Open-label, Multi-centre, Multi-national, Randomized 2-period Crossover Study Comparing Closed-loop Insulin Delivery With Sensor-augmented Pump Therapy Over 4 Months in Children 1-7 Years With Type 1 Diabetes at Home, With an Extension.
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Sponsor: University of Cambridge

The Artificial Pancreas in Very Young Children With T1D (KidsAP02) 
 
NCT03784027 
 
 
 
 
Study Protocol 
(1st October 2020) 
& 
Statistical Analysis Plan 
(5th May 2021) 

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Clinical Study Protocol 
 
 
Study Title: 
An open-label, multi-centre, multi-national, randomised, 2-
period crossover study to assess the efficacy, safety and utility 
of closed loop insulin delivery in comparison with sensor 
augmented pump therapy over 4 months in children with type 1 
diabetes aged 1 to 7 years in the home setting with extension to 
evaluate the efficacy of home use of closed loop insulin 
delivery. 
 
Short Title:   
The artificial pancreas in very young children with T1D 
(KidsAP02) 
 
Protocol Version: 
3.0    01 October 2020 
 
 
 
Chief Investigator Prof Roman Hovorka 
Wellcome Trust-MRC Institute of Metabolic Science 
University of Cambridge 
Box 289, Level 4 
Addenbrooke’s Hospital 
Hills Road, Cambridge 
CB2 0QQ 
UK 
Phone: +44 1223 762 862 
Fax:   +44 1223 336 996 
E-mail:  rh347@cam.ac.uk 
 
 
This protocol has been written in accordance with current ISO 14155:2011 standard 
 
 

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Principal 
Clinical 
Investigators 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr Ajay Thankamony 
Children’s Services 
Box 267 
Addenbrooke’s Hospital, Hills Road 
Cambridge, CB2 0QQ  
United Kingdom 
Phone: 01223 274311 
Email: ajay.thankamony@addenbrookes.nhs.uk 
 
Dr Carine de Beaufort 
Clinique Pédiatrique de Luxembourg 
Centre Hospitalier de Luxembourg  
4 rue Ernest Barblé 
L-1210 Luxembourg 
Luxembourg 
Phone: +352 44113133 
Fax: +352 44116466 
E-mail: bcschim@pt.lu 
 
Dr Fiona Campbell 
St James's University Hospital 
Beckett Street 
Leeds, LS9 7TF 
United Kingdom 
Phone: +44  113  218 5908/9 
E-mail: Fiona.Campbell26@nhs.net  
 
Dr Elke Fröhlich-Reiterer 
Medical University of Graz 
Department of Pediatrics and Adolescent Medicine 
Auenbruggerplatz 34/2 
A-8036 Graz 
Austria 
Phone:  +43 316 385 80562 
Fax: +43 316 385 13896 
E-mail: elke.froehlich-reiterer@medunigraz.at 
 
Dr Sabine Hofer 
Medical University of Innsbruck 
Department of Pediatrics I 
Anichstrasse 35 
A-6020 Innsbruck 
Austria 
Phone: +43 512 504 23600 
Fax: +43 512 504 25450 
E-mail: Sabine.E.Hofer@i-med.ac.at 

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Dr Thomas Kapellen 
University of Leipzig 
Division for Paediatric Diabetology 
Liebigstr. 20 
D-04103 Leipzig 
Germany 
Phone: +49 341 97 109 
Fax: +49 341 97 12 329 
E-mail: ThomasMichael.Kapellen@medizin.uni-leipzig.de 
 
Dr Birgit Rami-Merhar 
Medical University of Vienna 
Deptartment of Pediatrics 
Waehringer Gürtel 18-20 
A-1090 Vienna 
Austria 
Phone: +43-1-40400-32320 
Fax: +43-1-40400-59850 
E-mail: Birgit.Rami@meduniwien.ac.at 
 
Clinical 
Investigators 
Dr Heike Bartelt  
University of Leipzig 
University of Leipzig 
Division for Paediatric Diabetology 
Liebigstr. 20 
D-04103 Leipzig 
Germany 
Phone: +49 341 97 109 
Fax: +49 341 97 12 329 
E-mail: Heike.Bartelt@medizin.uni-leipzig.de  
 
Dr Charlotte Boughton 
Wellcome Trust-MRC Institute of Metabolic Science 
University of Cambridge 
Box 289, Level 4 
Addenbrooke’s Hospital, Hills Road  
Cambridge, CB2 0QQ 
United Kingdom 
Phone: +44 1223 769 066 
Fax: +44 1223 336 996 
Email: cb2000@medschl.cam.ac.uk 
 
Dr Elisabeth Binder 
Medical University of Innsbruck 
Department of Pediatrics I 

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Anichstrasse 35 
A-6020 Innsbruck 
Austria 
Phone: +43 512 504 23600 
Fax: +43 512 504 25450 
E-mail: Elisabeth.Binder@i-med.ac.at   
 
Dr Maria Fritsch 
Medical University of Vienna 
Deptartment of Pediatrics 
Waehringer Gürtel 18-20 
A-1090 Vienna 
Austria 
Phone: +43-1-40400-32320 
Fax: +43-1-40400-59850 
E-mail: maria.fritsch@meduniwien.ac.at 
 
Dr Lukas Hackl 
Medical University of Innsbruck 
Department of Pediatrics I 
Anichstrasse 35 
A-6020 Innsbruck 
Austria 
Phone: +43 512 504 23600 
Fax: +43 512 504 25450 
E-mail: Lukas.Hackl@i-med.ac.at 
 
Dr Hildegard Jasser-Nitsche 
Medical University of Graz 
Department of Paediatrics and Adolescent Medicine 
Division of Endocrinology and Diabetes 
Auenbruggerplatz 34 
A - 8036 Graz, Austria 
Tel. +43 316 385 82616 
Fax. +43 316 385 13896 
E-mail: Hildegard.nitsche@medunigraz.at 
 
Dr Katrin Nagl 
Medical University of Vienna 
Deptartment of Pediatrics 
Waehringer Gürtel 18-20 
A-1090 Vienna 
Austria 
Phone: +43-1-40400-32320 
Fax: +43-1-40400-59850 
E-mail: katrin.nagl@meduniwien.ac.at 

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Dr Julia Mader 
Medical University of Graz,  
Dept. of Internal Medicine 
Division of Endocrinology and Diabetology 
Auenbruggerplatz 15 
A- 8036 Graz 
Austria 
Phone: +43 316 385 80254 
Fax: +43 316 385 13428 
E-mail: julia.mader@medunigraz.at 
 
Dr Julia Fuchs 
Wellcome Trust-MRC Institute of Metabolic Science 
Box 289, Level 4 
Addenbrooke’s Hospital 
Hills Road 
Cambridge CB2 0QQ 
UK 
Tel: +44 1223 769 069 
Fax: +44 1223 336 996 
Email: jf674@medschl.cam.ac.uk 
 
Dr Ulrike Schierloh 
Clinique Pédiatrique de Luxembourg 
Centre Hospitalier de Luxembourg  
4 rue Ernest Barblé 
L-1210 Luxembourg 
Luxembourg 
Phone: +352 44113133 
Fax: +352 44116466 
E-mail: Schierloh.Ulrike@chl.lu 
 
Dr Elisabeth Steichen 
Medical University of Innsbruck 
Department of Pediatrics I 
Anichstrasse 35 
A-6020 Innsbruck 
Austria 
Phone: +43 512 504 23600 
Fax: +43 512 504 25450 
E-mail: elisabeth.steichen@i-med.ac.at 
 
Dr Elisabeth Suppan  
Medical University of Graz 
Department of Pediatrics and Adolescent Medicine 

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Auenbruggerplatz 34 
A-8036 Graz 
Austria 
Phone: +43 316 385 80254 
Fax: +43 316 385 13428 
E-mail: elisabeth.suppan@klinikum-graz.at 
 
Dr Martin Tauschmann 
Medical University of Vienna 
Department of Pediatrics 
Waehringer Gürtel 18-20 
A-1090 Vienna 
Austria 
Phone: +43-1-40400-32320 
Fax: +43-1-40400-59850 
E-mail: martin.tauschmann@meduniwien.ac.at 
 
Dr Rachel Williams  
Cambridge University Hospitals NHS Foundation Trust 
The Weston Centre for Paediatric Diabetes and Endocrinology 
Box 280 
Addenbrooke’s Hospital, Hills Road Cambridge, CB2 0QQ  
United Kingdom 
Phone: +44 1223 245151 ext 4311 
E-mail: rmw33@medschl.cam.ac.uk 
 
Dr James Yong 
St James's University Hospital 
Beckett Street 
Leeds, LS9 7TF 
United Kingdom 
Phone: +44  113  2066897 
E-mail: james.yong@nhs.net 
 
Other 
Investigators 
Dr Malgorzata E Wilinska  
Wellcome Trust-MRC Institute of Metabolic Science 
University of Cambridge 
Box 289, Level 4 
Addenbrooke’s Hospital 
Hills Road, Cambridge 
CB2 0QQ 
United Kingdom 
Phone: +44 1223 769 065 
Fax: +44 1223 336 996 
E-mail:  mew37@cam.ac.uk  
 

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Medical 
Sociologist 
Professor Julia Lawton 
Centre for Population Health Sciences 
The University of Edinburgh 
Teviot Place 
Edinburgh, EH8 9AG 
UK 
Tel: +44 (0)131 650 6197 
Fax: +44 (0)131 650 6902 
E-mail: J.Lawton@ed.ac.uk 
Health 
Economist 
Stéphane Roze 
Expert Health-Economist 
HEVA HEOR Sarl 
186 avenue Thiers 
69006 Lyon 
France 
Tel: +33 (0)4 72 14 52 43 
E-mail: SROZE@heva-heor.com 
Human Factor 
Assessment 
 
 
 
 
 
 
 
 
Sleep Quality 
Assessment 
Professor Korey K. Hood 
Stanford University School of Medicine 
291 Campus Drive 
Li Ka Shing Building 
Stanford, CA 94305-5101 
USA 
Tel:+1 (650) 497-6899 
E-mail: kkhood@stanford.edu  
 
Professor Alice M Gregory 
Department of Psychology 
Goldsmiths, University of London 
New Cross 
London, SE14 6NW 
UK 
Tel: +44 (0)2079 197 959 
E-mail: A.Gregory@gold.ac.uk 
 
Study  
Co-ordinator  
Mr Matthew Haydock 
Wellcome Trust-MRC Institute of Metabolic Science 
Box 289, Level 4 
Addenbrooke's Hospital 
Hills Road, Cambridge CB2 0QQ 
United Kingdom 
Phone: +44 1223 769 072 

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Fax  +44 1223 330 598 
E-mail:  mailto:mh968@medschl.cam.ac.uk 
 
Study 
Statistician 
Dr Craig Kollman 
Jaeb Centre for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
USA 
Phone: +1 (813) 975-8690 
Fax: +1 (813) 903-8227 
E-mail: ckollman@Jaeb.org  
 
Study Data 
Manager 
Mr Chris McCarthy 
Jaeb Centre for Health Research 
15310 Amberly Drive, Suite 350 
Tampa, FL 33647 
USA 
Tel: +1 (813) 975-8690 
Fax: +1 (813) 903-8227 
E-mail: cmccarthy@Jaeb.org  
 
Study Sponsor 
Cambridge University Hospitals NHS Foundation Trust, jointly with 
University of Cambridge  
Ms Carolyn Read 
Research Governance Office 
University of Cambridge 
School of Clinical Medicine 
Box 111, Cambridge Biomedical 
Campus 
Cambridge, CB2 0SP 
UK 
Tel: +44 (0)1223 769 291 
E-mail: 
researchgovernance@medschl.
cam.ac.uk 
 
Stephen Kelleher 
Cambridge University Hospitals  
NHS Foundation Trust              
Box 277, Addenbrooke's Hospital 
Hills Road, Cambridge, CB2 0QQ,  
UK 
Phone:  +44 1223 217 418 
Fax:  +44 1223 348 494 
E-mail: 
enquiries@addenbrookes.nhs.uk 
 
Collaborating 
Organisation 
Glooko (Diasend) 
Nellickevägen 20 
412 63 Göteborg  
Sweden 
Funder 
European Commission within the Horizon2020 Framework Programme 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
The signature below documents the approval of the protocol entitled “An open-
label, multi-centre, multi-national randomised, 2-period cross-over study 
to assess the efficacy,  safety and utility of closed loop insulin delivery in 
comparison with sensor augmented pump therapy over 4 months in 
children with type 1 diabetes aged 1 to 7 years in the home setting with 
extension to evaluate the efficacy of home use of closed loop insulin 
delivery.” Version _. _ dated _ _ / _ _ /_ _ _ _ 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 Roman Hovorka, Chief Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

250941 KidsAP02 Protocol v3.0 [2020_10_01]  
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SITE SIGNATURE PAGE 
 
I have read the attached protocol entitled " An open-label, multi-centre, multi-
national randomised, 2-period cross-over study to assess the efficacy,  
safety and utility of closed loop insulin delivery in comparison with 
sensor augmented pump therapy over 4 months in children with type 1 
diabetes aged 1 to 7 years in the home setting with extension to evaluate 
the efficacy of home use of closed loop insulin delivery." Version _._ dated 
_ _/_ _ _/_ _, 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.  
 
Signature ……………………………………. Date……………………….  
Name …………………………………….  
Site, Country………………………….  
  
Principal Clinical Investigator

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Table of Contents 
1 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS .................................. 14 
2 
STUDY SYNOPSIS .................................................................................................... 16 
3 
SUMMARY ................................................................................................................. 24 
4 
BACKGROUND.......................................................................................................... 25 
4.1 
INTRODUCTION .............................................................................................................. 25 
4.2 
CLOSED LOOP INSULIN DELIVERY .............................................................................. 26 
4.3 
CLOSED LOOP RESEARCH IN CAMBRIDGE ................................................................ 27 
 
Closed Loop Prototypes ........................................................................................... 27 
 
Preliminary Data with the Cambridge Control Algorithm .......................................... 28 
4.4 
KIDSAP CONSORTIUM ................................................................................................... 34 
4.5 
FLORENCEX CLOSED LOOP SYSTEM TO BE USED IN THE PRESENT STUDY ....... 35 
4.6 
RATIONALE FOR THE PRESENT STUDY ...................................................................... 35 
5 
OBJECTIVES ............................................................................................................. 36 
5.1 
EFFICACY ........................................................................................................................ 36 
5.2 
SAFETY............................................................................................................................ 36 
5.3 
UTILITY ............................................................................................................................ 36 
5.4 
HUMAN FACTORS .......................................................................................................... 37 
5.5 
HEALTH ECONOMICS .................................................................................................... 37 
5.6 
EXTENSION PHASE OBJECTIVES (UK SITES ONLY) .................................................. 37 
6 
STUDY DESIGN ......................................................................................................... 38 
7 
STUDY SUBJECTS ................................................................................................... 41 
7.1 
STUDY POPULATION ..................................................................................................... 41 
 
Inclusion criteria ....................................................................................................... 41 
 
Exclusion criteria ...................................................................................................... 41 
7.2 
RECRUITMENT ............................................................................................................... 42 
7.3 
RANDOMISATION ........................................................................................................... 43 
8 
METHODS UNDER INVESTIGATION ....................................................................... 43 
8.1 
NAME AND DESCRIPTION OF THE METHOD OF INVESTIGATION ............................ 43 
8.2 
INTENDED PURPOSE ..................................................................................................... 44 
8.3 
METHOD OF ADMINISTRATION .................................................................................... 44 
8.4 
REQUIRED TRAINING .................................................................................................... 44 
8.5 
PRECAUTIONS ................................................................................................................ 44 
8.6 
ACCOUNTABILITY OF THE METHOD UNDER INVESTIGATION .................................. 44 
9 
STUDY SCHEDULE ................................................................................................... 45 
9.1 
OVERVIEW ...................................................................................................................... 45 
9.2 
RECRUITMENT VISIT (VISIT 1) ...................................................................................... 49 
9.3 
STUDY CGM TRAINING (VISIT 2) ................................................................................... 49 
9.4 
STUDY PUMP TRAINING (VISIT 3) ................................................................................. 50 
9.5 
RUN-IN ............................................................................................................................. 50 
9.6 
END OF RUN-IN, COMPLIANCE ASSESSMENT (VISIT 4) ............................................ 51 
9.7 
RANDOMISATION ........................................................................................................... 51 
9.8 
INITIATION OF STUDY ARM VISITS (VISIT 5, VISIT 7) ................................................. 52 
 
Closed Loop Insulin Delivery ................................................................................... 52 
 
Sensor augmented pump therapy ............................................................................ 52 
 
Remote Monitoring................................................................................................... 52 
9.9 
TELEPHONE/MAIL CONTACTS AFTER STARTING STUDY TREATMENT (CONTACTS 
2-11) 52 
9.10 
END OF 1ST STUDY ARM (VISIT 6) ............................................................................ 53 
9.11 
WASHOUT ................................................................................................................... 53 
9.12 
SLEEP ASSESSMENT (VISIT 8A) (UK AND LUXEMBOURG ONLY) ........................ 53 
9.13 
END OF 2ND STUDY ARM (VISIT 8B) ......................................................................... 54 
9.14 
EXTENSION PHASE (UK SITES ONLY) ..................................................................... 54 
 
Routine Follow-up Contacts .................................................................................... 54 
 
End of Extension Phase (Visit 9) ............................................................................. 55 
9.15 
PARTICIPANT WITHDRAWAL CRITERIA .................................................................. 55 
9.16 
STUDY STOPPING CRITERIA .................................................................................... 56 
9.17 
CO-ENROLMENT GUIDELINES ................................................................................. 56 
9.18 
SUPPORT TELEPHONE LINE .................................................................................... 56 
9.19 
SUBJECT REIMBURSEMENT .................................................................................... 56 
10 
ENDPOINTS ............................................................................................................... 57 
10.1 
PRIMARY ENDPOINTS ............................................................................................... 57 
10.2 
OTHER KEY ENDPOINTS ........................................................................................... 57 
10.3 
SECONDARY ENDPOINTS ......................................................................................... 57 
10.4 
SAFETY EVALUATION................................................................................................ 57 
10.5 
UTILITY EVALUATION ................................................................................................ 57 
10.6 
HUMAN FACTORS ...................................................................................................... 58 
10.7 
HEALTH ECONOMICS ................................................................................................ 58 
10.8 
EXTENSION PHASE OUTCOMES (UK SITES ONLY) ............................................... 58 
 
Primary endpoint and key endpoints ....................................................................... 58 

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Secondary endpoints............................................................................................... 58 
11 
ASSESSMENT AND REPORTING OF ADVERSE EVENTS .................................... 59 
11.1 
DEFINITIONS .............................................................................................................. 59 
 
Reportable Adverse Events ..................................................................................... 59 
 
Adverse Events ....................................................................................................... 59 
 
Adverse Device Effect ............................................................................................. 59 
 
Serious Adverse Event ............................................................................................ 60 
 
Serious Adverse Device Effect ................................................................................ 61 
 
Unanticipated Serious Adverse Device Effect ......................................................... 61 
 
Device Deficiencies ................................................................................................. 61 
 
