherence / tolerance of using the flash-CGM over preceding 14 days will 
be assessed. To proceed with the study participant should have worn the blinded glucose monitoring 
device for at least 10 days’ during last 14 days of run-in period. If the participant fails to demonstrate 
adherence or develops any significant allergy or intolerance to the glucose sensor, the study will be 
terminated and participant will be removed from the study. If the sensor records less than 10 days’ 
worth of data due to a problem with the sensor itself (premature sensor failure) rather than a 
participant related issue,  a new sensor should be inserted to get a minimum of total 10 days’ worth 
of data. In cases in which there is a premature sensor failure, participant randomisation should only 
proceed once a minimum total of 10 days data has been downloaded. Participants who are opting 
for virtual consultations and who have <10 days data, will be provided with a new FSL2 pro sensor 
and reader to obtain the minimum data requirements prior to randomisation. 
9.4.1 Randomisation scheme 
Randomisation to one of the two intervention arms (24-weeks use of flash-glucose monitoring or 24 
weeks use of conventional finger-stick glucose monitoring) will use the minimisation method, with a 
random element to improve allocation concealment.  We will minimise over the following factors: 
study centre (Birmingham; Cambridge; Derby; Manchester; Norwich; Portsmouth), baseline HbA1c 
(7.5%-9.0%; >9.0%-11%), treatment modality (Multiple daily injections (MDI); Continuous 
Subcutaneous insulin Infusion (CSII)), prior participation in structured education course (yes; no) and 
current use of bolus calculator (yes; no).  
9.4.2 Method of implementing the allocation 
Participants not removed from the study due to non-adherence or significant allergy or intolerance 
to the glucose sensor will be randomised during visit 3 using the web-based randomisation platform 

 
 
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SealedEnvelope.com. The responsibility for randomising participants into the trial lies with the 
Principal Investigator and staff at sites. Access to the randomisation system will be limited to the 
core study team members at each trial site. The delegation log at each trial site should clearly 
identify which roles and/or individuals are delegated to perform the randomisation procedure on 
the SealedEnvelope.com web platform. Individuals undertaking the randomisation will be required 
to enter the patient’s initials, month/year of birth, date of randomisation, site and confirmation of 
eligibility criteria into the SealedEnvelope.com secure website, before being permitted to 
randomised participants. The system will need to record  the unique trial ID which will be assigned to 
each participant during screening (Visit 1) and should be used on all trial documentation (CRF, SAE 
forms etc.). This ID will be sequential across all NHS sites and will consist of a three digit site 
reference followed by the sequential across site ID. Following randomisation an email confirmation 
with the allocated randomised treatment and trial ID will be disseminated to the trial site staff and 
key CTU personnel, automatically via the randomisation system.  A copy of this confirmation should 
be filed in the participant’s study notes. An emergency contact card should be pre-populated will the 
trial ID. Further details of the randomisation process will be provided in a user manual. 
9.4.3 Initiation of study treatment 
Body weight measurement will be made where possible. Participants will be provided with necessary 
training on use of study devices according to randomisation. Participants will also be provided with a 
paper diary to collect information about insulin doses and carbohydrate intake in last 5 days before 
study visits 4, 5 and 7 (Appendix 13).  
9.4.4 Training session (Appendix 9) 
Participants randomised to the flash-glucose monitoring arm will receive education and training 
about insertion and initiation of the sensor as well as how to use flash-glucose monitoring data for 
treatment optimisation. They will be encouraged to download data at home to identify pattern 
recognition. This session will be conducted by a professional diabetes educator or a member of the 
study team. Education will be tailored to meet the needs of the individual.  
Participants randomised to conventional finger-stick glucose monitoring arm will be encouraged to 
use finger-stick glucose levels to optimise treatment and will receive education about insulin dose 
adjustments using finger-stick glucose levels. The study will try to mimic real-life conditions by 
continuing participant’s pre-study diabetes treatment unchanged and finger-stick glucose testing 
frequency as determined by the participant as required. Participants in both arms will also receive 
training on sick day rules and dealing with hypo and hyperglycaemia.  

 
 
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Participants assigned to either arm will receive an information leaflet following the training session. 
The information provided will be tailored to suit the trial arm for which they will be assigned to. The 
leaflet provided to those who will be randomised to the Flash Glucose Monitoring arm will include 
sign-posting to educational videos provided by the Association of British Clinical Diabetologists 
(ABCD) (https://abcd.care/dtn/education) and Bertie online (www.bertieonline.org.uk)for those in 
the blood glucose monitoring arm .  
9.5 Visit 4: (+4 weeks since randomisation): Review data and treatment 
optimisation 
Purpose of this visit is to review data from Flash-glucose monitoring and finger-stick glucose 
monitoring to further optimise treatment. Study devices will be downloaded. Information about 
insulin doses and any adverse events will be collected. 
9.6 Visit 5: (+12 weeks since randomisation): Review data and treatment 
optimisation 
 
Purpose of this visit is to review data from Flash-glucose monitoring and finger-stick glucose 
monitoring to further optimise treatment. Study devices will be downloaded. Information about 
insulin doses, participant diaries and any adverse events will be collected. Blood sample will be 
collected for HbA1c. 
9.7 Visit 6: (+22 weeks since randomisation): Finger-stick glucose 
monitoring arm only 
 
Participants randomised to finger-stick glucose monitoring arm will have an extra visit 10 weeks 
after visit 5 to insert a blinded glucose sensor for data capture. Participants who join the trial by 
virtual consultation will receive a Blinded FSL2 pro sensor and reader by post for self-insertion with 
relevant advice. At the end of the two weeks the participant can return the items to the research 
team by pre-paid postal services. 
 
 
9.8 Visit 7: (+24 weeks since randomisation): End of randomised study 
treatment 
   
The participant will be invited to attend the research centre approximately 12 weeks after Visit 5. 
This would be the end of 24 weeks randomised study period. All study devices will be downloaded. 

 
 
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Insulin usage data will be recorded and diaries collected. The participant will have a blood test for 
the HbA1c. Body weight measurement will be made where possible. Participant will be asked to 
complete questionnaires evaluating diabetes related quality of life, diabetes distress and diabetes 
treatment satisfaction. In addition, participants in the FSL2 arm will be asked to complete a 
questionnaire exploring expectations and experience of using FSL2 during the study. For those 
participants who have completed the trial by virtual means, any remaining devices, completed study 
documents and blood collections for HbA1c testing can be returned free of charge with pre-paid 
return postage. 
 
9.9 Participant Withdrawal Criteria 
 
The following pre-randomisation withdrawal criteria will apply: 
1. Participant is unable to demonstrate safe use of flash-glucose monitoring during run-in 
period as judged by the investigator 
2. Participant develops significant allergy to sensor plaster   
The following pre- and post-randomisation withdrawal criteria will apply: 
3. Participant 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-adherence 
5. Decision by the investigator or the sponsor that termination is in the Participant’s best 
medical interest 
6. Participant becomes pregnant during the study period 
7. Allergic reaction to insulin  
8. Allergic reaction to glucose sensor 
9. If patient cannot be contacted over a period of 4 weeks then the participant will be 
considered lost to follow up 
 
Participants who are withdrawn for reasons stated in (4), (5), (7), and (8) may be invited to provide 
the blood sample for the assessment of HbA1c and complete the self-report questionnaires at the 
end of the planned study intervention period.  
9.10 Study Stopping Criteria 
 
The study may be stopped if three consecutive participants withdraw on safety grounds or on the 
advice of an Independent Data Monitoring Committee (IDMC)  

 
 
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9.11 End of Trial 
 
For regulatory purposes, the end of trial will occur at each study site when the last participant has 
undergone their final assessment and the data has been collected. The declaration of end of trial 
form will be submitted to regulatory authorities. The Manchester CTU will notify the REC and the 
HRA at the end of a clinical trial (when all participating sites have completed final participant 
assessments) within 90 days of its completion. Following this, Manchester CTU will advise sites on 
the process for closing the trial at site.      
9.12 Support telephone line 
 
There will be a  telephone helpline to the local research teams for participants in case of any 
technical device or problems related to diabetes management such as hypo- or hyperglycaemia 
during normal working hours. Outside working hours participants will be advised to contact usual 
out hours NHS support services.  
9.13 Participant reimbursement 
 
The study will provide the FSL2 device and related consumables. Participant will continue their usual 
glucose meter, and glucose test strips. Reasonable travel expenses will also be reimbursed for those 
who adopt face-to-face clinic visits. No participant reimbursement will be provided to those who opt 
for virtual (at-home) visits. After completing the study, participants will not keep the study devices. 
They will revert to their conventional finger-stick glucose monitoring.  

 
 
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10  Endpoints 
10.1  Primary Endpoint 
The primary outcome (endpoint) is HbA1c at 24 weeks.  
10.2  Secondary Endpoints 
10.2.1 HbA1c based 
 
 
HbA1c at 12 weeks 
 
HbA1c ≤ 53 mmol/mol (7.0%) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 
HbA1c ≤ 59 mmol/mol (7.5%) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 
Reduction in HbA1c ≥5.5 mmol/mol (0.5%) from baseline (screening) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 
Reduction in HbA1c ≥ 11 mmol/mol (1.0%) from baseline (screening) 
o at 12 weeks  [yes/no] 
o at 24 weeks  [yes/no] 
 
10.2.2 Sensor based: 
 
Time spent in the target glucose range between 3.9 to 10.0 mmol/l (70 to 180mg/dl). 
 
Time spent below target glucose (<3.9mmol/l) (<70mg/dl) 
 
Time spent above target glucose (10.0 mmol/l) (180 mg/dl)  
 
Average glucose levels 
 
Standard deviation glucose levels 
 
Coefficient of variation glucose levels  
 
The time with sensor glucose levels: 
o  < 3.5 mmol/l  (63 mg/dl) 
o < 3.0 mmol/l (54mg/dl) 
o < 2.8 mmol/l (50 mg/dl) 

 
 
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 
The time with sensor glucose levels in the significant hyperglycaemia (glucose levels > 16.7 
mmol/l) (300mg/dl) 
 
AUC of glucose below 3.0mmol/l (54mg/dl) 
All the sensor based metrics will also be analysed separately for daytime (7:00-23:00 hours) and 
night-time (23:00-7:00 hours) in addition to overall period. 
 
10.2.3 Non- sensor based secondary clinical: 
 
Daily average total insulin dose 
 
Daily average basal insulin dose  
 
Daily average bolus dose 
 
Average number of boluses of rapid acting insulin per day 
 
Frequency of severe hypoglycaemic episodes as defined by American Diabetes Association 
 
Frequency of significant ketosis events (plasma ketones >3mmol/l)  
 
Nature and severity of other adverse events. 
10.2.4 Non-sensor based secondary patient-reported (psychosocial): 
 
Type 1 Diabetes Distress Scale (T1-DDS) 
 
Quality of Life (EQ-5D-5L) 
 
Patient Health Questionnaire (PHQ-9) 
 
Diabetes fear of injecting and self‐testing questionnaire (D‐FISQ) 
 
The revised Diabetes Eating Problem Survey (DEPS-R) 
 
10.2.5 Process evaluation (utility and acceptability) 
 
FSL2 device utilization data, including: average number of scans per day (7:00-23:00 hours), 
per night (23:00-7:00 hours) and over the full 24-hour period; average number of days of 
usage per week 
 
Number of finger-stick glucose level tests per day 
 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) 
 
Glucose Monitoring Satisfaction Survey (GMSS) 
 

 
 
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11 Assessment 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 participant 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 participant who has received an 
investigational device, whether or not related to the investigational medical device.  This definition 
included events related to the device under investigation or the comparator or to the study 
procedures.  For users or other persons, this definition is restricted to events related to the 
investigational device. 
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 participant, 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 hospitalisation 
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 
 

 
 
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A planned hospitalization 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 
participant 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 participant or may require intervention to prevent 
one of the other outcomes listed in the definition above, should also be considered serious. 
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 device 
manual.  
 
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 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.  Device deficiencies include malfunctions, use errors 
and inadequate labelling.  A device deficiency may lead to an Adverse Device Effect or Serious 
Adverse Device Effect. 
11.1.8 Adverse Event Intensity 
 
Intensity 
Definition 

 
 
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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 to work or perform 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.  
 
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. 
  
Definite/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)  
 

 
 
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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 their study participation. 
Adverse events that continue after the participant’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 participant, and appropriate 
medical intervention will be taken.  The investigator will elicit reports of adverse events from the 
participant at each visit and complete adverse event forms. All AEs, including those the participant 
reports spontaneously, those the investigators observe, and those the participant reports in 
response to questions will be recorded on electronic AE forms at each site within 30 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 adverse event and an adverse event form 
will be completed. Severe hypoglycaemia is not necessarily a serious adverse event and hence may 

 
 
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not require immediate reporting to the Sponsor. Non-severe hypoglycaemia will not be reported or 
considered an adverse event.  
11.2.4 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 (Sponsor Reference) 
2. Participant’s unique study number, Initials and Trial Arm Assignment 
3. Date of birth 
4. Event description 
5. Start date of event and whether initial / follow-up report. 
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. Principal and Chief Investigator’s assessment declaration with record of the 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 delegated members of the research team, 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  within 24 hours (one working day) of the 
Investigator learning of its occurrence.   
 