Adverse Event Intensity ........................................................................................... 61 
 
Adverse Event Causality ......................................................................................... 62 
11.2 
RECORDING AND REPORTING OF ADVERSE EVENTS, SERIOUS ADVERSE 
EVENTS AND DEVICE DEFICIENCIES ..................................................................................... 63 
 
Monitoring Period of Adverse Events ...................................................................... 63 
 
Recording and Reporting of Adverse Events .......................................................... 63 
 
Severe Hypoglycaemia ........................................................................................... 63 
 
Diabetic Ketoacidosis .............................................................................................. 64 
 
Reporting of Serious Adverse Events and Serious Adverse Device Effects ............ 64 
 
Recording and Reporting of Device Deficiencies .................................................... 66 
 
Healthcare Arrangements and Compensation for Adverse Events ......................... 66 
 
Country specific requirements ................................................................................. 66 
11.3 
ANTICIPATED ADVERSE EVENTS, RISKS AND BENEFITS .................................... 68 
 
Risks and Anticipated Adverse Events .................................................................... 68 
 
Hypoglycaemia and Hyperglycaemia ...................................................................... 68 
 
Blood Sampling for HbA1c and Blood Glucose Measurements .............................. 68 
 
Insulin Pump Therapy ............................................................................................. 69 
 
Continuous Glucose Monitoring .............................................................................. 69 
 
Questionnaires and Interviews ................................................................................ 69 
 
Risk Analysis and Residual Risk Associated with the Investigational Device .......... 70 
11.4 
BENEFITS .................................................................................................................... 70 
11.5 
DATA SAFETY MONITORING BOARD (DSMB) ......................................................... 71 
12 
METHODS AND ASSESSMENTS ............................................................................. 71 
12.1 
PROCEDURES ............................................................................................................ 71 
 
Height and Weight ................................................................................................... 71 
 
Blood Glucose Meter Data ...................................................................................... 72 
 
Insulin Pump and CGM Data ................................................................................... 72 
12.2 
LABORATORY METHODS .......................................................................................... 72 
 
HbA1c ..................................................................................................................... 72 
 
Total Blood Loss ..................................................................................................... 72 
12.3 
QUESTIONNAIRES ..................................................................................................... 72 
12.4 
SLEEP.......................................................................................................................... 73 
12.5 
QUALITATIVE INTERVIEW ......................................................................................... 74 
12.6 
HEALTH ECONOMICS ................................................................................................ 75 
 
Simulation cohort and treatment effects .................................................................. 75 
 
Costs and utilities .................................................................................................... 75 
13 
STUDY MATERIALS AND PRODUCTS ................................................................... 76 
13.1 
INSULIN ....................................................................................................................... 76 
13.2 
INSULIN PUMP ............................................................................................................ 76 
13.3 
CONTINUOUS SUBCUTANEOUS GLUCOSE MONITOR .......................................... 76 
13.4 
SMARTPHONE ............................................................................................................ 76 
13.5 
BLOOD GLUCOSE METER ......................................................................................... 76 
13.6 
CAMAPS FX HYBRID CLOSED LOOP APP ............................................................... 76 
13.7 
COMPUTER-BASED ALGORITHM ............................................................................. 77 
13.8 
ACTIWATCH ................................................................................................................ 77 
14 
DATA ANALYSIS ....................................................................................................... 77 
14.1 
PRIMARY ENDPOINT ANALYSIS ............................................................................... 77 
14.2 
OTHER KEY ENDPOINTS ........................................................................................... 78 
14.3 
SECONDARY EFFICACY ANALYSES ........................................................................ 78 
14.4 
EXTENSION PHASE ANALYSES ............................................................................... 79 
 
Primary Endpoint Analysis ...................................................................................... 79 
 
Secondary Efficacy Analyses .................................................................................. 80 
14.5 
SAFETY ANALYSES ................................................................................................... 81 
14.6 
UTILITY EVALUATION ................................................................................................ 82 
14.7 
QUESTIONNAIRES ..................................................................................................... 82 
14.8 
SLEEP ASSESSMENT ................................................................................................ 82 
14.9 
INTERVIEWS ............................................................................................................... 82 
14.10 
HEALTH ECONOMICS EVALUATION ........................................................................ 83 
14.11 
INTERIM ANALYSIS .................................................................................................... 83 
14.12 
SAMPLE SIZE AND POWER CALCULATIONS .......................................................... 84 
14.13 
DEVIATIONS FROM THE STATISTICAL PLAN .......................................................... 84 
15 
CASE REPORT FORMS ............................................................................................ 84 

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16 
DATA MANAGEMENT ............................................................................................... 85 
17 
ETHICS ....................................................................................................................... 85 
17.1 
INDEPENDENT RESEARCH ETHICS COMMITTEES (REC) ..................................... 85 
17.2 
INFORMED CONSENT OF STUDY SUBJECTS ......................................................... 86 
18 
AMENDMENTS TO THE PROTOCOL ...................................................................... 87 
19 
DEVIATIONS FROM PROTOCOL ............................................................................. 87 
20 
STUDY MANAGEMENT ............................................................................................ 87 
20.1 
DATA AND SAFETY MONITORING BOARD (DSMB) ................................................. 87 
20.2 
TRIAL STEERING COMMITTEE (TSC) ....................................................................... 88 
20.3 
STUDY MONITORING ................................................................................................. 88 
21 
RESPONSIBILITIES .................................................................................................. 88 
21.1 
CHIEF INVESTIGATOR ............................................................................................... 88 
21.2 
PRINCIPAL CLINICAL INVESTIGATOR...................................................................... 88 
21.3 
STUDY COORDINATOR ............................................................................................. 89 
22 
REPORTS AND PUBLICATIONS .............................................................................. 89 
23 
TIMETABLE ............................................................................................................... 89 
24 
RETENTION OF STUDY DOCUMENTATION ........................................................... 89 
25 
INDEMNITY STATEMENTS ....................................................................................... 89 
26 
REFERENCES ........................................................................................................... 91 
27 
DOCUMENT AMENDMENT HISTORY ..................................................................... 97 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 List of Abbreviations and Relevant Definitions  
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AP 
Artificial Pancreas 
AR 
Adverse Reaction 
ASADE Anticipated Serious Adverse Device Effect 
AUC 
Area under the Curve 
CE 
Conformité Européenne (CE-mark) 
CGM 
Continuous Glucose Monitoring 
CI 
Chief Investigator or Confidence Interval 
CL 
Closed loop 
CRF 
Case Report Form 
CSHQ 
Children’s Sleep  Habit Questionnaire 
CSII 
Continuous subcutaneous insulin infusion 
DKA 
Diabetic Ketoacidosis 
DSMB  
Data Safety and Monitoring Board  
EC 
European Commission  
eCRF 
Electronic Case Report Form 
EU 
European Union 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
H2020 
Horizon 2020: The EU Framework Programme for Research and 
Innovation 
HbA1c 
Glycated Haemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
IFCC 
International Federation of Clinical Chemistry and Laboratory 
Medicine 
ISPAD 
International Society for Pediatric and Adolescent Diabetes 
JDRF 
Juvenile Diabetes Research Foundation 
MHRA 
Medicine and Healthcare Products Regulatory Agency 
NGSP 
National Glycohemoglobin Standardization Program 
NHS 
National Health Service 
PIC 
Participant Identification Centre 
PLGM 
Predictive Low Glucose Management 
PSQI 
Pittsburgh Sleep Quality Index 
R & D 
Research and Development 
RCT 
Randomised Controlled Trial 
REC  
Research Ethics Committee 

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SADE 
Serious Adverse Device Effect  
SAE 
Serious Adverse Event  
SAP 
Sensor Augmented Pump Therapy 
SD 
Standard Deviation 
SMBG 
Self-Monitoring of Blood Glucose 
T1D 
Type 1 Diabetes Mellitus 
USADE Unanticipated Serious Adverse Device Effect 
WHO 
World Health Organization 

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2 Study Synopsis 
Title of clinical trial 
An 
open-label, 
multi-centre, 
multi-national, 
randomised, 2-period cross-over study to assess the 
efficacy, safety and utility of closed loop insulin 
delivery in comparison with sensor augmented pump 
therapy over 4 months in children with type 1 diabetes 
aged 1 to 7 years in the home setting (primary phase) 
with extension to evaluate the efficacy of home use of 
closed loop insulin delivery (extension phase, UK 
sites only). 
 
Short Title 
The artificial pancreas in very young children with T1D 
(KidsAP02) 
 
Sponsor name 
University of Cambridge & Cambridge University 
Hospitals NHS Foundation Trust 
 
Medical condition or disease 
under investigation 
 
Type 1 diabetes 
Study Phase 
Outcome study (primary phase) 
Extension phase (UK sites) 
 
Purpose of clinical trial 
To determine whether 24/7 automated hybrid closed 
loop will improve glucose control as measured by time 
within the target range compared with sensor 
augmented pump therapy in very young children with 
T1D (primary phase). In the extension phase, the 
purpose is to evaluate the effect of long-term home 
use of 24/7 automated hybrid closed loop insulin 
delivery on glucose control (UK sites only).    
Study objectives 
The study objective is to evaluate the safety, efficacy 
and utility of automated hybrid closed loop glucose 
control in very young children with type 1 diabetes.  
 
1.  EFFICACY: The objective is to assess the ability 
of a hybrid closed loop system to maintain CGM 
glucose levels within the target range of 3.9 to 10 
mmol/l (70 to 180 mg/dl) in comparison with sensor 
augmented pump therapy in very young children with 
type 1 diabetes (primary phase). In the extension 
phase the objective is to assess the long-term ability 
of a hybrid closed loop system to maintain CGM 
glucose levels within the target range of 3.9 to 10 
mmol/l 
compared 
to 
primary 
phase 
sensor 
augmented pump therapy.  
 
2.  SAFETY: The objective is to evaluate the safety of 
closed loop glucose control compared with sensor 
augmented pump therapy in terms of episodes and 

250941 KidsAP02 Protocol v3.0 [2020_10_01]  
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severity of hypoglycaemia, frequency of diabetic 
ketoacidosis (DKA) and nature and severity of other 
adverse events. 
 
3. UTILITY: The objective is to determine the 
acceptability and duration of use of the closed loop 
system in this population. 
 
4. HUMAN FACTORS: The objective is to assess 
emotional 
and 
behavioural 
characteristics 
of 
participants 
and 
parents/guardians 
and 
their 
response to the closed loop system and clinical trial 
using validated surveys (primary & extension phase), 
actigraphy and semi-structured qualitative interviews 
(primary phase only). 
 
5. HEALTH ECONOMICS: The objective is to perform 
a cost utility analysis to inform reimbursement 
decision-making. 
 
Study Design  
The primary phase adopts an open-label, multi-
centre, 
multi-national, 
randomised, 
two-period 
crossover study design contrasting closed loop 
glucose control and sensor augmented pump therapy 
in very young children with type 1 diabetes in the 
home setting. Two intervention periods will last 4 
months each with 1 to 4 weeks washout period. The 
order of the two interventions will be random. The 
extension phase adopts a multi-centre, single arm 
design evaluating closed loop glucose control in very 
young children with type 1 diabetes in the home 
setting for 18 months from the end of the primary 
phase (UK sites only). 
 
Study Endpoints 
The primary endpoint: 
The primary endpoint is the between group difference 
in time spent with sensor glucose levels between 3.9 
to 10.0 mmol/l (70 to 180 mg/dl) during the 4 months 
intervention period. 
 
Other key endpoints* 
 
Time spent above target glucose (10.0 mmol/l) 
(180 mg/dl) 
 
HbA1c 
 
Average of glucose levels 
 
Time spent below target glucose (3.9 mmol/l) 
(70 mg/dl) 
 
Secondary endpoints* include the following: 
 
Standard deviation, and coefficient of 
variation of glucose levels 

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 
Time with glucose levels <3.0 mmol/l (54 
mg/dl) 
 
Time with glucose levels in significant 
hyperglycaemia (glucose levels > 16.7 
mmol/l) (300 mg/dl) 
 
AUC of glucose below 3.5 mmol/l (63 mg/dl) 
 
BMI SDS 
 
Total, basal, and bolus insulin dose  
 
* Endpoints regarding glucose levels will be based 
on sensor glucose data. 
 
Extension Phase (UK sites only): 
 
Primary endpoint: Time spent with sensor 
glucose levels between 3.9 to 10.0 mmol/l (70 to 
180 mg/dl) over 18 months from the end of the 
primary phase, as compared to primary phase 
sensor augmented pump therapy 
 
Other key endpoints and secondary endpoints as 
previously 
 
Safety Evaluation 
Assessment 
of 
frequency 
and 
severity 
of 
hypoglycaemic episodes as defined by International 
Society for Pediatric and Adolescent Diabetes, 
frequency of diabetic ketoacidosis (DKA) and nature 
and severity of other adverse events. 
 
Utility Evaluation 
Assessment of the frequency and duration of use of 
the closed loop system. 
 Percentage of closed loop operation   
 Percentage of CGM availability 
 
Human factors assessment 
 
Emotional 
and 
behavioural 
characteristics 
of 
participants and family members and their response 
to the closed loop system and clinical trial will be 
assessed gathering both quantitative (validated 
surveys and actigraphy) and qualitative data 
(interviews) in the primary study phase. The extension 
phase will use quantitative data (validated surveys) 
only.  
 
Health economic evaluation 
Cost utility analysis on the benefits of closed loop 
insulin delivery to inform reimbursement decision-
making. 
 
Participating clinical centres 
1. Addenbrooke's Hospital, Cambridge University 
Hospital NHS Foundation Trust, Cambridge, UK 
2. Leeds Teaching Hospitals NHS Trust, Leeds, UK 
3. DECCP, Centre Hospitalier de Luxembourg, 
Grand Duché de Luxembourg 

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4. University of Leipzig, Leipzig, Germany 
5. Medical University of Graz, Graz, Austria 
6. Medical University of Innsbruck, Innsbruck, Austria 
7. Medical University of Vienna, Vienna, Austria 
 
Sample Size 
72 participants randomised (8-12 participants per 
centre). At the primary phase final visit, participants 
(UK sites only)  on sensor-augmented pump therapy 
as their standard clinical care will be invited to 
participate in an extension phase of closed loop 
therapy for a further 18 months.  
 
Summary of eligibility criteria 
Key inclusion criteria: 
1. Age between 1 and 7 years of age (inclusive) 
2. Type 1 diabetes for at least 6 months 
3. Insulin pump user for at least 3 months 
4. On sensor-augmented pump as standard 
clinical care (extension phase only) 
5. Treated with rapid or ultra-rapid acting insulin 
analogue  
6. Subject/carer is willing to perform at least 2 
finger-prick blood glucose measurements per 
day 
7. Screening HbA1c ≤ 11 % (97mmol/mol) based 
on analysis from local laboratory 
8. Able to wear glucose sensor  
9. Able to wear closed loop system 24/7  
10. The subject/carer is willing to follow study 
specific instructions 
11. The subject/carer is willing to upload pump 
and CGM data at regular intervals 
 
Key exclusion criteria: 
1. Physical or psychological disease likely to 
interfere with normal conduct of the study 
2. Untreated coeliac disease or thyroid disease  
3. Current treatment with drugs known to interfere 
with glucose metabolism 
4. Use of closed loop insulin delivery within the 
past two months (primary phase only) 
5. Known or suspected allergy to insulin 
6. Carer’s lack of reliable telephone facility for 
contact 
7. Subject/carer’s severe visual impairment  
8. Subject/carer’s severe hearing impairment 
9. Medically documented allergy towards the 
adhesive (glue) of plasters or subject is unable 
to tolerate tape adhesive in the area of sensor 
placement 
10. Serious skin diseases located at places of the 
body corresponding with sensor insertion sites  

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11. Sickle cell disease, haemoglobinopathy; or has 
received 
red 
blood 
cell 
transfusion 
or 
erythropoietin within 3 months prior to time of 
screening  
12. Plan to receive red blood cell transfusion or 
erythropoietin over the course of study 
participation 
13. Subject/carer not proficient in English (UK, 
Germany, Austria, Luxembourg) or German 
(Germany, Austria, Luxembourg) or French 
(Luxembourg)  
Further exclusion criteria for Germany are listed in 
section 7.1.2. 
 
Maximum duration of study 
for a subject 
 
11 months (primary phase).  
29 months for participants (UK sites only) opting to 
participate in 18-month extension phase. 
Recruitment 
The subjects will be recruited through paediatric 
diabetes outpatient clinics at participating clinical 
centres (see above). Enrolment for the primary phase 
will target up to 80 (aiming for 8-12 participants per 
centre) 
to 
allow 
for 
dropouts 
during 
run-in. 
Participants (UK sites only) completing the primary 
phase, who are on sensor-augmented pump therapy 
as their standard clinical care, will be invited to 
participate in the extension phase.  
 
Consent 
Written informed consent will be obtained from all 
parents/guardians and written assent from older 
children before any study related activities. 
 
Additional written consent will be obtained for the 
extension phase from all parents/guardians. 
 
Baseline Assessment 
Eligible subjects will undergo a baseline assessment 
including a blood sample for the measurement of 
HbA1c. Questionnaires will be completed by 
parents/guardians. 
 
Pre-Study Training 
and Run-in  
Training sessions on the use of the study CGM and 
insulin pump will be provided by the research team.  
During a 2-4 week run-in period, subjects will use 
study CGM and insulin pump. For compliance and to 
assess the ability of the subject to use the study 
devices safely, at least 8 days of CGM data need to 
be recorded and safe use of study insulin pump 
demonstrated during the last 14 days of run-in period. 
The CGM data will also be used to assess baseline 
glucose control and may be used for treatment 
optimization as necessary.  
 

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Competency Assessment 
Competency on the use of study pump and study 
CGM will be evaluated using a competency 
assessment tool developed by the research team.  
Training may be repeated if required. 
 
Randomisation 
Eligible 
subjects 
will 
be 
randomised 
using 
randomisation software to the initial use of automated 
hybrid closed loop glucose system or to sensor 
augmented pump therapy for 4 months with a 1 to 4 
week washout period before crossing over to the 
other study arm. In the extension phase participants 
will use automated hybrid closed loop glucose system 
for 18 months from the primary phase final visit. 
 
A blood sample for HbA1c will be taken if screening 
and randomisation are >28 days apart. 
1.  Automated day and night 
closed loop insulin delivery 
(intervention arm) 
 
 
 
 
 
 
 
Participants in the closed loop arm and their 
caregivers will receive an additional training session 
covering the use of the closed loop system provided 
by the research team prior to starting closed loop 
insulin delivery. During this 1-2 hour session, 
parents/guardians will operate the system under the 
supervision 
of 
the 
clinical 
research 
team. 
Competency on the use of closed loop system will be 
evaluated. 
Thereafter, 
subjects 
and 
their 
parents/guardians will use the hybrid closed loop 
system for 4 months at home. In the extension phase 
participants will receive refresher training on key 
aspects of the closed loop system provided by the 
research team prior to continuing or resuming closed 
loop insulin delivery for 18 months (from the primary 
phase final visit) at home. 
 