Specific reporting instructions: 
SAEs should be reported to the sponsor via Manchester Clinical Trials Unit (CTU). E-mail address 
specifically for SAE reporting is saereport_manctu@manchester.ac.uk. If record of receipt is not 
provided by the mCTU within 2 working days then there should be subsequent follow-up by the site 
PI.  
 
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.  
 
Manchester CTU will notify the Research Ethics Committee (REC) of any USADE in line with pertinent 
legal requirements. Manchester CTU will inform the Sponsor about all reports sent to the reporting 
organisation including follow-up information and answers by the reporting organisation. Manchester 
CTU is responsible for informing other site principal investigators and the CI of all SAEs. 
 
The main REC will be notified of all USADEs within 7 days if they resulted in death or categorised as 
life-threatening and 15 days for all other USADEs following  the occurrence of the event.  
11.2.5 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 CTU /Sponsor as for SAEs/SADEs.  
11.2.6 Reporting Urgent Safety Measures 
 
If any urgent safety measures are taken the CI / Manchester CTU shall immediately and in any event 
no later than 3 days from the date the measures are taken, give written notice to the relevant HRA 
REC of the measures taken and the circumstances giving rise to those measures. The study sponsor 

 
 
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will also be notified. A substantial amendment to the protocol and any relevant study 
documentation (e.g. PIS, CRF) will be applied. 
11.2.7 Healthcare Arrangements and Compensation for Adverse Events  
Healthcare arrangements for participants 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.  
 
The standard National Health Service insurance and indemnity will apply to this study.  If an adverse 
event occurs, there are no special compensation arrangements unless this was due to the negligence 
of one of the clinical investigators. In this case participants may have grounds for legal action for 
compensation. The normal national complaints mechanism will be available and NHS insurance and 
indemnity only covers negligent harm. There is no provision for non-negligent harm as a result of 
participating in the study. 
 
11.3 Expected Adverse Events, Risks and Benefits 
11.3.1 Risks and expected 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. 
11.3.2 Hypoglycaemia and Hyperglycaemia 
Participants 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 participant with 
type 1 diabetic 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. 

 
 
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11.3.3 Blood Sampling 
Participants will be required to have three blood tests for HbA1c during the whole study. This can be 
completed using the local laboratory (face to face clinic) or a home HbA1c where the participant will 
collect a blood sample using a self-test kit and send in a pre-paid envelope to a central or third party 
external laboratory.  
 
 
Slight discomfort or bruising at the site (common) 
 
Excess bleeding at the site (unlikely) 
 
Infection at the site (rare) 
 
Local anaesthetic cream or spray may be used to minimise the discomfort. 
11.3.4 Finger-prick Blood Glucose Measurements 
Finger-prick tests may produce pain and/or bruising at the site. 
11.3.5 Insulin Pump Therapy 
Some participants in this study are already using an insulin pump. Potential risks 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 / lipoatrophy (very rare) 
11.3.6 Flash Glucose Monitoring 
Potential risks associated with flash glucose monitoring: 
 
 
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 (rare) 

 
 
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 
Allergic reaction to the CGM sensor material (rare) 
 
If a skin reaction is classified as severe (the observation is noticeable and bothersome to participant 
and may indicate infection or risk of infection or potentially life-threatening allergic reaction), an 
adverse event form will be completed. 
11.3.7 Questionnaires 
As part of the study, participants will complete questionnaires which include questions about their 
private attitudes, feelings and behaviour related to diabetes. It is possible that some people may find 
these questionnaires to be mildly upsetting. Similar questionnaires have been used in previous 
research and these reactions are uncommon. 
 
11.4 Benefits 
 
It is expected that use of flash glucose monitoring will lead to improvements in HbA1c and play an 
important role in the management of type 1 diabetes. Therefore, the results of this study are likely 
to be beneficial for participants with diabetes. 
 
It is possible that participants 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 will be useful for participants’ 
diabetes self-management. 
11.5 Independent Data Monitoring Committee (IDMC) 
The IDMC (see 17.1) 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.  

 
 
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12  Data Collection 
12.1  Procedures 
12.1.1 Height and Weight 
These will be recorded at the study initiation visit at screening, where possible..   
12.1.2 Subcutaneous Glucose Monitoring  
At least 10 days of blinded continuous glucose (Freestyle Libre Pro) data will be collected prior to the 
randomisation with the aim of gaining knowledge of the specific participant’s glucose control 
characteristics at screening and assessing adherence before the beginning of any intervention arm. 
Participants in the intervention arm will be encouraged to upload freestyle libre 2 data at regular 
intervals.  
12.1.3 Insulin Pump Data  
Data from participants on insulin pump therapy will be downloaded periodically during each 
intervention. 
12.2  Questionnaires  
12.2.1 Questionnaires 
Quantitative data on health-related quality of life, diabetes distress, needle burden, disordered 
eating, depression and diabetes treatment satisfaction will be assessed using validated 
questionnaires. Participants will complete the questionnaires at screening and at the end of the 
study intervention. All results will be evaluated at the end of the study. 
List of questionnaires are: 
 
1. EQ-5D-5L questionnaire (Appendix 1) 
2. The Glucose Monitoring Satisfaction Survey (GMSS) (Appendix 2).  
3. Patient Health Questionnaire (PHQ-9) (Appendix 3) 
4. Diabetes Treatment Satisfaction Questionnaire (DTSQ) (Appendix 4) 
5. Diabetes fear of injecting and self-testing questionnaire (D-FISQ) (Appendix 5) 
6. Diabetes Eating Problem Survey (DEPS-R) (Appendix 6) 
7. Type 1 Diabetes Distress Scale (DDS) (Appendix 7) 
8. The Clarke questionnaire and Gold score. (Appendix 8) 
9. Additional non-validated questionnaires for subset of participants in the FSL2 arm (Appendix 10 
and 11) and clinical investigators (Appendix 12) exploring expectations and experience of using 
FSL2 during the study  

 
 
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12.3 Laboratory Methods  
   
12.3.1 HbA1c 
Blood samples for the measurement of HbA1c levels will be taken at three different time points: 
screening, 12 weeks and at the end of study intervention at 24 weeks.  This can be completed using 
the local laboratory (face to face clinic) or a home HbA1c where the participant will collect a blood 
sample using a self-test kit and send in a pre-paid envelope to a central or third party external 
laboratory. To maintain comparability across individual participant HbA1c values the same testing 
procedure will be consistently used each time a participant is required to have a HbA1c test as part 
of their schedule of assessment. 
12.4 Total Blood Loss 
The total blood loss will be less than 30 ml  

 
 
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13  Study Materials and Products 
13.1 Flash Glucose Monitor 
Freestyle Libre 2 (Abbott Diabetes Care, Oxon, UK) flash-glucose monitor will be used in the 
intervention arm. 
13.2 Standard Blood Glucose Meters  
Participants in the control arm will be using their usual finger-stick glucose monitor throughout the 
study. 
13.3 Insulin pumps  
Participants already on insulin pump therapy will continue their usual insulin pump throughout the 
study.  
13.4 Insulin 
Participants will continue their usual insulin therapy throughout the study.  
 