Crossover Assessment  
 
At the end of the first study arm, a blood sample for 
the measurement of HbA1c will be taken and weight 
and height will be measured. Validated surveys 
evaluating the impact of the devices employed on 
quality of life, psychosocial function, diabetes 
management and treatment satisfaction will be 
completed. 
 
Parents/guardians will be invited to be interviewed to 
gather feedback on and reactions to their current 
treatment, the clinical trial, and quality of life changes. 
 
2.  Sensor augmented pump 
therapy  
(control arm) 
Participants in the sensor augmented pump therapy 
arm and their caregivers will receive refresher training 
on key aspects of insulin pump therapy and CGM use.  
 

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Subjects and their parents/guardians will continue 
using sensor augmented pump therapy for 4 months 
at home.  
 
Study contacts 
Participants will be contacted 24h after starting each 
study arm to ensure there are no concerns regarding 
the 
study 
devices. 
In 
between 
study 
visits, 
participants will be contacted by the study team 
(email/phone) once monthly in the primary phase and 
3-monthly in the extension phase, in order to record 
any adverse events, device deficiencies, and changes 
in insulin settings, other medical conditions and/or 
medication. 
 
In case of any problems related to the technical device 
or 
diabetes 
management 
such as hypo- or 
hyperglycaemia, subjects will be able to contact a 24-
hour telephone helpline to the local research team at 
any time. The local research team will have access to 
central 24 hour advice on technical issues. 
End of study assessments 
(primary phase) 
A blood sample will be taken for measurement of 
HbA1c at the end of the study. Height and weight will 
be recorded. Study devices will be downloaded and 
returned. Participants will resume usual care using 
their pre-study insulin pump. Validated surveys 
evaluating the impact of the devices employed on 
quality of life, psychosocial function and diabetes 
management and treatment satisfaction will be 
completed. 
 
Parents/guardians will be invited to participate in a 
sleep sub-study prior to the final visit (UK & 
Luxembourg only).  
 
Parents/guardians will be invited to be interviewed to 
gather feedback on and reactions to their current 
treatment, the clinical trial, and quality of life changes. 
 
Extension phase (UK sites 
only) 
Follow up contacts will be conducted 3-monthly, in 
line with routine clinic visits, including recording of 
adverse events, medical history, insulin requirements 
and HbA1c. 
 
After 18 months from the end of the primary phase, 
parents/guardians 
will 
complete 
validated 
questionnaires 
evaluating 
the 
impact 
of 
the 
technology on quality of life, life change, diabetes 
management, 
sleep 
quality 
and 
fear 
of 
hypoglycaemia. Height and weight will be measured. 
A blood sample will be taken for measurement of 
HbA1c at the end of the extension phase.  

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Procedures for safety 
monitoring during trial 
Standard operating procedures for monitoring and 
reporting of all adverse events will be in place, 
including serious adverse events (SAE), serious 
adverse device effects (SADE) and specific adverse 
events (AE) such as severe hypoglycaemia.  
 
A data safety and monitoring board (DSMB) will be 
informed of all serious adverse events and any 
unanticipated serious adverse device effects that 
occur during the study and will review compiled 
adverse event data at periodic intervals. 
Criteria for withdrawal of 
subjects on safety grounds 
 
 
A subject/guardian may terminate participation in the 
study at any time without necessarily giving a reason 
and 
without 
any 
personal 
disadvantage. 
An 
investigator can stop the participation of a subject 
after consideration of the benefit/risk ratio. Possible 
reasons are: 
 
Serious adverse events 
 
Non-compliance 
 
Serious protocol violation 
 
Decision by the investigator, or the sponsor, 
that termination is in the subject’s best medical 
interest 
 
Allergic reaction to insulin 
 
 

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3 Summary 
The suggested clinical trial is part of the KidsAP project funded by the European 
Commission’s Horizon 2020 Framework Programme with additional funding by JDRF. 
The project evaluates the use of the Artificial Pancreas (or closed loop system) in very 
young children with type 1 diabetes (T1D) aged 1 to 7 years. The suggested trial is an 
outcome study to determine whether 24/7 automated closed loop glucose control will 
improve glucose control as measured by time in range compared to sensor augmented 
pump therapy. 
 
This is an open-label, multi-centre, multi-national, randomised, two period, cross-over 
design study, contrasting a 4 month period during which glucose levels will be 
controlled either by a closed loop system (intervention group) or by sensor augmented 
pump therapy (control group). The order of the two interventions will be random.  
Participants (UK sites only) completing the 8 month primary phase study, who are on 
sensor-augmented pump as their standard clinical care, will be invited to continue in 
an extension phase using the closed loop system for a further 18 months from the end 
of the primary phase. 
 
A total of up to 80 young children aged 1 to 7 years with T1D on insulin pump therapy 
(aiming for 72 randomised subjects) will be recruited through paediatric outpatient 
diabetes clinics of the investigation centres.  
 
Prior to the use of study devices, participants and parents/guardians will receive 
appropriate training by the research team on the safe use of the study pump and CGM 
device, and the hybrid closed loop insulin delivery system. Carers at nursey/school 
may also receive training by the study team if required.   
 
During the closed loop study arm, subjects and parents/guardians will use the closed 
loop system for 4 months under free-living conditions in their home and nursery/school 
environment. During the control study arm, subjects and parents/guardians will use 
sensor augmented pump therapy for 4 months under free-living conditions in their 
home and nursery/school environment. All subjects will have regular contact with the 
study team during the home study phase including 24/7 telephone support.  
 
The primary endpoint is time spent in target range, between 3.9 and 10.0 mmol/l as 
recorded by CGM. Secondary outcomes are the time spent with glucose levels above 
and below target, as recorded by CGM, and other CGM-based metrics. Safety 
evaluation comprises assessment of the frequency and severity of hypoglycaemic 
episodes and diabetic ketoacidosis (DKA). 

250941 KidsAP02 Protocol v3.0 [2020_10_01]  
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During the extension phase, participants will have follow-up contacts every 3 months.  
The primary endpoint is time spent in target range, between 3.9 and 10.0 mmol/l as 
recorded by CGM, over 18 months from the end of the primary phase, as compared 
to sensor augmented pump therapy during the primary phase. Secondary outcomes 
as well as safety and utility will be assessed as per primary phase.  
 
4 Background 
4.1 Introduction 
Type 1 diabetes is associated with life-long dependency on insulin administration and 
is caused by immune-mediated destruction of the pancreatic beta cells in genetically 
predisposed individuals (1). Type 1 diabetes (T1D) is one of the commonest chronic 
conditions in childhood, and the incidence is increasing worldwide (2) with an 
estimated overall annual rate of increase of approximately 3%, including in the 
youngest age group (3). Achievement of tight glycaemic control in T1D is limited by 
hypoglycaemia, contributing to the majority of youths failing to meet treatment 
guidelines for target glycated haemoglobin (HbA1c) below 7.5% (58.5 mmol/mol) (4). 
 
The continuing emergence of innovative technologies has shaped and changed 
management and care in T1D over the past decades. The use of insulin pumps is 
increasing, particularly in the paediatric population with 50% to 79% of those below 
the age of 6 years using pumps (5, 6). Real-time continuous glucose monitoring 
enables greater understanding of glucose excursions, provides low and high glucose 
alarms, and facilitates more responsive insulin dose adjustments (7) but provides little 
biochemical benefit in young children although it is well accepted by parents (8). 
 
The Artificial Pancreas is an emerging technology promising to transform management 
of T1D (9-11). The Artificial Pancreas gradually increases and decreases 
subcutaneous insulin delivery according to real-time sensor glucose levels, combining 
glucose sensor, insulin pump and a control algorithm, to achieve as much as possible 
functionality of a healthy pancreas. In the last five years, outpatient studies by 
University of Cambridge and collaborators (12-16), University of Virginia and 
collaborators (17-19), Boston University (20, 21), Medtronic 670G pump and 
prototypes (22), and MD-Logic group (23-25) showed feasibility and some efficacy of 
outpatient closed loop use.  
 

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The case for the Artificial Pancreas use in young children is supported by diabetes 
registries (4, 26, 27) which indicate that glycaemic control in pre-school children is 
often sub-optimal, even when applying continuous glucose monitoring (8, 28) with only 
between 22% and 56% achieving the recommended HbA1c below 7.5% 
(58.5mmol/mol) (10). A life-long exposure to hyperglycaemia may lead to an 
accentuated risk of late micro and macrovascular complications. An early onset of 
diabetes has also been more strongly associated with impaired cognitive function (29-
32) and reduced school achievements (33), with recent evidence of dysglycaemia-
related anatomical brain changes in young children with type 1 diabetes (34, 35). High 
insulin sensitivity as well as unpredictable food intake and physical activity, and day-
to-day variable insulin requirements (36) complicate insulin dose adjustments. 
Reductions in HbA1c using existing therapies are associated with an increased risk of 
hypoglycaemia, feared by children and their caregivers (37). Educational interventions 
in youth are failing (38) and immunotherapy struggles in clinical translation (39). CGM 
has little impact (28). Novel treatment strategies are needed to improve outcomes in 
this vulnerable and underserved population. 
 
4.2 Closed Loop Insulin Delivery 
The development of a closed loop system combines glucose monitoring with 
computer-based algorithm informed insulin delivery. The vital component of such a 
system, also known as an artificial pancreas (AP), is a computer-based algorithm. The 
role of the control algorithm is to translate, in real-time, the information it receives from 
the CGM and to compute the amount of insulin to be delivered by the pump. The other 
components include a real-time continuous glucose monitor and an infusion pump to 
titrate and deliver insulin (9). 
 
Automatic suspension of insulin delivery by the pump when a predefined glucose level 
is reached (threshold suspend insulin pump therapy) represents the simplest form of 
closed loop insulin delivery. Such a system (Veo (non-US) or Medtronic 530G (US) 
insulin pump coupled with Minilink sensor (Medtronic Minimed, Northridge, CA, USA) 
which stops insulin delivery for up to 2 hours is currently commercially available (40-
43). In comparison to threshold suspension, hypoglycaemia-prediction algorithms and 
automatic pump suspension of predictive log glucose suspension (PLGS) systems 
enable insulin delivery to be suspended when hypoglycaemia is predicted (44). The 
predictive low glucose management (PLGM) function of the MiniMed 640G (Medtronic 
Diabetes, Northridge, CA, USA) insulin pump was introduced into clinical practice in 
Australia and Europe early 2015. A slightly revised version was recently approved by 
the FDA in the US for the treatment of people with diabetes sixteen years of age and 

250941 KidsAP02 Protocol v3.0 [2020_10_01]  
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older (MiniMed 630G; Medtronic Diabetes, Northridge, CA, USA). Since insulin is not 
delivered in an automated fashion there is no risk of system-induced hypoglycaemia. 
The risk of consecutive rebound hyperglycaemia and ketonaemia after a temporary 
suspension of insulin administration is not negligible (45), but only mild rebound 
hyperglycaemia and no episodes of diabetic ketoacidosis following threshold 
suspension activation have been reported (43, 46). While threshold suspend insulin 
delivery systems and predictive low glucose suspension systems might reduce the risk 
and severity of hypoglycaemic events, neither system mitigates against higher 
glycaemic levels.  
 
Closed loop approaches beyond insulin suspension have been successfully evaluated 
in children and adolescents in controlled laboratory studies (23, 47, 48) and in home 
settings (12, 15, 16, 49). Investigations in adults have also been conducted (13, 14, 
16). In these studies more advanced control algorithms were used which 
autonomously and continually increased and decreased subcutaneous insulin delivery 
based on real-time sensor glucose levels. The results demonstrated improved glucose 
control and reduced risk of hypoglycaemia events. Psychosocial assessments 
supported acceptability and positive impact of this novel therapeutic approach among 
children/adolescents and carers (50). Evaluations during home, free living conditions 
have been limited to 3 months (16).  
 
4.3 Closed Loop Research in Cambridge 
The University of Cambridge and collaborators have a considerable track record 
investigating closed loop glucose control in young children, older children, 
adolescents, adults, and pregnant women with type 1 diabetes (12, 15, 16, 51, 52). 
Since 2012, the University of Cambridge with collaborators have enrolled over 180 
subjects in RCTs of free-living closed loop home conditions lasting 1 week to 2 years 
focusing on young people. 
 Closed Loop Prototypes  
The University of Cambridge developed several home prototypes differing in computer 
algorithm hosting device, connectivity to the CGM receiver, and remote data upload 
(details not shown) but using the same Cambridge control algorithm. The previous 
FlorenceD2A Android-based system is shown in Figure 1.  
 
Dana pump was selected due to its best-in-class remote functions enabling reliable 
closed loop operation and Navigator II CGM system was chosen because of its high 
accuracy. These systems used the Cambridge model predictive control algorithm 

250941 KidsAP02 Protocol v3.0 [2020_10_01]  
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including an interacting multiple model strategy with meal- and exercise-
announcement. The algorithm directs insulin delivery between meals and overnight 
with prandial insulin delivered using a standard bolus calculator. Key characteristics of 
the control algorithm are its ease of setup (body weight and total daily dose), 
adaptability, a safety layer, and extensive clinical data to support safety and efficacy.  
Figure 1 FlorenceD2A closed loop system using Android phone, Navigator II (Abbott 
Diabetes Care, USA), and Dana insulin pump (Sooil, South Korea) with wireless 
connection to Navigator II using translator (Triteq, UK) and remote cloud connectivity 
(left – system components, middle – combined graph shown on the phone, right – 
Navigator inserted in the translator). 
 Preliminary Data with the Cambridge Control Algorithm  
In 2012, the University of Cambridge and collaborators initiated a series of RCTs of 
free-living closed loop studies (Table 1). Characteristics of these home studies include 
no remote monitoring or close supervision, unlike most other transitional, diabetes 
camp, or outpatient studies (18, 21, 24, 25). Closed loop was used under free-living 
conditions at school, work, and over holidays.  
 
Table 1 Free-living home closed loop studies using Cambridge control algorithm. 
Study  
acronym 
Closed loop 
system 
Design & closed 
loop follow-up 
T1D 
population 
Status  
Key 
Refs 
APCam06 
FlorenceD2** 
Crossover RCT, 
overnight CL*, 3 weeks 
n=16 
10-18 years 
Study 
completed 
(12) 
Angela03 
FlorenceD2 
Multicentre crossover 
RCT, overnight CL, 4 wks 
n=24 
adults  
Study 
completed 
(13) 
APhome02  
FlorenceD2 
Multinational crossover 
RCT, 24/7 CL, 1 week 
n=17 
adults  
Study 
completed 
(14) 
APCam08 
FlorenceD2W
† 
Multicentre crossover 
RCT, o’night CL, 12 wks  
n=24  
6-18 years 
Study 
completed 
(16) 
Dan04 
Phase 1 
FlorenceD2A 
Crossover RCT, 24/7 CL, 
1 week 
n=12 
12-18 years 
Study 
completed 
(15) 
Dan04 
Phase 2 
FlorenceD2A 
Crossover RCT, 24/7 CL, 
3 weeks 
n=12 
12-18 years 
Study 
completed 
(53) 
Aphome04 
FlorenceD2A 
Multinational crossover 
RCT, 24/7 CL, 12 weeks 
n=31 
adults 
Study 
completed  
(16) 
APCam11 
FlorenceM 
Multinational parallel 
RCT, 24/7 CL, 12 weeks 
n=84 
6yrs-adults 
Study 
completed 
- 

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CLOuD 
FlorenceM 
Multicentre parallel RCT, 
24/7 CL; 2 years  
n=96 
10-18 years 
Started Q1 
2017 
- 
KidsAP01 
FlorenceM 
Multinational crossover 
RCT, 24/7 CL, 2x3 weeks 
n=24 
1-7yrs 
Study 
completed 
- 
*CL – closed loop ** Comprising ultramobile Windows laptop with wired connection to Navigator; no 
remote connectivity † Windows tablet with wired connection to Navigator II; no remote connectivity. 
 
APCam06 and Angela03. Overnight closed loop insulin delivery over 3 to 4 weeks 
reduced overnight glucose by mean 0.8 mmol/l in 16 adolescents (HbA1c 8.0% [64 
mmol/mol]) in a single centre randomised study (p<0.001) (12) and 24 adults (HbA1c 
8.1% [65 mmol/mol]) in a multicentre randomised control study (p<0.005) (13). After 
pooling data (total 850 closed loop nights) and adopting intention to treat analysis, the 
proportion of time spent overnight in hypoglycaemia below 3.9 mmol/l was reduced 
from median 2.9% to median 1.9% (p=0.014), mean overnight glucose reduced 
(p<0.001), and time spent in the target glucose range increased (p<0.001) (Table 2) 
(54). 
 
Table 2 Outcomes during overnight closed loop and sensor augmented pump therapy 
in the home setting over 3 to 4 weeks combining APCam06 and Angela03 
 
Closed loop 
(n=40) 
Control 
(n=40) 
P value 
Time spent at glucose level (%) 
 
 
 
       3.9 to 8.0 mmol/l 
59.2±11.5 
40.7±13.4 
<0.001 
       > 8 mmol/l 
37.9±12.4 
53.8±17.0 
0.001 
       < 3.9 mmol/l 
1.9 (0.7, 3.5) 
2.9 (1.0, 6.4) 
0.014 
Mean glucose (mmol/l) 
7.9±0.9 
8.7±1.4 
<0.001 
Total daily insulin delivery (U) 
40.3 (32.9, 52.6) 
39.4 (32.8, 55.8) 
0.84 
Data shown are mean ± SD or median (IQR) 
 
APhome02. A multicentre multinational crossover RCT in 17 adults (HbA1c 7.6% [59 
mmol/mol]) involving University of Cambridge and Medical University of Graz and 
investigating day-and-night free-living closed loop over one week documented 
reduced 24hour glucose by mean 0.7 mmol/l (p=0.027) while time spent in 
hypoglycaemia below 3.9 mmol/l was unchanged (p=0.34) (Table 3). The proportion 
of time spent with glucose in the target range from 3.9 to 10 mmol/l increased from 
median 62% to median 75% (p=0.005) with a trend towards reduced total daily insulin 
dose from mean 45 U/day to 39 U/day (p=0.11). This suggests that insulin can be 
more efficiently and sparingly titrated by an automated control algorithm compared to 
pre-programmed pump delivery (14). 
 
 

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Table 3 Glucose control during 24/7 closed loop and sensor augmented pump therapy 
over seven day free-living home use in 17 adults with type 1 diabetes (APhome02 study). 
 
Closed loop 
(n=17) 
Control 
(n=17) 
P value 
Time spent at glucose (%) 
 
 
 
3.9 to 10.0 mmol/l  
75 (61, 79) 
62 (53, 70) 
0.005 
     > 10 mmol/l 
22 (17, 32) 
31 (24, 41) 
0.013 
     < 3.9 mmol/l 
3.7 (2.2, 7.9) 
5.0 (2.3, 8.5) 
0.339 
Mean glucose (mmol/l) 
8.1 ± 1.0 
8.8 ± 1.0 
0.027 
Total daily insulin (U/day) 
39.1 (34.7, 45.7) 
44.7 (36.3, 51.0) 
0.109 
 
Dan04 Phase 1. In an open-label, crossover randomised study the University of 
Cambridge evaluated feasibility, safety and efficacy of 24/7 closed loop under free-
living conditions. In random order, 12 children and adolescents with T1D aged 12 to 
18 years (age 15.4±2.6 years; HbA1c 8.3 ± 0.9%) underwent two 7 day periods of 
sensor augmented insulin pump therapy or closed loop.  
 