14 Statistics and Data Analysis  
 
14.1 Sample size 
 
The sample size calculation (128 evaluable cases from 150 randomised 1:1, up to 180 recruited to 
allow for any dropouts pre-randomisation) was premised on a between trial arm t-test for follow-up 
HbA1c values (2-tail alpha = 0.05, power = 0.80 when the true mean difference is 0.4% and the SD is 
0.8% i.e. Standardised Effect Size [SES] = 0.5). There is expected to be a moderate-to-large 
correlation between baseline and follow-up HbA1c values, so the planned use of ANCOVA (see 14.2 
and 14.3) will in fact have greater power (assuming other inputs unchanged). 
 
We chose delta (MCID) of 0.4% as this is consistent with other relevant trials (REPOSE (31) used 
0.5%, DIAMOND (10) used 0.4% and GOLD (11) used 0.3%, for delta at the design stage), although 
there is no consensus as to which of these values is most appropriate.  We also considered findings 
from other RCTs (DIAMOND (10) 0.6%, GOLD (11) 0.43%, as detailed in our application) and a recent 
meta-analysis of trials and longitudinal observational studies (32) which have suggested that an 
effect of the order of 0.43%-0.7% might be expected, somewhat greater than the potential range for 
delta of 0.3%-0.5%, and therefore chose to power the proposed trial on a delta of 0.4%, deeming 

 
 
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that this was the most efficient approach without potentially over-powering the trial (an interim 
analysis is not possible given the length of follow-up relative to the recruitment period). 
 
The assumed SD was informed by published results from the DIAMOND (10) and GOLD (11) trials, 
although the eligible baseline HbA1c values for these trials were 7.5 to 10.0% and >=7.5%, 
respectively, which each differ somewhat from the 7.5% to 11.0% range intended for this trial (it is 
likely that the SD will be lower with a narrower eligibility range, suggesting that our SD may lie 
between the 0.8 reported for DIAMOND (10) and the 0.9 implied for GOLD (11)). Increasing SD and 
baseline/follow-up correlation (rho) act in opposite directions on power for a given sample size – the 
table below illustrates reasonable power for a range of plausible values.  
 
Power for an ANCOVA with 128 evaluable cases (150 randomised 1:1): 
                                       rho            
SES = delta/SD        | 
0 
0.3 
0.5 
0.7 
-------------------  -|------------------------------ 
0.44 (e.g. 0.4/0.9) | 
0.70 0.73 0.81 0.93 
0.50 (e.g. 0.4/0.8) | 
0.80 0.84 0.90 0.98 
 
As can be seen in the table above, if the correlation (rho) between baseline and 6-month HbA1c 
values is at least 0.5 (consistent with a scatterplot provided in the DIAMOND (10) paper), power will 
be at least 90% for a SES of 0.5, but will still detect a SES of 0.44 (e.g. SD 0.9 rather than 0.8) with at 
least 81% power.  We therefore believe that our choice of 128 participants with evaluable HbA1c at 
the 6-month time-point is optimal. 
 
 
14.2 Statistical Analysis Plan (SAP) 
All analyses will be conducted following the intention to treat (ITT) principle where all randomised 
participants are analysed in their allocated treatment group whether or not they receive their 
randomised treatment. All baseline, 12-week and 24-week outcome data will be presented 
descriptively, both overall and within treatment group, using mean (SD), median (IQR) or frequency 
(percentage), as appropriate. All statistical tests will use a 2-sided significance level of 5% (unless 
otherwise specified). All confidence intervals presented will be 95% and two sided.  

 
 
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A full, detailed SAP will be approved by the TSC (following drafting and review by the TMG, TSC and 
IDMC) before the first substantive statistical analysis. All statistical analyses will be performed using 
Stata (StataCorp, College Station TX, USA). 
 
14.2.1 Primary Outcome 
The primary outcome analysis will evaluate between group differences in HbA1c levels at the end of 
the 24-week treatment period. An analysis of covariance (ANCOVA) model will be used, with 24-
week HbA1c as the outcome and trial arm effect as the focus, and with adjustment for baseline 
HbA1c and the other baseline variables included in the minimisation allocation algorithm as 
covariates. We have allowed for up to 15% attrition by 24 weeks in our sample size calculation; 
should we have more than 10% missing HbA1c at 24 weeks (or more than a 10% difference between 
missing data percentages in the two arms) we will use multiple imputation will be used in order to 
implement a more complete ITT analysis of the substantive ANCOVA model (otherwise this will be 
performed as a sensitivity analysis, with a complete case analysis used as the primary analysis).  The 
imputation model will include baseline and 12-week  
HbA1c, all the baseline variables used in the allocation algorithm and any other recorded variables 
found to be predictive of missing the 24-week outcome in exploratory analyses. 
14.2.2 Secondary Outcomes 
 
HbA1c based 
For the HbA1c 12-week outcome, an ANCOVA model will be used, with trial arm effect as the focus, 
and with adjustment for baseline HbA1c and the other baseline variables included in the 
minimisation allocation algorithm as covariates. 
For the HbA1c-based [yes/no] variables, logistic regression models will be used.  For each model, 
trial arm effect will be the focus, with adjustment for the baseline variables included in the 
minimisation allocation algorithm (including baseline HbA1c category) as covariates. 
 
Sensor-based 
The respective sensor-based measures obtained during the last 2 weeks of the 24-week randomised 
interventions contrasting the flash-glucose against the SMBG will be compared using independent-
samples statistical techniques. For any non-normally distributed (substantially skewed) measures, 
transformation or nonparametric analyses will be used. Where possible, analysis will be adjusted for 
baseline sensor values obtained during blinded run-in period and the baseline variables included in 

 
 
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the minimisation allocation algorithm.  Analysis will also be repeated for day and night-time period 
(the interval from 7.00 to 23:00 defines day-time period; 23:00 to 07:00 am defines the night-time 
period). 
 
Non-sensor based clinical 
For the insulin dose data, independent-samples statistical techniques will again be used.  For any 
non-normally distributed (substantially skewed) measures, transformation or nonparametric 
analyses will be used. Analysis will be adjusted for the baseline value of the outcome measure and 
the baseline variables included in the minimisation allocation algorithm.   
 
Safety data, including severe hypoglycaemia events and ketone-positive hyperglycaemia, will be 
tabulated for all participants, including drop-outs and withdrawals, irrespective of whether CGM 
data are available and irrespective of whether closed-loop was operational. Severe hypoglycaemic 
events and ketone-positive hyperglycaemia will be tabulated in each treatment group, which will be 
compared using repeated measures logistic regression (generalised estimating equations). For 
purposes of analysis, a severe hypoglycaemic event will be defined as an event requiring assistance 
of another person actively to 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.  
 
Non-sensor based patient-reported (psychosocial) 
ANCOVA will also be used for the psychosocial outcome data evaluation, with trial arm effect as the 
focus, adjusting for baseline level of the outcome and the other baseline variables included in the 
minimisation allocation algorithm as covariates. 
 
14.2.3 Subgroup analysis 
 
Planned subgroup analysis will be applied for the primary outcome measure and will 
include: 
 
 
Those with baseline HbA1c 7.5%-9.0% and >9.0%-11%  
 
Treatment modality: Multiple daily injections (MDI) vs Continuous Subcutaneous Insulin 
Infusion (CSII) 

 
 
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 
Prior participation in structured education course (yes; no)  
 
Different age groups, 16 <30, 30 to <45, 45 to <60 and >=60 years at enrolment 
 
Education < Bachelor’s degree,  >= Bachelor’s degree 
 
Hypoglycaemia Unawareness (Clarke score >3) 
 
14.2.4 Interim analysis 
No interim analysis will be performed. 
 
14.3 Economic analysis 
 
The economic evaluation will determine the difference in costs and outcomes generated by the FSL2 
device compared with self-monitoring. The economic evaluation will be conducted prospectively 
alongside the randomised controlled trial from the perspective of NHS/Prescribed Specialised 
Services (PSS) following standard quality design and reporting criteria (33). During the study we will 
collect information about healthcare (NHS) resource use up to 24 weeks after commencement of 
randomised study period. These will include events such as A&E attendance (ambulance or walk-in), 
Readmissions or admissions to other hospitals, Outpatient attendance, GP surgery attendance (GP or 
nurse) / telephone contact/home visit, Paramedic calls and attendances 
 
A within-trial cost-utility analysis will compare differences in total costs and differences in quality of 
life using QALYs derived from the EQ-5D-5L. QALYs will be calculated by attaching available utility 
weights to the health states generated from the EQ5D-5L, using area under the curve methods with 
an assumption of a linear change between time points, controlling for baseline. Person-level costs 
will be generated for each person in the FSL2 device and self-monitoring arms from a combination of 
trial-based resource use with published unit costs, allowing comparison in terms of costs to NHS and 
PSS. The unit costs of resource use will be taken from publicly available sources including current 
editions of NHS reference costs and the Unit Costs of Health & Social Care (34-35). Costs will be 
compared between the two groups using a bootstrapped regression model (as the data are likely to 
be skewed). 
  
Modelling the potential effect of the intervention on costs and outcomes beyond the trial period will 
provide a better idea of overall impact as the benefits of controlling HbA1c are likely to be seen after 
the endpoint of the trial. Therefore, we will carry out an economic evaluation informed by modelling 
to estimate longer-term benefits and NHS/PSS costs. 

 
 
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 A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and 
Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), will be used for this 
economic evaluation. This model is an internet-based, interactive simulation model that predicts the 
long-term health outcomes and costs associated with the management of T1DM and type 2 
diabetes. The model consists of 15 submodels designed to simulate diabetes-related complications, 
non-specific mortality and costs over time. As the model simulates individuals over time, it updates 
risk factors and complications to account for disease progression. It also incorporates the costs and 
effects of hypoglycaemia, so is particularly well-suited to this study. Two major validation papers on 
the IMS CDM have been published to date. (36-37)The IMS Core Diabetes Model has also been used 
in a UK-based recent health technology assessment of CGM commissioned by NICE.(38) 
 
Given the degree of validation of the model, and in order to be in line with the updated T1DM NICE 
guideline NG17 which used this model, (17) It was considered important not to use an alternative 
model or develop a de novo cost effectiveness model for this evaluation. We will use input 
parameters based on the RCT. This will allow us to properly reflect our population (i.e. adults and 
adolescents with T1DM with poorly controlled HbA1c) and their specific risk factors, including age, 
sex, duration of diabetes and baseline HbA1c. We will use the results of the trial comparisons of 
change in HbA1c levels and the rates of severe hypoglycaemic events to model the treatment 
effects. 
 
The direct costs that will be included in the model are for: management (for primary prevention of 
complications); diabetes-related complications; the treatment of diabetes (this also includes the cost 
of the interventions) and other hospital costs. These will be taken from published sources.   Health 
benefits will be expressed in terms of life-years and QALYs gained. If more than one complication 
occurs at a time, a multiplicative approach will be applied.  
 
14.3.1 Incremental economic analysis for both economic evaluations 
 
Incremental cost-effectiveness ratios will be calculated in the event of the intervention having higher 
costs and better outcomes (based on QALYs and trial primary outcome). The base case analysis will 
express costs incurred in terms of QALY gain. Uncertainty will be addressed by generating cost-
effectiveness planes from bootstrapped resamples. Cost-effectiveness acceptability curves (CEACs) 
will be constructed to show the probability that the intervention is cost-effective for different QALY 

 
 
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thresholds. Incremental economic analysis using IMS CORE model will require the model’s time 
horizon to be set to 80 years. All costs and effects will be discounted by 3.5%.  
 
14.4 Process Evaluation Analysis 
 
The process evaluation will be undertaken ‘to explain discrepancies between expected and observed 
outcomes, to understand how context influences outcomes, and to provide insights to aid 
implementation’. Specifically, we will investigate whether: (1) treatment is consistent with the 
behaviour change theories, which underpin it and (2) contextual factors have affected 
implementation. Process evaluation will use a pipeline logic model, showing causal links between 
resources, activities and outcomes, integrating the National Institute for Health Behaviour Change 
Consortium’s (NIHBCC’s) approach to treatment fidelity (39) and a modified version of Linnan and 
Steckler’s framework for process evaluation.(40)  We will describe context qualitatively and take a 
mixed methods approach to characterising recruitment, reach, dose delivered/received and fidelity, 
with triangulation between data sources.(41) Free text response questionnaires will be completed 
by intervention designers, health professionals and trial participants (Appendices 10, 11 and 12), and 
analyses combined with trial data, including FSL2 device utilization and glucose finger-stick usage 
data, (DTSQs), Glucose Monitoring Satisfaction Survey (GMSS) which will be analysed descriptively 
(including the use of appropriate graphical representation), within arms where appropriate, will be 
synthesised and findings triangulated appropriately.  
 