 
Figure 2 Sensor glucose during 24/7 closed loop (pink area) and sensor augmented 
pump therapy (grey area) in 12 young people aged 12 to 18 years (n=12) 
participating in Dan04 phase 1 study [median (IQR) range]. 
 
Time when sensor glucose was in target range from 3.9 to 10 mmol/l, was significantly 
higher during closed loop compared to SAP (p<0.001, Table 4 and Figure 2). Mean 
glucose (p=0.03) and time spent above target (p=0.005) were lower during closed 
loop, without changing total daily insulin dose (15). 
 
Table 4 Glucose control during 24/7 closed loop and sensor augmented pump therapy 
over seven day home use in 12 youth aged 10 to 18 years with type 1 diabetes (Dan04 
phase 1 study). 
 
Closed loop 
(n=12) 
Control 
(n=12) 
P value 
Time spent at glucose (%) 
 
 
 
3.9 to 10.0 mmol/l   
72 (59, 77) 
53 (46, 59) 
<0.001 

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     > 10 mmol/l  
26 (21, 35) 
43 (38, 52) 
0.005 
     < 3.9 mmol/l  
2.9 (1.8, 4.8) 
1.7 (0.9, 5.1) 
0.87 
Mean glucose (mmol/l) 
8.7 ± 1.1 
10.2 ± 1.3 
0.03 
Total daily insulin (U/day) 
57.3 (45.6, 65.2) 
56.6 (44.7, 61.3) 
0.55 
 
Dan04 Phase 2. In an open-label, crossover randomised study the University of 
Cambridge evaluated feasibility, safety and efficacy of 24/7 closed loop under free-
living conditions. In random order, 12 children and adolescents with suboptimally 
controlled T1D aged 12 to 18 years (age 14.6±3.1 years; HbA1c 69±8 mmol/mol 
[8.5±0.7%]; duration of diabetes 7.8±3.5 years; mean±SD) underwent two 21 day 
periods of sensor augmented insulin pump therapy or closed loop.  
 
 
Figure 3 Sensor glucose during 24/7 closed loop (pink area) and sensor augmented 
pump therapy (grey area) in 12 young people aged 12 to 18 years (n=12) 
participating in Dan04 phase 2 study [median (IQR) range]. 
 
Time when sensor glucose was in target range from 3.9 to 10 mmol/l, was significantly 
higher during closed loop compared to SAP (p<0.001, Table 5 and Figure 3). Mean 
glucose (p=0.001) and time spent above target (p<0.001) were lower during closed 
loop, with a slight increase in total daily insulin dose (p=0.006) (53). 
 
Table 5 Glucose control during 24/7 closed loop and sensor augmented pump therapy 
over seven day home use in 12 youth aged 10 to 18 years with type 1 diabetes (Dan04 
phase 2 study). 
 
Closed loop 
(n=12) 
Control 
(n=12) 
P value 
Time spent at glucose (%) 
 
 
 
3.9 to 10.0 mmol/l   
66.6±7.9 
47.7±14.4 
<0.001 
     > 10 mmol/l  
29.7±9.2 
49.1±16.5 
<0.001 
     < 3.9 mmol/l  
4.3 (1.4 to 5.2) 
2.4 (0.3 to 5.7) 
0.33 
Mean glucose (mmol/l) 
8.7±0.9 
10.5±1.8 
0.001 

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Total daily insulin (U/day) 
53.5 (39.5 to 72.1) 
51.5 (37.6 to 64.3) 
0.006 
 
 
APCam08. The University of Cambridge and Leeds Teaching Hospital completed a 
multicentre crossover RCT comparing 12 week overnight closed loop with 12 week 
sensor augmented pump therapy in 25 children and adolescents aged 6 to 18 years. 
The intention to treat analysis (Table 6) documents reduced mean overnight glucose 
(p<0.003), increased time spent in target range (p<0.001) (16). 
 
Table 6 Glucose control during overnight closed loop and sensor augmented pump 
therapy over 12 weeks free-living home use in young people aged 6 to 18 years with type 
1 diabetes (APCam08 study). 
 
Closed loop 
(n=25) 
Control 
(n=24) 
P value 
Time spent at glucose (%)  
 
 
 
3.9 to 8.0 mmol/l 
60 ± 12 
34 ± 11 
<0.001 
     > 8 mmol/l  
37 ± 12 
61 ± 13 
<0.001 
     < 3.9 mmol/l 
2.2 (1.8, 4.3) 
3.5 (1.2, 5.9) 
0.7 
Mean overnight glucose (mmol/l) 
8.1 ± 1.2 
9.8 ± 1.6 
<0.001 
Total daily insulin (U/day) 
41.4 ± 20.3 
40.9 ± 20.6 
0.8 
 
APhome04. In a 12-week open-label prospective multinational randomised crossover 
study involving the University of Cambridge and Medical University of Graz, we 
analysed data from adults with type 1 diabetes on insulin pump therapy (18 male, age 
40.0±9.4 years, HbA1c 8.5±0.7%; duration of diabetes 20.9±9.3 years) who underwent 
two 12-week periods of SAP and 24/7 closed loop (16). 
 
The proportion of time when sensor glucose was in target range between 3.9 and 10.0 
mmol/l was increased during closed loop compared to SAP (p<0.001; Table 7). 
 
Table 7 Glucose control during 24/7 closed loop and sensor augmented pump therapy 
over 12 weeks free-living home use in adults with type 1 diabetes (APhome04 study). 
 
Closed loop 
(n=32) 
Control 
(n=33) 
P value 
Time spent at glucose (%)  
67.7 ± 10.6 
56.8 ± 14.2 
<0.001 
3.9 to 10.0 mmol/l   
 
 
 
     > 10 mmol/l 
29.2 ± 11.4 
38.9 ± 16.6 
<0.001 
     < 3.9 mmol/l 
2.9 (1.4, 4.5) 
3.0 (1.8, 6.1) 
0.02 
Mean glucose (mmol/l) 
8.7 ± 1.1 
9.3 ± 1.6 
<0.001 
HbA1c (%) 
7.3 ± 0.8 
7.6 ± 1.1 
0.002 
Total daily insulin (U/day) 
48.8 ± 16.1 
48.1 ± 15.4 
0.6 

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HbA1c, mean glucose and time spent above target range were significantly reduced 
during closed loop, while time spent below target was low and comparable during both 
interventions. Hypoglycaemia exposure measured by AUC <3.5 mmol/l was reduced 
during closed loop (p=0.004). Reduction in mean glucose and time spent above target 
range during closed loop was brought about without changing the total daily insulin 
delivery (p=0.6). 
 
KidsAP01. In an open-label, multinational, randomised crossover study involving 
KidsAP Consortium we analysed data from 23 young children aged 1 to 7 years on 
insulin pump therapy (age 5 (3 to 6) years, median (IQR): median HbA1c 7.4±0.7%, 
mean±SD: duration of diabetes 3.1 ±1.7 years) who underwent two 21-day periods of 
unrestricted living comparing CL with diluted insulin aspart (U20) and CL with standard 
strength insulin aspart (U100) in random order.   
The proportion of time that sensor glucose was in the target range between 3.9 and 
10mmol/l (primary endpoint) was similar between interventions (72±8% vs. 70±7%; CL 
with diluted U20 insulin vs. CL with standard strength U100 insulin; p=0.14: Table 8).  
 
Table 8 Glucose control during 24/7 closed loop with diluted insulin aspart (U20) and CL 
with standard strength insulin aspart (U100) over two 21-day periods of free-living home 
use in 23 children with type 1 diabetes aged 1 to 7 years (KidsAP01 Study). 
 
 
Diluted 
(n=23) 
Non diluted 
(n=23) 
P 
value 
% Time in Range 3.9-10.0 mmol/L 
72% ± 8% 
70% ± 7% 
0.14 
% Time >10.0 mmol/L 
23% ± 9% 
25% ± 7% 
0.21 
% Time <3.9 mmol/L 
4.5% ± 1.7% 
4.7% ± 1.5% 
0.46 
Mean Glucose (mmol/L) 
8.0 ± 0.8 
8.2 ± 0.6 
0.12 
Total Insulin (U/day) 
17.3 ± 5.6 
18.4 ± 6.6 
0.09 
Data shown are mean ± SD 
 
There was no difference between interventions either in mean sensor glucose 
(8.0±0.8mmol/l vs. 8.2±0.6mmol/l; p=0.12) or sensor glucose variability (SD 
3.1±0.5mmol/l vs. 3.3±0.4mmol/l; p=0.14). The proportion of time when sensor 
glucose was below 3.9mmol/l (4.5±1.7% vs. 4.7±1.5%; p=0.46) or below 2.8mmol/l 
(0.6±0.5% vs. 0.6±0.4%; p=0.98) was comparable. Total daily insulin dose did not 
differ between interventions (17.3±5.6U/day vs. 18.4±6.6U/day; p=0.09).  
No CL-related severe hypoglycaemia or ketoacidosis occurred. 

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Figure 4. Sensor glucose during 24/7 closed loop with diluted insulin aspart (U20) (pink 
area) and CL with standard strength insulin aspart (U100) (grey area) over two 21-day 
periods of free-living home use in 23 children with type 1 diabetes aged 1 to 7 years 
participating KidsAP01 study [median (IQR) range]. 
 
Psychosocial outcomes. We examined parental attitudes to overnight closed loop in 
families with children and young people with type 1 diabetes (55). The development of 
closed loop to manage diabetes was welcomed by all parents (100%). All parents were 
ready to respond to additional alarms at night with 90% parents not worried about their 
child's overnight insulin delivery being controlled by a computer (55). These positive  
attitudes towards closed loop were confirmed in semi-structured interviews with 
15 adolescents aged 12 to 18 years and 13 parents participating in a three week long 
home overnight closed loop APCam06 study (50) (47). Similar observations were 
made in 24 adults undergoing home overnight closed loop (56). 
 
4.4 KidsAP Consortium 
In December 2016, the European Union granted funding for the KidsAP project, a 
consortium of European academic medical centres, biotechnology companies and 
industrial partners to carry out artificial pancreas/closed loop research in the paediatric 
population outside clinical research centres. The ultimate goal of the KidsAP project is 
to assess the ability of the artificial pancreas to improve glucose control in the most 
vulnerable population with type 1 diabetes, children aged 1 to 7 years. A pilot study 
(KidsAP01) assessed the efficacy and safety of closed loop insulin delivery using 
diluted insulin in comparison with closed loop with non-diluted insulin over 21 days in 
children with type 1 diabetes aged 1 to 7 years in the home setting. It was 
demonstrated that diluted insulin during CL does not provide additional benefits 
compared to standard strength insulin.  
The results of the KidsAP01 study have informed the design of this outcome study.  
 

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4.5 FlorenceX Closed Loop System to be used in the Present 
Study  
In the present study, we will use the FlorenceX closed loop system comprising: 
 
 
Dana insulin pump (Diabecare, Sooil, Seoul, South Korea) 
 
Dexcom G6 real-time CGM sensor (Dexcom, Northridge, CA, USA)  
 
An Android smartphone hosting FlorenceX Application with the Cambridge model 
predictive control algorithm and communicating wirelessly with the insulin pump  
 
Cloud upload system to monitor CGM/insulin data. 
 
An overview of this proposed automated closed loop system is given in Figure 4. 
 
Figure 4 FlorenceX comprises Samsung Galaxy phone (or similar) running Cambridge 
control algorithm, Dana insulin pump (Sooil), G6 real-time CGM sensor (Dexcom). 
 
4.6 Rationale for the present study  
Despite advances in insulin pump and sensor technology, the majority of small children 
with type 1 diabetes are still unable to achieve optimal glycaemic control. Application 
of closed loop insulin delivery systems in a range of populations and settings, including 
children and adolescents in home settings, has been shown to improve glycaemic 

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control, and to reduce the burden of hypoglycaemia (15, 23, 49, 57, 58). Performance 
of closed loop systems in small children in home settings is yet to be determined. 
 
In the present study we will compare closed loop insulin delivery with sensor 
augmented pump therapy in very young children with T1D. We hypothesize that closed 
loop glucose control will give increased time in range compared to sensor augmented 
pump therapy. This study builds on previous and on-going studies of closed loop 
systems that have been performed in Cambridge in children and adolescents with T1D 
in clinical research facilities and in the home setting. 
 
The extension phase will allow ongoing assessment of the impact of continued closed 
loop insulin delivery on glucose control and quality of life measures as well as 
evaluating the acceptability of this therapy over a longer duration than has previously 
been studied in this unique population. 
 
The ultimate goal of the KidsAP project is to assess the ability of the artificial pancreas 
to improve glucose control and health outcomes in the most vulnerable population with 
type 1 diabetes: children aged 1 to 7 years. 
 
 
5 Objectives 
5.1 Efficacy  
The objective is to assess the ability of day-and-night hybrid closed loop glucose 
control to maintain CGM glucose levels within the target range of 3.9 to 10 mmol/l (70 
to 180 mg/dl) in comparison to sensor augmented pump therapy in young children with 
type 1 diabetes.   
 
5.2 Safety 
The objective is to evaluate the safety of day-and-night hybrid closed loop glucose 
control, in terms of frequency and severity of hypoglycaemia, as defined by 
International Society for Pediatric and Adolescent Diabetes, frequency of diabetic 
ketoacidosis (DKA), and nature and severity of other adverse events.  
 
5.3 Utility 

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The objective is to determine the acceptability, duration and frequency of use of the 
closed loop system in this population. A series of questionnaires will be given to 
parents/guardians at the end of each intervention arm. 
 
 
 
 
5.4 Human Factors 
The objective is to assess emotional and behavioural characteristics of participating 
subjects and family members and their response to the closed loop system and clinical 
trial using quantitative (validated surveys and actigraphy) and qualitative data 
(interviews). 
 
5.5 Health Economics 
The objective is to perform a cost utility analysis on the benefits of closed loop insulin 
delivery to inform reimbursement decision-making. 
 
5.6 Extension Phase Objectives (UK sites only)  
The objective of the extension phase is to evaluate the long-term efficacy of closed 
loop insulin delivery in maintaining glucose levels in the target range of 3.9 to 10.0 
mmol/l (70 to 180 mg/dl) over 18 months from the end of the primary phase, as 
compared to sensor augmented pump therapy during the primary study phase. 
 
The extension phase will also examine the effect of hybrid closed loop on glucose 
control, comparing HbA1c and parameters based on continuous glucose monitoring 
(CGM) to primary phase sensor augmented pump therapy. 
 
The safety of hybrid closed loop glucose control will be evaluated in terms of episodes 
of severe hypoglycaemia and other adverse events. 
 
The frequency and duration of use of the automated closed loop system will be 
assessed.  
 
Emotional and behavioural characteristics of parents/guardians and their response to 
the closed loop system and clinical trial will be evaluated using questionnaires. 

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6 Study Design 
The study adopts an open-label, multi-centre, multi-national, randomised, two-period 
crossover design contrasting closed loop glucose control to sensor augmented pump 
therapy in young children with type 1 diabetes in the home setting. Two intervention 
periods will last 4 months each with 1 to 4 weeks washout period in between. The 
order of the two interventions will be random. 
 
It is expected that up to 80 young children with type 1 diabetes will be recruited, aiming 
for 72 randomised subjects. 
The study flow chart is outlined in Figure 5. 
 
There will be an 18-month extension phase (UK sites only) that adopts a multi-centre, 
single arm design evaluating long-term hybrid closed loop glucose control in very 
young children in the home setting.  At the final primary phase study visit, all 
participants on sensor augmented pump therapy as their standard clinical care will be 
invited to participate in the extension phase using hybrid closed loop for a further 18 
months from the end of the primary phase. 
 
The extension phase flow chart is outlined in Figure 6.  
 

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Figure 5 Study flow chart. 
Recruitment (up to n=80) 

Subjects aged 1-7 years 

On insulin pump therapy for at least 3 months 
Day-and-night hybrid closed loop (CL)  
(4 months)  

CL training over 1-2 hours 

Competency assessment 
Treatment adherence assessment 
& 
Randomisation 
Sensor augmented pump therapy  
(4 months)   

Refresher training over 1-2 hours 
 
End of study (primary phase) 

HbA1c 

Return of study devices 

Questionnaires/Interviews 

Subjects resume usual care 

Data analysis 
Consent/assent 

Baseline HbA1c 

Baseline Questionnaires 
End of first study arm; 1-4 week washout period  

HbA1c 

Questionnaires/Interviews 
Day-and-night hybrid closed loop (CL)  
(4 months)  

CL training over 1-2 hours 

Competency assessment 
 
Sensor augmented pump therapy  
(4 months)   

Refresher training over 1-2 hours 
Training Sessions 

Study CGM training 

Study pump training/switch to study pump 

Competency assessments 
Run-in 
 
Familiarising with study devices over 2-4 weeks 
 
Adjustment of pump settings 

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Figure 6 Study flow chart for extension phase. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of study (primary phase) 

HbA1c 

Questionnaires/Interviews 

Data analysis 
Subjects 
resume 
usual care 
Day-and-night hybrid closed loop (CL)  
(18 months)  

CL refresher training
3-monthly contacts  
End of study 
 

Questionnaires 

HbA1c 

Return of study devices 
 
Subjects resume usual care 

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7 Study Subjects 
7.1 Study Population 
Young children aged 1 to 7 years with type 1 diabetes on insulin pump therapy will be 
recruited.   
 Inclusion criteria 
1. 
Age between 1 and 7 years (inclusive) (Luxembourg and Austria) 
2. 
Age between 2 and 7 years (inclusive) (Germany and UK) 
3. 
Type 1 diabetes as defined by WHO for at least 6 months 
[WHO definition: ‘The aetiological type named type 1 encompasses the majority 
of cases which are primarily due to beta-cell destruction, and are prone to 
ketoacidosis. Type 1 includes those cases attributable to an autoimmune 
process, as well as those with beta-cell destruction for which neither an aetiology 
nor a pathogenesis is known (idiopathic). It does not include those forms of beta-
cell destruction or failure to which specific causes can be assigned (e.g. cystic 
fibrosis, mitochondrial defects, etc.).’] 
4. 
Insulin pump user (with or without continuous glucose monitoring or flash 
glucose monitoring system) for at least 3 months, with subject/carer good 
knowledge of insulin self-adjustment as judged by the investigator 
5. 
On sensor-augmented pump therapy as standard clinical care (extension phase) 
6. 
Treated with rapid or ultra-rapid acting insulin analogue  
7. 
Subject/carer is willing to perform regular finger-prick blood glucose monitoring, 
with at least 2 blood glucose measurements taken every day 
8. 
Screening HbA1c ≤ 11% (97mmol/mol) on analysis from local laboratory  
9. 
Able to wear glucose sensor  
10. 
Able to wear closed loop system 24/7 during intervention arm 
11. 
The subject/carer is willing to follow study specific instructions 
12. 
The subject/carer is willing to upload pump and CGM data at regular intervals 
 Exclusion criteria 
1. 
Physical or psychological disease likely to interfere with the normal conduct of 
the study and interpretation of the study results as judged by the investigator 
2. 
Untreated coeliac disease or thyroid disease based on local investigations prior 
to study enrolment  
3. 
Current treatment with drugs known to interfere with glucose metabolism, e.g. 
systemic corticosteroids 
4. 
Use of closed loop insulin delivery within the past 2 months (primary phase) 
5. 
Known or suspected allergy to insulin 

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6. 
Carer’s lack of reliable telephone facility for contact 
7. 
Subject/carer’s severe visual impairment  
8. 
Subject/carer’s severe hearing impairment 
9. 
Medically documented allergy towards the adhesive (glue) of plasters or subject 
is unable to tolerate tape adhesive in the area of sensor placement 
10. 
Serious skin diseases (e.g. psoriasis vulgaris, bacterial skin diseases) located 
in parts of the body which could potentially be used for localisation of the glucose 
sensor) 
11. 
Sickle cell disease, haemoglobinopathy; or has received red blood cell 
transfusion or erythropoietin within 3 months prior to time of screening  
12. 
Plan to receive red blood cell transfusion or erythropoietin over the course of 
study participation 
13. 
Subject/carer not proficient in English (UK, Germany, Austria, Luxembourg) or 
German (Germany, Austria, Luxembourg) or French (Luxembourg)  
 
Additional exclusion criteria - Germany only 
14. 
Known microvascular diabetes complications (retinopathy, renal disease, 
neuropathy) 
15. 
Eating disorders 
16. 
Psychiatric diseases of the parents that would possibly interfere with the ability 
to comply to study procedures 
17. 
Major needle phobia that would complicate to wear pump catheter and sensor 
18. 
Congenital malformations that would interfere with diabetes treatment (e.g. 
congenital heart malformations, lung diseases, renal malformations) 
19. 
Growth hormone deficiency 
20. 
Combined Hypopituitarism 
21. 
Down Syndrome (high risk for comorbidity with coeliac disease, autoimmune 
thyroiditis) 
22. 
Cancer under treatment 
23. 
Current participation in other interventional clinical trials 
 
7.2 Recruitment 
The study will aim for 72 randomised subjects. Recruitment will target up to 80 subjects 
to allow for drop-outs. Participants will be recruited from paediatric diabetes outpatient 
clinics at each of the following sites.  
 
1. Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation 
Trust, Cambridge, UK 

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2. Leeds Teaching Hospitals NHS Trust, Leeds, UK 
3. Centre hospitalier de Luxembourg, Luxembourg 
4. University of Leipzig, Leipzig, Germany 
5. Medical University of Graz, Graz, Austria 
6. Medical University of Innsbruck, Innsbruck, Austria 
7. Medical University of Vienna, Vienna, Austria 
 
Each centre will aim to recruit between 8 and 12 participants. Paediatric Diabetes 
Centres in the East Anglia region and London may be included as a Patient 
Identification Centre (PIC) to recruit participants for the Addenbrooke’s site, and a 
centre in York will be a PIC for the Leeds site. 
 
Potential participants will be identified by their treating clinicians and invited to contact 
the research team. They will be sent the study information leaflets and an invitation to 
join the study by the research team.   
 
At the primary phase final study visit, participants (UK sites only) on sensor-augmented 
pump therapy as their standard clinical care will be invited to participate in the 
extension phase for a further 18 months from the end of the primary phase. Additional 
written consent will be obtained for the extension phase from all parents/guardians 
before any study-related activities.  
 
 
7.3 Randomisation 
Eligible subjects will be randomised using central randomisation software. The 
randomisation will be stratified by centre.  
 
8 Methods under Investigation 
8.1 Name and Description of the Method of Investigation  
The investigational treatment is hybrid closed loop system, see section 4.5, or follow 
up prototypes of the automated closed loop insulin delivery system manufactured by 
the Cambridge University Hospitals NHS Foundation Trust. Component versions will 
be identified during regulatory submission to the national regulatory bodies.   
In the extension phase participants will be using the CE marked CamAPS FX closed 
loop app (CamDiab, Cambridge, UK).  
 

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8.2 Intended Purpose 
The investigated medical device is used to manage glucose levels in people with type 
1 diabetes, aged 1 year and older, using a hybrid closed loop approach. 
 
 
 
8.3 Method of Administration 
The closed loop system consists of components directly attached to the patient, which 
are the CGM sensor/transmitter and the insulin pump. The component not directly 
attached to the patient is the handheld smartphone containing closed loop algorithm 
and communicating wirelessly with the insulin pump. 
 
8.4  Required Training 
Prior to commencement of the study, the research team nurses/clinicians at each of 
the investigation centres will be trained to use the closed loop system and its 
components. Prior to the use of study devices, participants and parents/guardians will 
be trained to use the real-time CGM device and study pump, and the closed loop 
system. If participants and parents/guardians are already proficient in use of the study 
devices, training may be modified as deemed appropriate by the research team. 
Carers at nursery or school may be trained by the study team if required. Competency 
assessments of the family’s capability to use study devices including the closed loop 
system will be made. 
 
8.5 Precautions 
During treatment with insulin there is a risk of hypoglycaemia and hyperglycaemia. In-
hospital testing and hazard analysis have documented reduced risk of hypoglycaemia 
and hyperglycaemia during closed loop compared to conventional treatment.  
 
8.6 Accountability of the Method under Investigation 
The local Investigator will provide training for the study participants and will make every 
effort, through regular contact, to ascertain that the closed loop system is used for the 
study purposes only. Devices will be identified using batch/lot/serial numbers and the 
location of investigational devices and their dates of use by subjects will be 
documented throughout the study. 

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9 Study Schedule 
9.1 Overview  
The study will be coordinated from the Institute of Metabolic Science, Addenbrooke’s 
Hospital, Cambridge, UK. The study will be performed at clinical sites in Austria, 
Germany, Luxembourg and UK. 
 
After recruitment, consent, training and run-in period, subjects will be randomised to 4 
months home use of real-time CGM combined with automated day and night closed 
loop insulin delivery or 4 months home use of sensor augmented pump therapy. 
Subjects will then crossover to the other study arm for the following 4 months. The 
order of the two interventions will be allocated at random. There will be a one to four 
week washout period between the two study periods.   
 
The study will consist of up to 8 visits and 11 telephone/email contacts for subjects 
completing the study. The visit to set up automated closed loop for the first time may 
take place in the home setting or alternatively in a clinical facility. All other visits can 
take place at the hospital clinic, home or other suitable meeting place, according to 
participants’ convenience. Maximum time in the study is 11 months.  
 
Prior to the final visit, parents/guardians in the UK and Luxembourg will be invited to 
participate in a sleep sub-study.  
 
At the primary phase final study visit, participants (UK sites only) on sensor augmented 
pump therapy as their standard clinical care will have the option to continue using 
automated hybrid closed loop system for a further 18 months in the extension phase. 
Contacts will be conducted every 3 months in line with routine clinic visits, with the 
final extension study visit 18 months after the end of the primary study phase. All 
participants will continue to be seen by their clinical team at frequencies as appropriate 
in line with usual clinical practice.   
 
Table 8 outlines study activities when closed loop intervention precedes sensor 
augmented pump therapy.  
 
 
Table 9 outlines study activities when sensor augmented pump therapy precedes 
closed loop intervention.  

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Table 8 Schedule of study visits when closed loop intervention precedes sensor 
augmented pump therapy 
 
Visit / 
contact 
Description 
Start relative to 
previous / next 
Visit / Activity 
Duration 
Comment 
Consent and training 
 
Visit 1 
 
 
Recruitment visit: 
Consent/assent, HbA1c 
questionnaires  
- 
1-2 
hours 
 
Visit 2 
CGM start: CGM training, 
initiation of CGM, competency 
assessment 
Within 2 weeks of 
Visit 1 (may coincide 
with Visit 1) 
2-3 
hours 
 
May be repeated 
if competency 
not achieved 
Visit 3 
Pump start: insulin pump 
training, study pump initiation, 
competency assessment 
Within 1 week of 
Visit 2 (may coincide 
with Visit 2) 
2-4 
hours 
May be repeated 
if competency 
not achieved 
Run-in 
2-4 weeks 
Contact 1 
Review pump settings and 
CGM data; adjustment of 
treatment 
After 1 week of visit 
3 (± 3 days) 
30 
minutes 
 
Visit 4* 
End of run-in, adjustment of 
treatment, treatment 
adherence assessment 
After 2-4 weeks of 
visit 3 (minimum of 2 
weeks) 
1 hour 
Run-in and Visit 
4 may be 
repeated if non-
compliant 
 
Randomisation 
Immediately after 
Visit 4 
 
If compliant with 
pump 
& 
CGM 
use 
CL Intervention 
16 weeks  
Visit 5 
CL initiation: training (CL), 
competency assessment 
Within 1 week of 
Visit 4  
1-2 
hours 
 
Contact 2 
Follow up after CL start 
Within 24 to 48 
hours after Visit 5 
30 
minutes 
 
Contact 3 
Follow up, review use of study 
devices 
After 1 week of Visit 
5 (± 3 days) 
30 
minutes 
 
Contact 4 
Follow up, review use of study 
devices 
After 4 weeks of 
Visit 5 (± 2 weeks) 
30 
minutes 
 
Contact 5 
Follow up, review use of study 
devices 
After 8 weeks of 
Visit 5 (± 2 weeks) 
30 
minutes 
 
Contact 6 
Follow up, review use of study 
devices 
After 12 weeks of 
Visit 5 (± 2 weeks) 
30 
minutes 
 
Visit 6 
End of 1st study arm: device 
download, HbA1c, 
questionnaires, interview 
After 16 weeks of 
Visit 5 (± 2 weeks) 
< 1 hour 
 
WASHOUT PERIOD (1-4 WEEKS) 
Sensor augmented pump therapy  
16 weeks 
Visit 7 
Sensor augmented pump 
therapy initiation: refresher 
training   
After 1-4 weeks of 
Visit 6 
1-2 
hours 
 
Contact 7 
Follow up after Sensor 
augmented pump therapy start 
within 24 to 48 hours 
after Visit 7 
30 
minutes 
 
Contact 8 
Follow up, review use of study 
devices 
After 1 week of Visit 
7 (± 3 days) 
30 
minutes 
 
Contact 9 
Follow up, review use of study 
devices 
After 4 weeks of 
Visit 7 (± 2 weeks) 
30 
minutes 
 
Contact 10 
Follow up, review use of study 
devices 
After 8 weeks of 
Visit 7 (± 2 weeks) 
30 
minutes 
 
Contact 11 
Follow up, review use of study 
devices 
After 12 weeks of 
Visit 7 (± 2 weeks) 
30 
minutes 
 

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Visit 8a 
(caregiver 
only) 
(UK and  
Luxembourg 
only) 
Sleep assessment 
After 12 weeks of 
Visit 7 (± 2 weeks) 
(Visit 8 may coincide 
with Contact 11) 
30 
minutes 
 
Visit 8b 
End of study, return and 
download of devices if not 
continuing in extension phase, 
HbA1c, questionnaires, 
interview, resume standard 
pump therapy if not continuing 
in extension phase. 
Consent for extension phase if 
applicable.  
After 16 weeks of 
Visit 7 (± 2 weeks) 
<1 hour 
 
Extension phase 
(18 months - UK sites only) 
Contact 12 
Follow up, review use of study 
devices, HbA1c 
3 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Contact 13 
Follow up, review use of study 
devices, HbA1c 
6 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Contact 14 
Follow up, review use of study 
devices, HbA1c 
9 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Contact 15 
Follow up, review use of study 
devices, HbA1c 
12 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Contact 16 
Follow up, review use of study 
devices, HbA1c 
15 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Visit 9 
End of study extension phase: 
HbA1c, questionnaires, return 
of devices & resume usual 
care 
18 months after Visit 
8b (±6 weeks) 
<1 hour 
 
* could be done via phone/email 
 
Table 9 Schedule of study visits when sensor augmented pump therapy precedes closed 
loop intervention. 
 
 
Visit / 
contact 
Description 
Start relative to 
previous / next 
Visit / Activity 
Duration 
Comment 
Consent and training 
 
Visit 1 
 
 
Recruitment visit: 
Consent/assent, HbA1c, 
questionnaires 
- 
1-2 
hours 
 
Visit 2 
CGM start: CGM training, 
initiation of CGM, competency 
assessment 
Within 2 weeks of 
Visit 1 (may coincide 
with Visit 1) 
2-3 
hours 
 
May be repeated 
if competency 
not achieved 
Visit 3 
Pump start: insulin pump 
training, study pump initiation, 
competency assessment 
Within 1 week of 
Visit 2 (may coincide 
with Visit 2) 
2-4 
hours 
May be repeated 
if competency not 
achieved 
Run-in 
2-4 weeks 
Contact 1 
Review pump settings and 
CGM data; adjustment of 
treatment 
After 1 week of visit 
3 (± 3 days) 
30 
minutes 
  
Visit 4* 
End of run-in, adjustment of 
treatment, treatment 
adherence assessment 
After 2-4 weeks of 
visit 3 (minimum of 2 
weeks) 
1 hour 
Run-in and Visit 4 
may be repeated 
if non-compliant 
 
Randomisation 
Immediately after 
Visit 4 
 
If compliant with 
pump 
& 
CGM 
use 

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 Sensor augmented pump therapy  
16 weeks 
Visit 5 
Sensor augmented pump 
therapy initiation: refresher 
training   
Within 1 week of 
Visit 4  
1-2 
hours 
 
Contact 2 
Follow up after Sensor 
augmented pump therapy start 
Within 24 to 48 
hours after Visit 5 
30 
minutes 
 
Contact 3 
Follow up, review use of study 
devices 
After 1 week of Visit 
5 (± 3 days) 
30 
minutes 
 
Contact 4 
Follow up, review use of study 
devices 
After 4 weeks of 
Visit 5 (± 2 weeks) 
30 
minutes 
 
Contact 5 
Follow up, review use of study 
devices 
After 8 weeks of 
Visit 5 (± 2 weeks) 
30 
minutes 
 
Contact 6 
Follow up, review use of study 
devices 
After 12 weeks of 
Visit 5 (± 2 weeks) 
30 
minutes 
 
Visit 6 
End of 1st study arm: device 
download, HbA1c, 
questionnaires, interview 
After 16 weeks of 
Visit 5 (± 2 weeks) 
<1 hour 
 
 
WASHOUT PERIOD (1-4 WEEKS) 
CL Intervention 
16 weeks 
Visit 7 
CL initiation: training (CL), 
competency assessment 
After 1-4 weeks of 
Visit 6 
1-2 
hours 
 
Contact 7 
Follow up after CL start 
within 24 to 48 hours 
after Visit 7 
30 
minutes 
 
Contact 8 
Follow up, review use of study 
devices 
After 1 week of Visit 
7 (± 3 days) 
30 
minutes 
 
Contact 9 
Follow up, review use of study 
devices 
After 4 weeks of 
Visit 7 (± 2 weeks) 
30 
minutes 
 
Contact 10 
Follow up, review use of study 
devices 
After 8 weeks of 
Visit 7 (± 2 weeks) 
30 
minutes 
 
Contact 11 
Follow up, review use of study 
devices 
After 12 weeks of 
Visit 7 (± 2 weeks) 
30 
minutes 
 
Visit 8a 
(caregiver 
only) 
(UK and  
Luxembourg 
only) 
Sleep assessment 
After 12 weeks of 
Visit 7 (± 2 weeks) 
(Visit 8 may coincide 
with Contact 11) 
30 
minutes 
 
Visit 8b 
End of study, return and 
download of devices if not 
continuing with the extension 
phase, HbA1c, questionnaires, 
interview, resume standard 
pump therapy if not continuing 
with the extension phase.  
Consent for extension phase if 
applicable.  
After 16 weeks of 
Visit 7 (± 2 weeks) 
<1 hour 
 
Extension phase 
(18 months -  UK 
sites only) 
Contact 12 
Follow up, review use of study 
devices, HbA1c 
3 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Contact 13 
Follow up, review use of study 
devices, HbA1c 
6 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Contact 14 
Follow up, review use of study 
devices, HbA1c 
9 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 

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Contact 15 
Follow up, review use of study 
devices, HbA1c 
12 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Contact 16 
Follow up, review use of study 
devices, HbA1c 
15 months after Visit 
8b (±6 weeks) 
<30 
minutes 
 
Visit 9 
End of study extension phase: 
HbA1c, questionnaires, return 
of devices & resume usual 
care 
18 months after Visit 
8b (±6 weeks) 
<1 hour 
 
* could be done via phone/email 
9.2 Recruitment Visit (Visit 1) 
During the screening visit the responsible investigator will inform the patient and the 
parents/guardians about the nature of the study and will answer all questions arising. 
If the family decides to participate in the study, the parents or legal representatives will 
be asked to sign the informed consent form before study-specific procedures are 
initiated. Whenever possible and according to local laws and recommendations of the 
local Ethics Committees, the assent of the subjects will be obtained in addition to the 
consent of the parents or legal representatives. All families will receive a copy of the 
informed consent/assent form. 
 
During this visit, patients will be screened for eligibility according to the 
inclusion/exclusion criteria. Eligible subjects will have a blood test to determine their 
HbA1c. HbA1c eligibility criterion will be based on local measurement. Height and 
weight will be recorded. Parents/guardians will complete a set of questionnaires (see 
section 12.3) assessing participants’ and families’ quality of life, psychosocial 
functioning, diabetes management and response to their current treatment before 
entering the study. Visits 1-3 may be combined.  
 
9.3 Study CGM Training (Visit 2) 
The training session will cover key aspects of the study real-time CGM and particular 
attention will be paid to the following areas: 
 
 
Insertion and initiation of sensor session 
 
When a finger-stick BG reading needs to be taken 
 
How to calibrate successfully 
 
Blood glucose targets and alarm settings 
 
Handling real-time CGM feedback including glucose trend arrows, reported 
high and low glucose 
 
Use of software to upload and analyse CGM data 

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Written easy to use guidelines for the operation of study CGM will be provided. Sensor 
settings will be established. Parents/guardians will have to complete a competency 
assessment at the end of the training session. This training session could be repeated 
if competency was not achieved. Visits 1-3 may be combined. 
 
9.4 Study Pump Training (Visit 3) 
This session will cover key aspects of insulin pump use with respect to the study pump, 
and particular attention will be paid to the following areas:  
 
 
Importance of carbohydrate counting and refresher on carbohydrate counting 
skills 
 
Understanding insulin to carb ratios and correction factors 
 
Correct use of bolus calculator – subjects and parents/guardians will be 
required to use this bolus calculator for all insulin boluses during the study 
period 
 
Insulin cartridge and Infusion set changes and correct priming procedure 
 
Dealing with exercise 
 
Sick day rules 
 
Dealing with hypo- and hyperglycaemia 
 
Uploading data from study devices 
 
Written easy to use guidelines for the operation of the study insulin pump will be 
provided. Parents/guardians will have to complete a competency assessment at the 
end of the training session. This session will be conducted by a professional pump 
educator ± member of the study team following a written curriculum. Those competent 
in the use of the study pump will be switched to the study pump. Training session could 
be repeated if competency is not achieved. 
 