 
 

 
 
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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 and conform to the 
Manchester CTU SOPs.  
 
Electronic CRFs (eCRFs) will be created for the study using the REDCap Cloud electronic data capture 
system (https://www.redcapcloud.com/) and these will follow the visit schedule outlined in this 
protocol. The REDCap Cloud 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 and only those who are signatories of the Manchester CTU site delegation 
log will be able to enter participant data. Paper based CRFs will be used for SAE reporting although 
information will also be recorded in REDCap Cloud. Standardised questionnaires will be completed 
on paper form with a record of their completion being provided electronically in REDCap Cloud. An 
export of the eCRF will be provided to sites so local workbooks can be utilised to ensure all 
participant data is effectively recorded, as some information may be obtained retrospectively (e.g. 
test result obtained following participant visit). Site workbooks will also act as another level of 
source documentation that could be used alongside patient records for monitoring purposes.   
 
The site PI will be responsible for ensuring the accuracy, completeness, legibility and timely provision 
of the data recorded in the electronic CRFs that is provided to the Manchester CTU. 
 
Sites must retain all original reports, traces and images from trial investigations, measures and 
assessments. Sites should keep sufficient information for all participants to enable records to be 
linked (e.g. CRFs, hospital records and samples) for the purposes of site monitoring and auditing. Any 
data recorded directly in the CRF that will not be verifiable from other sources are considered to be 
source data. 
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 participant data shall be observed at all times during the study.  Personal details 
for each participant taking part in the research study and linking them to a unique identification 

 
 
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number will be held locally on a study screening log in the Investigator site 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 
full addresses will not be used. The full postcode of each participant will be recorded as part of 
demographic information collection as this will be required to ascertain whether deprivation has an 
impact on device usage. Collected samples will be stored securely and locked away. Only researchers 
directly involved in the study will have access to the samples. 
 
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 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. 
 
Direct access to the source data will be provided for monitoring, audits, REC review 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 Manchester Clinical Trials Unit, 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 
17.1 Independent Data Monitoring Committee (IDMC)  
An IDMC will comprise a chairperson, a clinical expert and an independent statistician.  The IDMC 
will be informed of all serious adverse events and any unanticipated adverse device effects/events 
that occur during the study. The IDMC will review compiled adverse event data at periodic intervals. 
The IDMC will report to the Study Management Committee any safety concerns and 
recommendations for suspension or early termination of the investigation.  
17.2  Trial Steering Committee (TSC)  
Trial Steering Committee with an independent chair will be appointed. Membership of the TSC will 
include two service users, independent health economist, two to three members of the study team 

 
 
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including chief investigator (CI) (Only CI voting), independent statistician and independent clinical 
psychologist.  Other members of the study team and representatives from Manchester CTU and 
sponsor may also attend TSC meetings but will not have voting rights.  
 
17.3 Trial Management Group (TMG)  
Trial management group consisting of the Chief Investigator, Principal Clinical Investigators, Study 
Coordinators, and Study Data Manager will meet quarterly to discuss the operational aspects of the 
study. 
17.4 Study Monitoring  
A detailed risk assessment completed by the Sponsor and the Manchester CTU will inform the 
development of a Project Delivery Plan. This will be developed by the Manchester CTU trial team and 
will require CI / sponsor approval. The procedures, source data transfer modalities and anticipated 
frequency for monitoring will be documented in the Project Delivery Plan. Both a copy of the risk 
assessment and the project delivery plan will be stored in the TMF.  Manchester CTU study monitors 
will be fully independent of both the Sponsor and Site Principal Investigators. 
 
Authorised representatives of Sponsor, regulatory authority, or an Ethics Committee may perform 
audits or inspections at the recruiting centres, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the approved protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonisation (ICH), and any applicable regulatory 
requirements. Investigators should agree to allow trial related monitoring, including audits and 
regulatory inspections, by providing direct access to source data/documents as required. Participant 
consent for this will be obtained. 
18 Responsibilities 
18.1 Chief Investigator 
The Chief Investigator (CI) is the person with overall responsibility for the research and all ethics and 
HRA 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.  

 
 
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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 Coordinators 
Manchester CTU will provide overall co-ordination and project management for the trial, including 
planning investigator meetings, site initiation and routine monitoring visits. Additionally, local study 
coordinators will provide day-to-day support for the sites. 
 
  
 
19 Ethics 
The study will be conducted in accordance with the Declaration of Helsinki Ethical Principles for 
Medical Research involving Human Subjects (October 2000). 
19.1 Research Ethics Committee and HRA approval  
Prior to commencement of the study, the protocol, any amendments, participant information and 
informed consent forms, any other written information to be provided to the participant, participant 
recruitment procedures, current investigator CVs, and any other documents as required by the 
Research Ethics Committee / HRA will be submitted. Written approval will be obtained from the REC 
/ HRA prior to the commencement of the study.  Any additional requirements imposed by the REC 
shall be followed. 
19.2 Informed Consent of Study Participants 
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 participants.  
 
Potential participants 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 patient to participate and potential participants will be given 

 
 
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ample time to consider participation in the study.  Potential participants will be informed about their 
right to withdraw from the study at any time. 
 
The participant and/or their legal representative 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 participants. If a participant considers joining 
the trial by virtual consultation, they will receive the consent form along with participant 
information sheet by post before the recruitment visit is scheduled. Any questions they have can be 
answered by email, telephone or video consultation. If they decide to participate, they will need to 
provide initials to each declaration box on the consent form, sign it and return it to the research 
team in a pre-paid envelope. Once the research team receive their fully completed consent form, 
they will schedule the virtual recruitment consultation (Visit 1). At the start of the virtual recruitment 
consultation, the investigator will ask the participant if they are happy to proceed and they will sign / 
date the consent form. A copy of the fully completed consent form will be returned to the 
participant. Once the participant receives this, they can let the research team know before or at 
their next visit. 
 
 
20 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 sponsor, prior to implementation as per nationally 
agreed guidelines. 
 
21  Deviations from the 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 participants. If 
deviations do occur, they will be documented, stating the reason and the date, the action taken, and 
the impact for the participant and for the study. The documentation will be kept in the Investigator’s 

 
 
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Site File.  Deviations will be logged electronically and will require chief investigator or local principal 
investigator acknowledgement and sign-off. 
 
Deviations affecting the participant’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. 
 
22 Timetable 
Inclusion of the first participant in the study is planned to take place in September 2019, with an 
enrolment period of up to 30 weeks. The expected completion of the last participant is March 2020 
and the planned completion of the Clinical Study Report is June 2021. 
23  Reports and Publications 
Data will be submitted for publication in internationally peer-reviewed scientific journals; members 
of the investigator group will all be co-authors.  The privacy of each participant and confidentiality of 
their information shall be preserved in reports and publication of data. 
 
24  Retention of Study Documentation 
Participant notes must be kept for the maximum time period as permitted by each individual site. 
Other source documents and the Investigator’s Site File must be retained for at least 15 years, in line 
with the Data Protection Act 2018. The Principal Investigator will archive the documentation 
pertaining to the study after completion or discontinuation of the study. 
 
25  Indemnity Statements 
The clinical investigators are indemnified to cover negligent harm to patients participating in the 
study by their membership of medical defence organisations. 

 
 
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26 Appendices  
 
26.1 Appendix 1: EQ-5D-5L questionnaire 
 
 
 
 

 
 
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26.2 Appendix 2: Glucose Monitoring Satisfaction Survey 
 
 
 
 

 
 
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26.3 Appendix 3: Patient Health Questionnaire 9 
 
 
 
 
 
 
 
 
 

 
 
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26.4 Appendix 4: Diabetes Treatment Satisfaction  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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26.5 Appendix 5: Diabetes fear of injecting and self-testing (D-FISQ) questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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26.6 Appendix 6: Diabetes Eating Problem Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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26.7 Appendix 7: Type 1 Diabetes Distress Survey 
 
 
 
 
 
 
 

 
 
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26.8 Appendix 8: Clarke Questionnaire and Gold Score 
 
 
 

 
 
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26.9 Appendix 9: Outline of educational curriculum: FLASH-UK study 
 
During the trial each participant will attend 3 visits for therapy optimisation.  
 
Visit 3: at randomisation with ~1 hour for education/optimisation 
 
Visit 4: 4 weeks after randomisation - ~40 minutes for education/optimisation 
 
Visit 5: 12 weeks after randomisation - ~1 hour for education/optimisation 
 
 
The principles of therapy optimisation are broadly similar between the fingerstick glucose testing group and 
the Flash monitoring group and are based on Dose Adjustment for Normal Eating (DAFNE) principles. 
 
Each individual participant will have their needs assessed by an experienced diabetes educator. They will 
work with the individual to optimise insulin therapy based on available glucose data (SMBG or flash glucose). 
 
Areas covered at each visit will include participant goals and any barriers and their personal action plan. 
Insulin dosing will be reviewed: basal, bolus, correction, calculation of doses. All participants will be 
encouraged to review their data between study visits to identify patterns and make alterations to their 
therapy as needed. All participants will be given information about currently available online diabetes 
education support tools (Bertie online (https://www.bertieonline.org.uk)and DTN-UK flash glucose 
monitoring education platform (https://abcd.care/dtn/education). 
Throughout the trial all participants will be encouraged to follow the management principles: 
General advice 
1.     Check your glucose regularly, particularly before each meal and before bed 
2.     Aim for a flat stable glucose overnight, most nights (ask for support if this is difficult) 
3.     Try to give mealtime insulin 15-20 minutes pre-meal 
4.     If the insulin:carbohydrate ratio is correct your glucose should return to target after 4-5 hours of a meal 
bolus 
5.     If your correction ratio is correct, your glucose should return to target 4-5 hours after a correction dose 
6.     Hypo management: If < 3.5 mmol/L: treat with 15-20g rapid-acting carbohydrate; if below target but ≥ 
3.5 mmol/L: eat 10g carbohydrate. 
7.     Try to find time to regularly review your data and think what changes may be needed to improve 
glucose control 
 
 
 

 
 
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Control arm: 
Participants randomised to conventional finger-stick glucose monitoring arm will be encouraged to use 
finger-stick glucose levels to optimise treatment and will receive education about insulin dose adjustments 
using finger-stick glucose levels. The study will try to mimic real-life conditions by continuing participants 
pre-study diabetes treatment and insulin dose adjustment will be based on finger-stick glucose testing in the 
control arm and flash glucose monitoring in the intervention arm. Participants will be provided with a paper 
diary to collect information about insulin doses and carbohydrate intake. 
 
 
Intervention arm: 
Participants randomised to flash-glucose monitoring arm will receive education and training about insertion 
and initiation of the sensor as well as how to use flash-glucose monitoring data for treatment optimisation. 
The education sessions will be conducted by a professional diabetes educator or a member of the study 
team. Education will be tailored to meet the needs of the individual.  
Advice specific to flash glucose arm 
1. Scan as much as possible, aiming >15/day 
2. Work towards increasing % time in range (3.9-10mmol/l). If you are struggling to improve time in 
range, ask your team for support 
3. Aim to keep hypos (<3.9mmol/l) below 10%, ideally <5% 
4. If glucose below 7 and falling, stop and consider the need or additional carbohydrate to help avoid 
hypoglycaemia  
5. Do a blood glucose if the FreeStyle Libre 2 suggests you are hypo (<3.9mmol/l) 
6. If < 3.5 mmol/L: treat with 15-20g rapid-acting carbohydrate; if below target but ≥ 3.5 mmol/L: eat 
10g carbohydrate. 
7. Avoid insulin stacking: avoid the temptation to give correction doses within 3 hours of a meal bolus 
unless willing and able to scan every 20-30 minutes for the next few hours to avoid hypoglycaemia 
8. Remember the libre 2 reading lags behind blood glucose by 5-10 minutes 
9. Blood glucose above 5mmol/l is legally required for driving 
10. Use of alarm features of FSL 2 
 
 
  
 
 
 

 
 
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26.10 
Appendix 10: Assessing expectations and experience of using Freestyle      
Libre 2 during FLASH-UK Clinical Trial 
 
 
1. Why did you choose to go into the trial? 
 
2. What would you say your expectations were before you entered the trial?   
      
Was there anything that you particularly hoped for? 
      
Was there anything you were concerned about? 
 
3. Thinking outside of glycaemic control for a minute, did you think the Libre 2 would have any impact 
on your quality of life? If so, in what way?   How did that work out now that you are at the end of the 
trial? 
 
4. Thinking now about using the Libre 2 system for the last few months: 
Was there anything in particular that you found positive about using the Libre 2 system?  If so, 
please state. 
 
5. 'What was your experience of the alarms on the Libre 2 system?  [prompt for further detail 
e.g.:  positive, negative, intrusive, unhelpful , helpful, reassuring, worrying] 
 
 
6. If you were asked to describe your experience of using the Libre 2 system to a friend, what would 
you say about it? 
 
7. Were there occasions when you found yourself 'flashing' more than others? If so, please state. What 
prompted you to flash more often? How did this make you feel?  
 
8. Did having the flexibility to flash rather than finger prick impact the way you view your control over 
diabetes and its management? If so, how was that?  
 
9. Thinking along the same lines, did having access to the trend data impact the way you view your 
control over diabetes and its management?  If so, how? 
 