For self-monitoring of blood glucose (SMBG) throughout the study, subjects will 
continue using their own glucose meter provided the meter type meets ISO standards 
(Standard 15197: 2013) and has the capability to allow study staff to download data at 
each visit. Whenever possible, the participant should use the same blood glucose 
meter throughout the study. If the subject’s current meter is not compliant, a study 
meter will be provided for use. Appropriate devices and test strips will be provided at 
Visit 2 as required. Visits 1-3 may be combined. 
 
9.5 Run-in 

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The family will use the study insulin pump and the study CGM over a 2 to 4-week run-
in period. Pump, CGM and glucometer data will be downloaded from home on a 
regular basis. To download study devices, Glooko/Diasend software or similar will be 
used.  
 
One week after Visit 3, parents/guardians will be contacted by email or telephone to 
assess device use, and to troubleshoot any problems. Uploaded data may be used for 
treatment optimisations. Additional contacts will be scheduled as required. 
Parents/guardians will also be able to contact the research team in between visits and 
contacts for support or to provide any additional training on the devices as required. 
Additional contacts and/or visits will be recorded on the study case report forms.  
 
9.6 End of Run-in, Compliance Assessment (Visit 4) 
At the end of the run-in, the families will be invited to attend the research centre or 
contacted via e-mail/telephone. Study insulin pump and CGM device will be 
downloaded and reviewed. Uploaded data may be used for treatment optimisations. 
There should be a minimum of two weeks run-in period for all subjects (end of Visit 3 
to end of Visit 4).  
 
During Visit 4, participant’s compliance of using the study CGM and study pump over 
run-in will be assessed. To proceed with the study, subjects/guardians need to 
demonstrate correct use of study insulin pump and CGM including use of bolus 
calculator over 75% of meal boluses and at least 8 days’ worth of CGM data during 
the last 14 days of the run-in period. Run-in could be repeated if compliance 
assessment was unsatisfactory. However, if subject/guardians repeatedly fail to 
demonstrate compliance, the study will be terminated and subject will be removed 
from the study. 
 
9.7 Randomisation 
Immediately after Visit 4, eligible subjects who have gained confidence in the use of 
the study insulin pump and the study CGM system, as assessed by the research team, 
will be randomised using a randomisation based on a computer-generated random 
code. Randomisation will take place centrally, with an independent person being 
responsible for the randomisation sequence. Subjects will be assigned to receive four 
months of day and night closed loop insulin delivery followed by four months of sensor 
augmented pump therapy, or vice versa. 
 

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9.8 Initiation of Study Arm Visits (Visit 5, Visit 7) 
 Closed Loop Insulin Delivery 
Those subjects/guardians randomised to closed loop intervention will receive training 
required for safe and effective use of the closed loop system. This will include training 
on connection and disconnection of the closed loop system, and switching between 
closed loop and sensor augmented pump therapy. Written step by step guidance will 
also be provided. During the training session, subjects/guardians will use closed loop 
system under supervision from study staff. Competency on the use of closed loop 
system will be assessed by the study team. Only subjects/guardians who demonstrate 
competency on use of the system will be allowed to continue to the home study phase, 
and will be allowed to use closed loop at home without supervision by study staff.  
 
Subjects/guardians are expected to use the closed loop at all times during the four 
month intervention period. Subjects/guardians are expected to upload study devices 
at regular intervals using Glooko/Diasend software or similar.    
 Sensor augmented pump therapy 
Those subjects/guardians randomised to sensor augmented pump therapy will receive 
refresher training including key aspects of insulin pump and CGM use. During the 4-
month treatment period, subjects/guardians will use the study pump and the study 
CGM, and will be followed up as outlined below.  
 
Subjects/guardians are expected to upload study devices at regular intervals using 
Glooko/Diasend software or similar. 
 Remote Monitoring   
During both study arms, in the event of hypo- or hyperglycaemia (levels predefined) a 
message may be sent to the parent/guardian providing real-time alerts. 
Parents/guardians will also be able to access sensor glucose readings and trends via 
Glooko/Diasend (or similar) software on-demand.  
 
9.9 Telephone/Mail Contacts after Starting Study Treatment 
(Contacts 2-11) 
During each of the study arms, the families will be contacted via telephone/e-mail 
approximately 24-48 hours (Contact 2, Contact 7), and 1 week after study arm initiation 
(Contact 3, Contact 8). The purpose of these contacts will be to review the use of study 
devices, to troubleshoot, or to provide any additional training required. 

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During both study periods, the families will be contacted via telephone/e-mail every 
month (Contacts 4-6, Contact 9-11). The purpose of these contacts will be to 
troubleshoot any problems, and to record any adverse events, device deficiencies, 
and changes in insulin settings, other medical conditions and/or medication. 
 
After randomisation, subjects/parents and/or the clinical team are free to adjust insulin 
therapy as per usual clinical practice, but no active treatment optimisation will be 
undertaken by the research team. 
 
9.10  End of 1st Study Arm (Visit 6) 
Sixteen weeks after the start of the first treatment arm (Visit 5), participants will 
complete their respective study arm. Study devices will be downloaded. A blood 
sample will be taken for measurement of HbA1c (see section 12.2.1). Body weight and 
height measurements will be made. Parents/carers will be asked to complete 
questionnaires (see section 12.3). A subset of parents/carers will be invited to 
participate in an interview study (see section 12.4).  
 
Subjects will then cross over to the other treatment arm. Those randomised to sensor 
augmented pump therapy initially will undergo closed loop training exactly as 
described above (see section 9.8.1). Those completing the closed loop arm will receive 
refresher training on key aspects of sensor augmented pump use exactly as described 
above (see section 9.8.2).   
 
9.11  Washout 
A one to four week washout period will follow when subjects/guardians could continue 
using the study pump and CGM (but not closed loop), or revert to their own insulin 
pump. Subjects will then cross over to the alternative intervention.   
 
9.12  Sleep assessment (Visit 8a) (UK and Luxembourg only)  
Parents/guardians will be invited to participate in a sleep sub-study prior to the final 
visit. Parents will be fitted with an Actiwatch (a simple wristwatch used to measure 
sleep non-invasively in the participant’s home). The wristwatch will be worn for up to 
7 days. Concomitantly, a sleep diary will be kept. PSQI and CSHQ questionnaires will 
be completed by the parents/guardians. The wristwatch, the completed diary and 

250941 KidsAP02 Protocol v3.0 [2020_10_01]  
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questionnaires, will be will be sent back to the research team or collected by the 
research team. 
 
9.13 End of 2nd Study Arm (Visit 8b) 
Sixteen weeks after the start of the second treatment arm (Visit 7) subjects will have 
completed the primary study phase. Study devices will be downloaded. A blood 
sample will be taken for measurement of HbA1c (see section 12.2.1). Body weight and 
height measurements will be made. Parents/carers will be asked to complete 
questionnaires (see section 12.3). Parents/carers who were interviewed at the end of 
the 1st arm of the study will be re-interviewed (see section 12.4). 
 
This will be the end of the primary phase 8-month study period and subjects who are 
not continuing with the extension phase will return to their normal diabetes care. These 
subjects/guardians will be asked to return the study devices used, and will revert to 
their conventional insulin therapy by switching back to the insulin pump they were 
using before entering the study. 
 
9.14  Extension Phase (UK sites only) 
At the primary phase final study visit, participants on sensor-augmented pump therapy 
as their standard clinical care will have the option to continue using automated hybrid 
closed loop system for a further 18 months in the extension phase. Parents/guardians 
of participants opting to continue with the extension phase will be asked to re-consent. 
Participants who had sensor-augmented pump therapy during the second arm of the 
primary phase will receive refresher training and recommence use of the automated 
hybrid closed loop system.  
 
 Routine Follow-up Contacts  
Parents/guardians will be contacted every 3 months during the extension phase. This 
can be at routine clinic appointments or by email/telephone. The purpose of this 
contact would be to troubleshoot any problems, and to record any adverse events, 
device deficiencies, changes in insulin requirements, other medical conditions and/or 
medication. Local or point-of-care HbA1c values will be recorded at these contacts. 
Throughout the extension phase, parents/guardians and/or the clinical team are free 
to adjust insulin therapy as per usual clinical practice, but no active treatment 
optimisation will be undertaken by the study team. 

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  End of Extension Phase (Visit 9) 
At 18 months after the end of the primary study phase, parents/guardians will be asked 
to complete questionnaires as outlined in section 12.3. A blood sample will be taken 
for measurement of HbA1c (see section 12.2.1). Height and weight will be recorded. 
Adverse events, device deficiencies, changes in insulin requirements, other medical 
conditions and/or medication will be recorded.  
 
Participants will return all study devices and will transition to usual care as described 
in section 9.13.  
 
9.15  Participant Withdrawal Criteria  
The following pre-randomisation withdrawal criteria will apply: 
1. Subject/guardian is unable to demonstrate safe use of study insulin pump and 
CGM as judged by the investigator 
2. Subject/guardian fails to demonstrate compliance with insulin pump and CGM 
during run-in 
 
The following pre- and post-randomisation withdrawal criteria will apply: 
 
3. Subjects/guardians may terminate participation in the study at any time without 
necessarily giving a reason and without any personal disadvantage 
4. Significant protocol violation or non-compliance 
5. Any severe hypoglycaemia event related to the use of the closed loop system 
6. Two severe hypoglycaemia events not related to the use of the closed loop 
system 
7. DKA unrelated to infusion site failure and related to the use of the closed loop 
system 
8. Decision by the investigator or the sponsor that termination is in the subject's 
best medical interest 
9. Allergic reaction to insulin  
10. Allergic reaction to adhesive surface of infusion set or glucose sensor 
 
Efforts will be made to retain subjects in follow up for the final primary endpoint 
assessment even if the intervention is discontinued, unless the investigator believes 
that it will be harmful for the subject to continue in the trial. Subjects/guardians who 
are withdrawn for reasons stated in (4) to (10) will be invited to provide a blood sample 
at the end of the planned study intervention for the assessment of HbA1c. 

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Subjects/guardians who discontinue study intervention prior to the final visit will 
receive an exit survey and may be invited for an interview. 
   
9.16  Study stopping criteria  
The study may be stopped if three consecutive participants withdraw on safety 
grounds or on the advice of an independent Data Safety Monitoring Board (DSMB). 
 
9.17  Co-enrolment Guidelines  
To avoid potentially confounding issues, ideally participants should not be recruited 
into other trials. Where recruitment into another study is considered to be appropriate 
and without having any detrimental effect on the present study, this must first be 
discussed with the Chief Investigator, or the Sponsor or its representative.  
 
Germany only 
Participants will not be recruited into other trials and patients currently participating in 
other interventional clinical trials will be excluded from participation in KidsAP02. 
 
9.18  Support Telephone Line 
There will be a 24-hour telephone helpline to the local research teams for 
subjects/guardians in case of any technical device or problems related to diabetes 
management such as hypo- or hyperglycaemia (primary phase only). The local 
research team will have access to central 24 hour advice on technical issues (primary 
phase only). 
 
9.19  Subject Reimbursement 
The study will provide the CGM device, insulin pump, closed loop components and 
related consumables for the primary study phase. For the extension phase, the study 
will provide the closed loop app and the host device (Android phone), and insulin 
pump. Glucose meters and glucose test strips will also be provided where required. A 
study payment will be made to reflect local practice. The amount paid will be specified 
in the participant information sheet/informed consent form and REC application form. 
Reasonable travel expenses will also be reimbursed. After completing the study, 
subjects/guardians will not keep the study devices. They will revert to their 
conventional insulin pump therapy.  
 

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10 Endpoints 
10.1  Primary Endpoints 
The primary endpoint is the between group difference in time spent with sensor 
glucose levels between 3.9 to 10.0 mmol/l (70 to 180 mg/dl) during the 4 months 
intervention period. 
 
10.2  Other Key Endpoints 
 
Time spent above target glucose (10.0 mmol/l) (180 mg/dl) 
 
HbA1c 
 
Average of glucose levels 
 
Time spent below target glucose (3.9 mmol/l) (70 mg/dl) 
 
10.3  Secondary Endpoints 
Secondary endpoints include: 
 Standard deviation, and coefficient of variation of glucose levels 
 Time with glucose levels <3.0 mmol/l (54 mg/dl) 
 Time with glucose levels in significant hyperglycaemia (glucose levels > 16.7 
mmol/l) (300 mg/dl) 
 AUC of glucose below 3.5 mmol/l (63 mg/dl) 
 BMI SDS 
 Total, basal, and bolus insulin dose  
 
Endpoints regarding glucose levels will be based on sensor glucose data. 
 
10.4  Safety Evaluation 
Safety evaluation will comprise the number of episodes of severe hypoglycaemia as 
well as the number of subjects experiencing severe hypoglycaemia, frequency of 
diabetic ketoacidosis, and other adverse events or serious adverse events. 
 
All subjects including those who withdraw will be included in the safety evaluation. 
 
10.5  Utility Evaluation 

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Utility evaluation is the frequency and duration of CGM use and use of the closed loop 
system at home. 
 
Percentage of time of closed loop operation   
 
Percentage of time of CGM availability 
 
10.6  Human Factors 
Human Factors evaluation will assess the emotional and behavioural characteristics 
of participating subjects and family members and their response to the closed-loop 
system and clinical trial using validated surveys, sleep assessment and semi-
structured interviews. 
 
10.7  Health Economics 
Health economic analysis will be performed contrasting the artificial pancreas (closed-
loop) and sensor augmented pump therapy using a health economic simulation model: 
the IMS IQ VIA Core Diabetes Model (CDM). Long-term outcomes derived from the 
simulation will include total direct costs, life expectancy, quality-adjusted life 
expectancy and time to onset of complications. Incremental costs versus incremental 
effectiveness (quality-adjusted life years [QALYs]) for closed-loop vs sensor 
augmented pump therapy will be compared. 
 
10.8  Extension Phase Outcomes (UK sites only) 
 Primary endpoint and key endpoints 
The primary endpoint is the difference in time spent with sensor glucose levels 
between 3.9 to 10.0 mmol/l (70 to 180 mg/dl) during the 18 months extension phase, 
as compared to sensor augmented pump therapy during the primary phase. 
 
 Secondary endpoints 
Secondary endpoints include: 
 
Time spent above target glucose (10.0 mmol/l) (180 mg/dl) 
 
HbA1c 
 
Average of glucose levels 
 
Time spent below target glucose (3.9 mmol/l) (70 mg/dl) 
 
Standard deviation, and coefficient of variation of glucose levels 
 
Time with glucose levels <3.0 mmol/l (54 mg/dl) 

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 
Time with glucose levels in significant hyperglycaemia (glucose levels > 16.7 
mmol/l) (300 mg/dl) 
 
BMI SDS 
 
Total, basal, and bolus insulin dose  
 
Endpoints regarding glucose levels will be based on sensor glucose data. 
 
Safety and utility evaluations will be assessed as described above. Human factor 
evaluation will assess the emotional and behavioural characteristics of participating 
subjects and family members and their response to the closed loop system and 
extension phase using validated surveys.  
11 Assessment and Reporting of Adverse Events 
11.1  Definitions 
  Reportable Adverse Events 
A reportable Adverse Event is any untoward medical occurrence that meets criteria for 
a serious adverse event. Device deficiencies that could have led to a serious adverse 
device effect will also be reported. 
  Adverse Events 
An adverse event (AE) is any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory findings) in a subject 
who has received an investigational device, whether or not related to the 
investigational medical device. This definition includes events related to the device 
under investigation or the comparator or to the study procedures. For users or other 
persons, this definition is restricted to events related to the investigational device. 
 
The following anticipated adverse events will not be recorded: 
 
Non clinically significant skin reactions as judged by investigator 
 
Pre-existing medical conditions 
 
New illnesses or conditions not requiring concomitant medication or medical 
intervention/procedures 
 
Non severe hypoglycaemia 
 
Hyperglycaemia without significant ketonaemia (>0.6 mmol/l) 
  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, 

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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. 
 
The following anticipated adverse device effects will not be recorded: 
 
Non clinically significant skin reactions due to sensor or infusion set use as 
judged by investigator 
  Serious Adverse Event 
A serious adverse event (SAE) is an adverse event that: 
 
led to a death  
 
led to a serious deterioration in the health of the subject, that either resulted in: 
o a life threatening illness or injury  
o a permanent impairment of a body structure or function    
o in-patient hospitalisation or prolonged 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 
 
A planned hospitalisation for pre-existing condition, or a procedure required by the 
study protocol, without a serious deterioration in health, is not considered to be a 
serious adverse event. 
 
More than one of the above criteria can be applicable to one event. Life-threatening in 
the definition of a serious adverse event or serious adverse reaction refers to an event 
in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. Medical 
judgement should be exercised in deciding whether an adverse event or reaction is 
serious in other situations.  
 
Important adverse events or reactions that are not immediately life-threatening or do 
not result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above, should 
also be considered serious. 
 
The following serious adverse events, should they occur, will be classified as 
anticipated: 
 
Severe hypoglycaemia 
 
DKA 

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  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. 
  Unanticipated Serious Adverse Device Effect 
An Unanticipated Serious Adverse Device Effect (USADE) is a serious adverse device 
effect which by its nature, incidence, severity or outcome has not been identified in the 
current version of the protocol. 
 
This includes unanticipated procedure related serious adverse events; that is, serious 
adverse events occurring during the study procedure that are unrelated to any 
malfunction or misuse of the investigational medical device. 
 
An Anticipated Serious Adverse Device Effect (ASADE) is a serious adverse device 
effect which by its nature, incidence, severity or outcome has been identified in the 
protocol. 
  Device Deficiencies 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. A device deficiency may lead to an 
Adverse Device Effect or Serious Adverse Device Effect. The following anticipated 
device deficiencies and device-related issues will not be recorded: 
 
Infusion set occlusion/leakage not leading to ketonaemia 
 
Sensor failure due to miscalibration/detachment 
 
Premature interruption of sensor-life  
 
Battery lifespan deficiency due to inadequate charging or extensive 
wireless communication 
 
Control algorithm device error messages not needing system 
replacement 
 
Intermittent device communication failure not leading to system 
replacement 
  Adverse Event Intensity 
Intensity 
Definition 
 
Mild 
 
Patient is aware of signs and symptoms but they are easily tolerated  
 
Moderate 
 
Signs / symptoms cause sufficient discomfort to interfere with usual 
activities 
 

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Severe 
 
Patient is incapable of working or performing usual activities 
 
NB. The term “severe” is often used to describe the intensity (severity) of a specific 
event. This is not the same as ‘serious’, which is based on patient/event outcome or 
action criteria (see definition 11.1.4). For example, itching for several days may be 
rated as severe, but may not be clinically serious. 
  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 

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plausible. 
The 
event 
must 
be 
unambiguous, 
either 
pharmacologically 
or 
as 
phenomenon, 
using 
satisfactory 
rechallenge procedures if necessary.  
 