10. Was there anything in particular that you didn't like or found frustrating about using the Libre 
2 system?  What was that? 
 
11. If you were asked to recommend the Libre 2 system, what would you say?  
 
12. Thinking about your experience of using the Libre 2 system, is there anything you would change 
about it? If yes, what is that? 
 
13. If given the choice, would you wish to continue using the system? Why is that?  
 
 
 
 

 
 
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26.11 
Appendix 11: Process Evaluation, Topic guide: Participants 
 
Notes: This topic guide is a flexible tool and may be revised as new areas of interest arise during the process 
of data collection. The wording of questions is for guidance only and can be varied to suit the natural style of 
the interviewer and the level of understanding of the participant.  
 
Questions 
1. 
How did you find the libre 2 study?  
 
Was there anything in particular that you liked about it? 
 
Was there anything in particular that you didn’t like about it? 
 
How many visits did you attend?  
 
Did you feel you got any benefit from the study?  
 
Were there any downsides? 
 
Did the study meet your needs? 
 
2. 
Was it easy to fit the study demands into your usual routine? 
3. 
Would you have preferred fewer study visits? 
4. 
How did you hear about this study?  
 
How did you feel about being approached to participate in the study? 
 
 
How did you feel about a computer deciding whether you were going to get the libre 2 or not? 
 
5. 
We asked you to fill in some questionnaires at the beginning of the study and again recently.  
 
What did you think about the number of questions you were asked? 
 
Did you have any trouble answering any of the questions? 
 
We use those questions to find out whether how you are feeling. Did you feel any of the questions 
were more important than others? 
 
 
Thank you for your time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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26.12 
Appendix 12: Process Evaluation, Topic guide: Health Professionals and 
Triallists 
 
Notes: The detailed version of the topic guide will be tailored by the research team following the 
intervention development. This topic guide is a flexible tool and may also be revised as new areas of interest 
arise during the process of data collection. The wording of questions is for guidance only and can be varied 
to suit the natural style of the interviewer and the level of understanding of the participant.  
 
 
For Study Healthcare Professionals: 
 
First, a few questions about the Libre 2 intervention and the service in which you work 
Coherence (meaning and sense-making by professionals): 
 
Is the intervention easy to describe when you’re talking to patients and professionals? 
 
Is it clearly distinct from other interventions? 
 
Does it have a clear purpose for patients and professionals? 
 
Do you think patients and professionals have a shared sense of its purpose? 
 
What benefits do you think the intervention will bring; to whom? 
 
Are these benefits likely to be valued? 
 
Does the intervention fit with the overall goals and activity of your organisation? 
 
Cognitive participation (commitment and engagement by professionals) 
 
Do patients and professionals think the Libre 2 is a good device? 
 
Do they see the point of the libre 2 device as part of routine care? 
 
Are patients and professionals prepared to invest time, energy and work into it? 
 
Collective action (the work professionals and patients do to make the intervention function) 
 
How has the libre 2 affected your work; 
 
What effect has it had on your consultations and communication with patients and carers? 
 
Does it impact on the way that health professionals in the unit relate to each other? 
 
How compatible is the trial with existing work practices? 
 
Does it seem to be the right thing to be doing? 
 
It is perceived as valid…. as useful?  
 
Who needs to be involved in its use? 
 
Does rolling out the libre 2 mean health professionals learning new skills or doing things differently? 
 
Do all individuals involved in using libre 2 have the right set of skills? 
 
What impact does the libre 2 have on: 
 the division of labour in your unit 
 resources 
 responsibility between different professional groups? 
 
Does a rigorous protocol for libre 2 challenge professional autonomy over working practices?  
 
Does the libre 2 impact on case load and allocation of work? 

 
 
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 
Who has the power to make the libre 2 part of routine care? 
 
Do you think the system wants the libre 2 to be part of routine care? 
 
Do we need to and, if so, how can we divert resources to libre 2 prescribing? 
 
Reflexive Monitoring (professionals reflect on or appraise the intervention) 
 
 
How are users likely to perceive the device once they’ve been using it for a while? 
 
Is it likely to be perceived as advantageous for patients or staff? 
 
Will it be clear what effects the device has had? 
 
Can patients and professionals contribute feedback about study procedures? 
 
Can the intervention procedures be adapted/improved on the basis of experience? 
 
 
“Thank you, is there anything else you want to say about the libre 2 research?” 
 
 
For Triallists: 
Now, a few questions about the trial and its procedures: 
Any general comments about the trial? 
Coherence (meaning and sense-making by professionals): 
 
Is the trial easy to describe when you’re talking to patients and professionals? 
 
Is it clearly distinct from other trials? 
 
Does it have a clear purpose for patients and professionals? 
 
Do you think patients and professionals have a shared sense of its purpose? 
 
What benefits do you think the trial will bring; to whom? 
 
Are these benefits likely to be valued by professionals and patients who might take part in the main 
trial? 
 
Does the trial fit with the overall goals and activity of your organisation? 
 
Cognitive participation (commitment and engagement by professionals) 
 
Do patients and professionals think the trial is a good idea? 
 
Do they see the point of the trial easily? 
 
Are they prepared to invest time, energy and work in it? 
 
Collective action (the work professionals and patients do to make the trial function) 
 
How do the trial procedures affect your work; do they promote or impede it? 
 
What effect has the trial had on your consultations? 
 
Does participation in the trial require extensive training for staff involved? 
 
How compatible is the trial with existing work practices? 
 
What impact does it have on division of labour, resources, power, and responsibility between  
 
different professional groups? 
 
Reflexive Monitoring (professionals reflect on or appraise the trial) 
 
How are users likely to perceive the trial once it’s been on-going for a while? 
 
Is it likely to be perceived as advantageous for patients or staff? 

 
 
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 
Will it be clear what effects the study has had? 
 
Can users/staff contribute feedback about study procedures? 
 
Can the study procedures be adapted/ improved on the basis of experience? 
 
 

 
 
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26.13 
 Appendix 13: FLASH-UK study: Participant Diary  
 
 
To be completed starting five days before visits  4, 5 and 7: 
 
 
 
Rapid acting insulin dose (Novorapid, Humalog, Apidra, Fiasp etc)   
(meal dose+ correction) 
Long acting Insulin 
(Lantus, Levemir, 
Toujeo, Tresiba etc) 
Date 
Breakfast   
 Lunch 
Evening meal 
Corrections 
or snacks 
(add total) 
Morning 
Evening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Notes: 
 
 
 
 

 
 
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26.14 Appendix 14: Participant Information Leaflet Freestyle Libre 2 Treatment 
Arm 
  
 
 
 

 
 
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26.15 Appendix 15: Participant Information Leaflet Self-Monitoring Blood Glucose 
Control Arm 
 
 
 

 
 
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