(Reference: WHO-UMC Causality Categories)  
 
 
11.2  Recording and Reporting of Adverse Events, Serious 
Adverse Events and Device Deficiencies 
  Monitoring Period of Adverse Events  
The period during which adverse events will be reported is defined as the period from 
the beginning of the study (obtaining informed consent) until 3 weeks after the end of 
the study participation. Adverse events that continue after the subject’s discontinuation 
or completion of the study will be followed until their medical outcome is determined 
or until no further change in the condition is expected. The follow up of AEs may 
therefore extend after the end of the clinical investigation; however no new AEs will be 
reported after the trial reporting period.   
  Recording and Reporting of Adverse Events 
Throughout the course of the study, all efforts will be made to remain alert to possible 
adverse events or untoward findings. The first concern will be the safety of the subject, 
and appropriate medical intervention will be taken. The investigator will elicit reports 
of adverse events from the subject at each visit and complete adverse event forms. 
All AEs, including those the subject/guardian reports spontaneously, those the 
investigators observe, and those the subject/guardian reports in response to questions 
will be recorded on paper or electronic AE forms at each site within seven days of 
discovering the event. 
 
The study investigator will assess the relationship of any adverse event to be device-
related or unrelated by determining if there is a reasonable possibility that the adverse 
event may have been caused by the study device or study procedures. The individual 
investigator at each site will be responsible for managing all adverse events according 
to local protocols, and decide if reporting is required. 
  Severe Hypoglycaemia  
In line with current ISPAD consensus guidelines (59), hypoglycaemic events will be 
considered severe if the event requires assistance of another person due to altered 
consciousness to actively administer carbohydrate, glucagon, or other resuscitative 
actions. This means that the subject is impaired cognitively to the point that he/she is 

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unable to treat him- or herself, is unable to verbalize his or her needs, is incoherent, 
disoriented, and/or combative, or experiences seizure or coma. If plasma glucose 
measurements are not available during such an event, neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration.  
 
Severe hypoglycaemia will be regarded as a foreseeable serious adverse event and 
a serious adverse event form will be completed. Non-severe hypoglycaemia will not 
be reported or considered an adverse event.  
  Diabetic Ketoacidosis  
Biochemical criteria for the diagnosis of diabetic ketoacidosis (DKA) are defined as 
per current ISPAD consensus guidelines (60):  
 
hyperglycaemia (blood glucose >200 mg/dl or >11 mmol/l) 
 
with either low pH (<7.3) or low serum bicarbonate (<15 mmol/l) 
 
and ketonemia or ketonuria  
 
DKA will be regarded as a foreseeable serious adverse event and a serious adverse 
event form will be completed.  
 
  Reporting of Serious Adverse Events and Serious Adverse 
Device Effects 
When reporting adverse events, all pertinent data protection legislation must be 
adhered to. 
 
The serious adverse event report should contain the following information*: 
1. Study identifier (EudraCT number if applicable) 
2. Participant’s unique study number 
3. Date of birth 
4. Event description 
5. Start date of event 
6. Laboratory tests used and medical interventions used to treat the SAE 
7. Planned actions relating to the event, including whether the study device was 
discontinued 
8. Statement on the patient’s current state of health 
9. Reason for seriousness (i.e. death, life threatening, hospitalisation, 
disability/incapacity or other) 

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10. Evaluation of causality (including grade of relatedness) with the following (more 
than one may apply): 
a. the investigational treatment/medical device 
b. the clinical study/a study specific procedure 
c. other: e. g. concomitant treatment, underlying disease  
11. Reporter’s name, date and signature 
*In the case of incomplete information at the time of initial reporting, all appropriate 
information should be provided as soon as this becomes available.   
 
The relationship of the SAE to the investigational treatment / medical device should 
be assessed by the investigator at site, as should the anticipated or unanticipated 
nature of any SAEs and SADEs. 
 
All SAEs whether or not deemed investigational method/device related and whether  
anticipated or unanticipated must be reported to the Sponsor by email or fax within 24 
hours (one working day) of the Investigator learning of its occurrence.   
 
SAEs should be reported to:  
Stephen Kelleher 
Cambridge University Hospitals  
NHS Foundation Trust              
Box 277, Addenbrooke's Hospital 
Hills Road, Cambridge, CB2 0QQ, UK 
Phone:  +44 (0) 1223 217418 
Fax:  +44 (0) 1223 348494 
E-mail: enquiries@addenbrookes.nhs.uk. 
 
A written report must follow within five working days and is to include a full description 
of the event and sequelae, in the format detailed on the Serious Adverse Event 
reporting form. If applicable, the Sponsor will notify the competent authority of all 
Serious Adverse Events in line with pertinent legal requirements.  
 
The Investigator will notify the Research Ethics Committee (REC) in UK of all Serious 
Adverse Events in line with pertinent legal requirements. The Investigator will inform 
the Sponsor about all reports sent to the reporting organisation including follow-up 
information and answers by the reporting organisation. The local investigator is 
responsible for informing other site principal investigators and the CI of all SAEs. 
 

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The respective national regulatory authority (e.g. MHRA) will be notified of all SAEs as 
soon as possible within ten days of the event occurring during the study. The main 
REC will be notified of all unexpected and related SAEs within 15 days of the 
occurrence of the event.  
  Recording and Reporting of Device Deficiencies 
All device deficiencies will be documented throughout the study. The investigator at 
each site will be responsible for managing all device deficiencies and determine and 
document in writing whether they could have led to a serious adverse device effect.   
 
All device deficiencies that might have led to a serious adverse device effect(s) if: 
suitable action had not been taken, intervention had not been made, or if 
circumstances had been less fortunate, must be reported to the Sponsor as for 
SAEs/SADEs.   
  Healthcare Arrangements and Compensation for Adverse Events  
Healthcare arrangements for subjects who suffer an adverse event as a result of 
participating in the study may include advice from clinical members of the study team 
or the patient’s treating diabetes team, or use of emergency health services.   
 
If an adverse event occurs, there are no special compensation arrangements unless 
this was due to the negligence of one of the clinical investigators or due to harm 
resulting from study protocol design. In this case subjects may have grounds for legal 
action for compensation. The normal national complaints mechanism will be available. 
In addition, any harm arising due to study design (both negligent and non-negligent) 
will be covered under Sponsor’s insurance policy as applicable. 
 
 
  Country specific requirements 
 
1. UK - The Investigator will notify the ethics committee of all Serious Adverse 
Events in line with pertinent legal requirements. The Investigator will inform the 
Sponsor about all reports sent to the ethics committee including follow-up 
information and answers by the ethics committee. The MHRA and REC will be 
notified of all SAEs/SADEs occurring during the study according to the 
timelines specified in section 11.1.5. 
 
2. Germany - According to the German Ordinance on Medical Devices Vigilance 
(Medizinprodukte-Sicherheitsplanverordnung – MPSV), §2 (5) a Serious 
Adverse Event (SAE) is defined as:  

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„Ein 
schwerwiegendes 
unerwünschtes 
Ereignis 
ist 
jedes 
in 
einer 
genehmigungspflichtigen 
klinischen 
Prüfung 
oder 
einer 
genehmigungspflichtigen 
Leistungsbewertungsprüfung 
auftretende 
ungewollte Ereignis, das unmittelbar oder mittelbar zum Tod oder zu einer 
schwerwiegenden 
Verschlechterung 
des 
Gesundheitszustands 
eines 
Probanden, eines Anwenders oder einer anderen Person geführt hat, geführt 
haben könnte oder führen könnte ohne zu berücksichtigen, ob das Ereignis 
vom Medizinprodukt verursacht wurde; das Vorgesagte gilt entsprechend für 
schwerwiegende unerwünschte Ereignisse, die in einer klinischen Prüfung 
oder Leistungsbewertungsprüfung, für die eine Befreiung von der 
Genehmigungspflicht nach § 20 Absatz 1 Satz 2 des Medizinproduktegesetzes 
erteilt wurde, aufgetreten sind.“ 
 
(English translation: A serious adverse event in a licensable clinical trial or a 
licensable performance evaluation is an unintended event which directly or 
indirectly caused, may have caused in the past, or may cause in the future, 
death or a serious aggravation of the state of health of a patient, a user or 
another person, without considering whether or not the event was caused by 
the medical device; this applies also to serious adverse events, which occur in 
a clinical trial or performance evaluation, for which an exemption of approval 
was granted according to § 20 paragraph 1 sentence 2 of the German Medical 
Devices Act) 
 
According to MPG and MPGSV §5: 
a) The sponsor has to report all SAEs with possible causal relationship to the 
investigational medical device (=SADE) and all SAEs with possible causal 
relationship to study procedure to BfArM immediately (BfArM SAE form). 
b) The sponsor has to report SAEs without possible causal relationship to the 
investigational medical device or procedure to BfArM quarterly (MEDDEVform 
and as report) or upon request. 
 
3. Austria - All SAEs have to be documented by the sponsor and immediately 
reported according to § 42 (8) and § 70 of the Austrian Medical Device 
Directive (StF: BGBl. Nr. 657/1996, BGBl. I Nr. 143/2009) to the competent 
authority (AGES) and the competent authorities of other countries within the 
European Union where the study is conducted. All SAEs must be reported 
using the templates provided by AGES. The Investigator must notify the 
affected ethics committee without delay of any serious side effects and any 
serious adverse events during the clinical trial (MPG § 61). The clinical 

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investigator must inform the sponsor of any medical device effects and any 
serious adverse events during the clinical trial (MPG § 64, (5)). Furthermore a 
continuous reporting form (tabular listing = line listing) F_I287 (SAE report 
table) must be maintained for all SAEs (occurring abroad or in Austria), and 
the BASG must immediately be notified if new SAEs or changes to or additions 
to previously reported SAEs occurred. 
 
4. Luxembourg - The Investigator will notify the ethical committee (CNER) of all 
Serious Adverse Events in line with pertinent legal requirements (directives 
90/385/eec and 93/42/eec). The Investigator will inform the Sponsor about all 
reports sent to the ethics committee including follow-up information and 
answers by the ethics committee. The Competent Authority will be notified of 
all SAEs/SADEs occurring during the study according to the timelines specified 
in section 11.2.5. 
 
 
11.3  Anticipated Adverse Events, Risks and Benefits 
  Risks and Anticipated Adverse Events  
Known risks represent hazardous situations which may result in anticipated adverse 
events. In the following text, where appropriate, the term “risk” and “anticipated 
adverse events” are used interchangeably without affecting meaning. 
  Hypoglycaemia and Hyperglycaemia 
Subjects with type 1 diabetes have a pre-existing risk of hypoglycaemia and 
hyperglycaemia. Potential risks are: 
 
 
Risk of mild to moderate hypoglycaemia and associated symptoms such as 
sweating, trembling, difficulty thinking and dizziness. There is also a rare risk 
of severe hypoglycaemia when conscious level is altered, needing help from a 
third party to correct the hypoglycaemia. These risks are pre-existent in any 
patient with type 1 diabetes and the study objective is to develop systems to 
minimise these risks 
 
Risk of possible mild to moderate hyperglycaemia similar to the risk that a 
subject with type 1 diabetes experiences on a daily basis  
 
Risk of hyperglycaemia leading to diabetic ketoacidosis (DKA). This risk is pre-
existent in any patient with type 1 diabetes. 
  Blood Sampling for HbA1c and Blood Glucose Measurements 
Finger-prick tests may produce pain and/or bruising at the site. 

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  Insulin Pump Therapy 
Patients participating in this study are already using an insulin pump. 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) 
 
Infusion set and cannula occlusions (rare) 
 
Bleeding at insertion site (rare) 
 
Infection at the site of insertion (rare) 
 
Allergy to the insulin delivery cannula or adhesive (rare) 
 
Insulin pump malfunction and mechanical problems (rare) 
 
Allergy to insulin (very rare) 
 
Lipodystrophy / lipoatrophy (very rare) 
  Continuous Glucose Monitoring 
Risks associated with CGM include: 
 
 
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) 
 
Allergic reaction to the CGM sensor material (rare) 
 
If a skin reaction is classified as severe (the observation is noticeable and bothersome 
to subject/guardian and may indicate infection or risk of infection or potentially life-
threatening allergic reaction), an adverse event form will be completed. 
  Questionnaires and Interviews 
As part of the study, parents/guardians will complete questionnaires and take part in 
interviews which include questions about their private attitudes, feelings and behaviour 
related to diabetes. It is possible that some people may find the questions to be mildly 
upsetting. Similar questionnaires and interview structures have been used in previous 
research and these reactions are uncommon. If questionnaire responses or interview 
discussions indicate serious psychological distress as judged by the investigators, 
appropriate clinical services will be arranged. Any treatment will be documented in the 
case-report form. 
 
The study teams take the safeguarding of children very seriously and should any 
concerns be raised during the course of the study, including questionnaires and 

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interviews, these concerns will be dealt with in accordance with local policy. 
Parents/guardians will be made aware of this. 
 
  Risk Analysis and Residual Risk Associated with the 
Investigational Device 
After in-depth analysis and consideration of all the potential hazards in relation to use 
of the FlorenceX system in the home environment, it is concluded that the FlorenceX 
system is safe, if used as intended. 
 
Risk Assessment of the FlorenceX system has been carried out in accordance with 
ISO 14971:2012. A preliminary Hazard Determination has been carried out including 
consideration of the questions in Annex C of ISO 14971:2012. 
 
One hazard ‘Hazard S7: Incorrect Calibration of Blood Glucose Sensor due to error of 
reading resulting in overestimation of blood glucose’ is the only hazard identified that 
could not be reduced to an acceptable risk level, post mitigation. Our in-detail 
risk/benefit assessment concluded that the benefits of the system outweigh the risk 
with respect to this specific hazard. 
 
As per our risk management process, further risk analysis shall be undertaken post 
production and release as to ensure any issues raised are acted upon to ensure the 
FlorenceX system continues to improve and develop. 
 
11.4  Benefits 
It is expected that day and night closed loop may have an important role in the 
management of diabetes. The closed loop system may impact on the frequency of 
hypoglycaemia with suspected fewer low glucose levels with closed loop insulin 
delivery compared with sensor augmented pump therapy. The closed loop system 
may lead to an improvement in quality of life and reduction of parental fears regarding 
hypoglycaemia in very young children with type 1 diabetes. In addition to this, higher 
blood glucose levels above target should be reduced with use of the closed loop 
algorithm. Therefore, participation in this study is likely to lead to improved metabolic 
control and be beneficial for study participants.  
 
It is possible that subjects will not directly benefit from being a part of this study. 
However, it is also possible that the blood glucose information from the CGM device 
along with the information about insulin dosing during day and night closed loop will 
be useful for subjects’ diabetes self-management. 

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Further information on benefits - Germany only 
It is expected that day and night closed loop may have an important role in the 
management of diabetes. The closed loop system will have impact on frequency of 
hypoglycemia with suspected fewer low glucose levels in the closed loop setting 
compared to regular treatment. In addition to this also higher blood glucose levels 
beyond the target should be reduced with the used algorithm. Especially in the night 
blood glucose levels closer to target should be reached. It is expected that within the 
study, metabolic control will be better controlled in when using closed loop. Therefore, 
the results of this study are likely to be beneficial for subjects with diabetes. The study 
may have an impact on the long term outcome of the study participants. 
 
The implementation of a closed loop system with improved near target blood glucose 
levels and reduced rate of hypoglycemia will then lead to improvement in quality of 
life, metabolic control and reduction of parental fears regarding hypoglycemia and 
outcome of very young children with type 1 diabetes. 
 
It is possible that subjects will not directly benefit from being a part of this study. 
However, it is also possible that the blood sugar information from the CGM devices 
along with the information about insulin dosing during day and night closed loop will 
be useful for subjects’ diabetes self-management. 
 
11.5  Data Safety Monitoring Board (DSMB) 
An independent Data Safety Monitoring Board (DSMB) will be informed of all serious 
adverse events and any unanticipated adverse device effects that occur during the 
study and will review compiled adverse event data at periodic intervals. 
12 Methods and Assessments 
12.1  Procedures 
  Height and Weight 
These will be recorded at the study initiation visit at baseline and at the end of each 
study arm. Those participating in the extension phase will have height and weight 
recorded at 18 months after the primary phase final study visit. Height will be measured 
in centimetres using calibrated measuring devices. Weight will be measured in 
kilograms using a calibrated electronic scale. 

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  Blood Glucose Meter Data 
The blood glucose meter will be downloaded periodically during the whole duration of 
the study. 
  Insulin Pump and CGM Data  
The study pump and study CGM data will be downloaded periodically during the 
control arm by the participant and during study visits.  
 
12.2  Laboratory Methods  
  HbA1c 
A blood sample for the measurement of HbA1c levels will be taken at four different 
time points: baseline, at the end of each primary phase study arm, and at the end of 
the extension phase (UK sites only). HbA1c will be measured using an International 
Federation of Clinical Chemistry and Laboratory Medicine (IFCC) aligned method. All 
HbA1c testing must follow National Glycohemoglobin Standardization Program 
(NGSP) standards. Those participating in the extension phase will have local or point-
of-care HbA1c measurements taken 3-monthly (UK sites only). 
 
  Total Blood Loss 
The total blood loss will be approximately 300 μl. For those participating in the 
extension phase there will be up to a maximum of 600 μl additional blood loss.  
 
12.3  Questionnaires 
Quantitative data on health-related quality of life will be assessed using validated 
questionnaires. Parents/guardians will complete a series of validated questionnaires 
at baseline and at the end of each study arm. In the extension phase 
parents/guardians will complete the same series of validated questionnaires at the end 
of the extension phase, 18 months after the primary phase final study visit (UK sites 
only). It is estimated that parents/guardians will take 15-25 minutes to complete the 
surveys. All results will be evaluated at the end of the study. All questionnaires are 
available in English, French and German  
 
Table 10 – Questionnaires to be completed by parents/guardians at baseline, at 
the end of each intervention arm (Visit 1, 6, and 8) and at the end of the extension 
phase (Visit 9). 
 

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Measure 
Construct Measured / Relevant Points 
Duration 
Strengths and 
Difficulties 
Questionnaire (SDQ) 
(61) 
This is a widely used 25 item self-report inventory behavioural 
screening questionnaire for children and adolescents. The 
same 25 items are included in questionnaires for completion by 
the parents.  
5-10 min 
Hypoglycaemia Fear 
Survey (HFS) Parents of 
Young Children (62-64) 
Validated questionnaire to measure several dimensions of fear 
of hypoglycaemia. It consists of a “Behaviour subscale” that 
measures behaviours involved in avoidance and over-treatment 
of hypoglycaemia and a “Worry subscale” that measures 
anxiety and fear surrounding hypoglycaemia.  
5- 10 min 
WHO Well-Being Index 
(WHO-5) (65) 
Widely used 5-item questionnaire assessing subjective 
psychological well-being. 
2-3 min 
Epworth sleepiness 
scale (ESS) (66) 
Simple 8-item questionnaire to measure the parents general 
level of daytime sleepiness and average sleep propensity in 
daily life. 
3-5 min 
Insulin delivery Systems: 
Perceptions, Ideas, 
Reflections, and 
Expectations (INSPIRE) 
Survey 
Measures the psychological side of automated insulin delivery. 
Child version has 27 items; Parent version has 30 items. 
5-10 min 
Pittsburgh Sleep Quality 
Index (PSQI)  
The PSQI is a 19 item questionnaire that holistically assesses 
sleep quality and sleep duration. 
5-10 min 
(Visit 8 only) 
Children’s Sleep Habit 
Questionnaire (CSHQ) 
The CSHQ is a validated retrospective 45-item questionnaire 
that examines sleep behaviour in young children. 
10-15 min 
(Visit 8 only) 
 
At the end of the closed loop intervention arm, parents’/guardians' experience using 
closed loop will be documented using the parent closed loop experience 
questionnaire. 
 
 
12.4  Sleep 
Quality, duration and fragmentation of sleep will be assessed subjectively (using the 
Pittsburgh Sleep Quality Index (PSQI) or similar validated questionnaire, and a daily 

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sleep diary) and objectively (by actigraphy) in parents/guardians. These measures will 
be conducted over 7 days at Visit 8a prior to the end of the study in both arms.  
 
The PSQI is a validated 19 item questionnaire that holistically assesses sleep quality 
and sleep duration. The CSHQ is a validated 45 item questionnaire examining sleep 
behaviour in young children. The sleep diary will record time of going to bed and 
waking, plus time of, and reason for any nocturnal awakenings. 
 
An Actiwatch (Philips Respironics, Bend, Oregon, USA) worn on the non-dominant 
wrist will provide objective measures of sleep and wakefulness based on motor activity 
- a low cost, non-invasive and objective method for evaluating sleep in free-living 
participants. Actiwatches will record time in bed and actual sleep time, as well as 
changes in sleep quality from measures of sleep maintenance, sleep efficiency, sleep 
latency, fragmentation index, total nocturnal activity, and percentage moving time. 
Light exposure will be measured by the Actiwatch’s photovoltaic sensor.  
 
12.5  Qualitative Interview  
A subset of parents/guardians will be interviewed at the end of each study arm. 
Approximately 30 parents/guardians will be interviewed with representation from each 
study country. Parents will be asked to opt‐in to the interview study when they enter 
the study.  
 
The objective of the interviews is to understand and explore parents’ experiences of 
using closed loop insulin delivery compared with sensor-augmented pump therapy to 
manage their child’s diabetes. The same participants/guardians will be interviewed 
after completing each study arm to look at whether, in what ways, and why, use of a 
closed loop system (as compared to sensor-augmented pump therapy) has impacted 
on their diabetes management practices, their worries and concerns about 
hyperglycaemia and hypoglycaemia; and their work and family lives. Interviews will 
also explore participants’ likes and dislikes of using the closed loop system and how 
the technology might be improved for future use. Interviews will be informed by topic 
guides which will enable the discussion to stay relevant to the study aims while 
affording the flexibility needed for participants to discuss issues they see as important, 
including those unforeseen at the outset of the study.  
 
Interviews will take place at a time chosen by the parents/guardians and will be carried 
out by telephone or Skype (where local regulations permit). Participants will be 
interviewed in English or German by an experienced qualitative researcher who is 

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fluent in both languages. Interviews will be audio-recorded with consent. All interviews 
will be transcribed in full for in-depth analysis; with interviews undertaken in German 
translated into English. 
 
12.6  Health Economics 
The analysis will be performed using the IQVIA Core Diabetes Model (CDM; QVIA, 
Basel, Switzerland). The CDM is a validated non-product-specific policy analysis tool 
for cost-effectiveness analysis in both type 1 and type 2 diabetes; a detailed 
description of the model architecture (including schematic diagrams) and validation is 
available in publications by Palmer et al (67, 68) and more recently McEwan et al (69). 
In summary, the model is based on a series of inter-dependent submodels that 
simulate both acute and long-term diabetes-related complications (angina, myocardial 
infarction, congestive heart failure, stroke, peripheral vascular disease, diabetic 
retinopathy, macula oedema, cataract, hypoglycaemia, ketoacidosis, lactic acidosis, 
depression, oedema, nephropathy and end-stage renal disease, neuropathy, foot 
ulcer and amputation, and non-specific mortality). The sub-models have a semi-
Markov structure and use time, state, time-in-state and diabetes type-dependent 
probabilities derived from published sources to simulate disease progression. Monte 
Carlo simulation using tracker variables is used to overcome the memory-less 
properties of the standard Markov model and allows for interconnectivity and 
interaction between individual sub-models. 
  Simulation cohort and treatment effects 
Baseline characteristics of the simulation cohort will come from the study. They will 
include: age, sex ratio, Hb1Ac and other risk factors. Treatment effects will be based 
on the study findings comparing 4 months of closed-loop with 4 months of sensor 
augmented pump therapy. 
  Costs and utilities 
Country specific direct costs will be sourced from published literature and where 
necessary inflated to the current year costs.  
 
For treatment costs, only the incremental costs between the two arms will be 
considered, namely the difference between closed-loop therapy and sensor 
augmented pump therapy.  
 
Health state utility values will be taken from published literature (70) and references 
therein. 

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13 Study Materials and Products 
13.1  Insulin 
The participant’s pre-enrolment rapid or ultra-rapid acting insulin analogue (U-100 
100U/ml or at a concentration used pre-enrolment) will be used in the insulin pumps 
during run-in, washout and during both study arms, and during the extension phase. 
Diluted insulin is a standard treatment approach for children with low insulin 
requirements. Study participants using diluted insulin prior to study enrolment will 
remain on diluted insulin throughout the study.  
 
13.2  Insulin Pump  
During the run-in period and both study arms, the Dana insulin pump (SOOIL) will be 
used. Glooko/Diasend software or similar will be used to download insulin pump data 
at regular intervals. 
 
13.3  Continuous Subcutaneous Glucose Monitor 
The Dexcom G6 real-time sensor with sensor applicator (Dexcom, Northridge, CA, 
USA) will be the study CGM. The sensor will be calibrated according to manufacturer’s 
instructions.  
 
13.4  Smartphone  
An Android smartphone hosting FlorenceX App (see section 4.5) will be used. 
 
13.5 Blood Glucose Meter  
Study participants will use their own approved glucose meter for self-monitoring of 
capillary blood glucose (SMBG) during the study. The capillary glucose meter readings 
may be used to calibrate the sensor according to manufacturer’s instructions.  
13.6  CamAPS FX Hybrid Closed loop App 
The closed loop app that will be used in the extension phase of the study is the 
CamAPS FX hybrid closed loop app (CamDiab, Cambridge, UK). This app is identical 
to ‘FlorenceX’, which was used as an investigational device in the primary study phase, 

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and is described in section 4.5. The CamAPS FX app was CE-marked in March 2020 
and is licensed for use from age 1 year with both rapid-acting and ultra-rapid acting 
insulin analogues.  
 
13.7  Computer-Based Algorithm 
 
The Cambridge closed loop controller has been used safely and effectively in the 
closed loop studies in both children and adults with T1D (study REC Ref. 
06/Q0108/350, REC Ref. 07/H0306/116, REC Ref. 08/H0304/75, REC Ref. 
08/H0308/297, REC Ref. 09/H0306/44, REC Ref. 10/H0304/87, REC Ref. 
12/EE/0155, REC Ref. 12/EE/0034, REC Ref. 12/EE/0424, REC Ref. 13/EE/0120, 
REC Ref. 13/WM/0498, REC Ref. 13/EE/0251, REC Ref. 13/EE/0321, REC Ref. 
13/EE/0018, REC Red 15/EE/0324, REC ref 16/EE/0286, REC ref 16/EE/0380 and 
REC Ref 17/LO/0576). 
13.8 Actiwatch 
An Actiwatch (Philips Respironics, Bend, Oregon, USA) will be used to measure sleep 
over 7 day at Visit 8a prior to the end of the study in both arms.   
 
14 Data Analysis  
14.1  Primary Endpoint Analysis  
The primary analysis will evaluate the between group difference in time spent in the 
target glucose range from 3.9 to 10.0 mmol/l (70 to 180 mg/dl) based on CGM glucose 
levels during the four month intervention periods.  
 
Mean ± SD or summary statistics appropriate to the distribution will be reported for the 
primary endpoint over the four month period by treatment intervention. The treatment 
interventions will be compared using a linear mixed model adjusting for period as a 
fixed effect and site as a random effect. The model will account for correlated data 
from the same subject. A 95% confidence interval will be reported for the difference 
between the interventions based on the linear mixed model.  
 
Residual values will be examined for an approximate normal distribution. If values are 
highly skewed, then a ranked normal score transformation will be used instead. 
However, previous experience suggests that the primary endpoint will follow an 
approximately normal distribution. A separate model will also be built with the inclusion 

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of a period by treatment interaction to assess for the presence of a carryover effect. A 
two-sided p-value will be reported. 
 
The primary analysis will be a single statistical comparison of a single outcome 
measure. No formal corrections for multiple comparisons will be performed for the 
secondary analyses in this study. 
 
The primary analysis will be performed on an intention-to-treat basis using the 
treatment order assigned by randomization. Only subjects with the minimum number 
of hours of CGM data as specified in the analysis plan will be included.  
 
A per-protocol analysis restricted to participants with a minimum of 60% CGM data 
during control period and 60% use of closed-loop during closed-loop period will be 
conducted for the primary endpoint. 
 
A detailed analysis plan will be provided separately. 
 
Primary endpoint hypotheses 
 
Null Hypothesis: There is no difference in the true mean time spent in the target 
range (3.9 to 10.0 mmol/L) over the four month period between the two treatment 
groups. 
 
Alternative Hypothesis: There is a nonzero difference in the true mean time spent 
in the target range over the four month period between the two treatment groups. 
 
14.2  Other Key Endpoints 
For the following key endpoints, the familywise type I error rate (FWER) will be 
controlled at two sided α = 0.05. A gatekeeping strategy will be used, where the 
primary endpoint will be tested first, if passing the significance testing, other key 
endpoints will be tested in the order listed below using the fixed-sequence method at 
α = 0.05. 
• 
Time spent with sensor glucose levels between 3.9 to 10.0 mmol/l (70 to 180 
mg/dl)  
• 
Time spent above target glucose (10.0 mmol/l) (180 mg/dl) 
• 
HbA1c 
• 
Average of glucose levels 
• 
Time spent below target glucose (3.9 mmol/l) (70 mg/dl) 
 
14.3  Secondary Efficacy Analyses  

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The following endpoints will be considered exploratory and Benjamini-Hochberg false 
discovery rate (FDR) adjusted p-values will be calculated within each subcategory 
below: 
CGM derived indices: 
• 
Standard deviation, and coefficient of variation of glucose levels 
• 
Time with glucose levels <3.0 mmol/l (54 mg/dl) 
• 
Time with glucose levels in significant hyperglycaemia (glucose levels > 16.7 
mmol/l) (300 mg/dl) 
• 
AUC of glucose below 3.5 mmol/l (63 mg/dl) 
Insulin and Other Endpoints: 
• 
BMI SDS 
• 
Total, basal, and bolus insulin dose 
 
For all secondary endpoints, summary statistics appropriate to the distribution will be 
tabulated by treatment group. Analysis of all secondary CGM and insulin endpoints 
will parallel the primary analysis. The models comparing BMI standard deviation score 
and HbA1c will also adjust for baseline value at the start of each period.  
 
For BMI standard deviation score and HbA1c, a longitudinal model adjusting for period 
as a fixed effect will be constructed to compare treatment arms. The model will include 
two time points: (1) period 1 outcome, and (2) period 2 outcome. 
 
A ranked normal score transformation will be applied to all highly skewed secondary 
endpoints. 
 
Summary statistics for the following outcome metrics will also be tabulated separately 
for daytime (defined as 8am to less than 12am) and night time (defined as 12am to 
less than 8am) over the four month period:  
• 
Percent time with glucose levels spent in the target range (3.9 to 10.0 mmol/L) 
• 
Mean of glucose levels 
• 
Standard deviation of glucose levels 
• 
Percent time with glucose levels below 3.9 mmol/L 
• 
Total insulin dose 
14.4  Extension Phase Analyses 
 Primary Endpoint Analysis 
The primary analysis will evaluate the difference in time spent in the target glucose 
range, between 3.9 to 10.0 mmol/l (70 to 180 mg/dl) as recorded by CGM, over 18 

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months from the end of the primary phase, as compared to sensor augmented pump 
therapy during the primary study phase.   
 
Mean ± SD or summary statistics appropriate to the distribution will be reported for the 
primary endpoint for the sensor augmented pump phase of the main study and over 
the extension period. During the extension period, the primary outcome will be 
calculated by pooling all CGM readings occurring throughout the entire extension 
phase. This will include all readings from the day after the last visit of the main study 
up until the final day of the extension phase. A paired t-test will be used to compare 
values using sensor augmented pump to values during the extension phase. If the 
outcome is skewed, then a nonparametric test will be used instead. 
 
However, previous experience suggests that the primary endpoint will follow an 
approximately normal distribution. Analyses will include individuals with at least 168 
hours (1 week) of CGM data during the sensor augmented pump phase and at least 
672 hours (4 weeks) of CGM data during the extension phase 
 
 
A detailed analysis plan will be provided separately. 
 Secondary Efficacy Analyses  
The following endpoints will be considered exploratory and no corrections for multiple 
comparisons will be made: 
CGM derived indices and HbA1c metrics: 
 
Time spent above target glucose (10.0 mmol/l) (180 mg/dl) 
 
HbA1c at 18 months  
 
Average of glucose levels 
 
Time spent below target glucose (3.9 mmol/l) (70 mg/dl) 
 
Standard deviation, and coefficient of variation of glucose levels 
 
Time with glucose levels <3.0 mmol/l (54 mg/dl) 
 
Time with glucose levels in significant hyperglycaemia (glucose levels > 16.7 
mmol/l) (300 mg/dl) 
Insulin and Other Endpoints: 
 
BMI SDS 
 
Total, basal, and bolus insulin dose 
Questionnaire Scores: 
 
Strengths and Difficulties Questionnaire 
 
Hypoglycaemia Fear Survey 
 
WHO-5 

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 
Epworth Sleepiness Scale 
 
INSPIRE Survey 
 
Analysis of all secondary CGM, HbA1c and insulin endpoints will parallel the primary 
analysis.  
 
A ranked normal score transformation will be applied to all highly skewed secondary 
endpoints. For HbA1c and the CGM metrics, summary statistics will be reported every 
three months. 
 
Summary statistics for the following outcome metrics will also be tabulated separately 
for daytime (defined as 8am to less than 12pm) and night time (defined as 12pm to 
less than 8am) over the 18-month period: 
 
Percent time with glucose levels spent in the target range (3.9 to 10.0 mmol/l) 
 
Mean of glucose levels 
 
Standard deviation of glucose levels 
 
Percent time with glucose levels below 3.9 mmol/l 
 
Total insulin dose 
 
14.5  Safety Analyses  
For each of the following safety outcomes, mean ± SD or summary statistics 
appropriate to the distribution will be tabulated by treatment group: 
 
Number of subjects with any diabetic ketoacidosis events 
 
Number of episodes of diabetic ketoacidosis events per subject and incidence 
rate per 100 person years 
 
Number of subjects with any severe hypoglycaemia events 
 
Number of episodes of severe hypoglycaemia events per subject and 
incidence rate per 100 person years 
 
Number of adverse events per subject 
 
Number of serious adverse events per subject 
For purposes of analysis, a severe hypoglycaemic event will be defined as described 
in section 11.2.3. 
 
All of the above safety outcomes will be tabulated for all subjects (including dropouts 
and withdrawals), regardless of whether CGM data are available and irrespective of 
whether closed loop was operational. All adverse events will be listed for the entire 
study duration, including run-in and washout period. 
  

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For each of diabetic ketoacidosis and severe hypoglycaemia (if enough events), the 
event rates will be compared using a repeated measures Poisson regression model 
adjusting for period. Binary variables will also be compared using a repeated measures 
logistic regression model adjusting for period. 
 
14.6  Utility Evaluation  
The amount of CGM use will be tabulated for each treatment arm, in addition to the 
amount of closed loop system use in the CL arm and the extension phase. Summary 
statistics appropriate to the distribution and range will be reported for the percentage 
of time using the CGM over the four month period (as defined above) for each 
treatment group. The same will be done for the percentage of time using the closed 
loop system in the CL arm and the extension phase. Tabulations of summary statistics 
will also be performed for the percentage of time spent using the closed loop system 
while using the CGM in the CL arm and the extension phase. 
 
14.7  Questionnaires  
For each questionnaire (and their corresponding subscales), total scores will be 
calculated and reported at each time point. They will also be compared between 
treatment arms and with the sensor augmented pump therapy arm in the extension 
phase using the same model described above for the primary endpoint. The 
distribution of responses for each individual question at each time point will also be 
reported in a separate table. 
 
14.8  Sleep assessment 
Sleep will be automatically scored by Actiware software using previously described 
and validated algorithms. Sleep duration will be calculated as the sum of all epochs 
scored as sleep during the time in bed. Variability across nights in a parent/guardian’s 
sleep duration will be summarised using the coefficient of variation.  
  
14.9 Interviews  
To maximise rigour at least two experienced qualitative researchers will be involved in 
data analysis. A thematic analysis will be undertaken by these individuals who will 
independently review data and write separate reports before attending regular 
meetings to compare their interpretations and reach agreement on recurrent themes 

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and findings. Interviews conducted in German will be translated and transcribed into 
English prior to data analysis. 
 
Interviews will be read through repeatedly and cross-compared in order to identify 
issues and themes which cut across different participant’s accounts.  
 
A key aspect of the analysis will involve comparison of the experiences and views of 
participants in the sensor augmented pump therapy arm and closed loop arm of the 
study, to better understand the impact of closed loop as compared to sensor 
augmented pump therapy on diabetes self-management practices and quality of life.  
A final coding frame, reflecting the initial research questions and emergent themes, 
will be developed once all data have been reviewed and consensus reached on key 
themes and findings. NVivo9, a qualitative software package, will be used to facilitate 
data coding/retrieval. 
 
14.10 
 Health Economics Evaluation 
For each simulation, a simulated cohort of 1,000 patients will be run through the model 
1,000 times using first-order Monte Carlo simulation. Long-term outcomes will include 
total direct costs, life expectancy, quality-adjusted life expectancy and time to onset of 
complications. Future costs and clinical benefits will be discounted based on each 
country recommendations. The mean values from the simulation (a total of 1,000 mean 
values, each from a cohort of 1,000 patients run through the model) will then be used 
to generate scatterplots of incremental costs versus incremental effectiveness (quality-
adjusted life years [QALYs]) for closed loop vs. sensor augmented pump therapy. Data 
from the scatterplot will then be used to generate a cost-effectiveness acceptability 
curve. 
 
Sensitivity analysis 
In order to explore the robustness of the base-case findings and establish the key 
drivers of results, a series of one-way simulations will be performed on those 
parameters. 
 
Additional exploratory health-economic analysis might be conducted on other 
endpoints such as but not limited to sleep disorders and indirect costs for the society. 
 
14.11 
 Interim Analysis 
No formal interim analyses or stopping guidelines are planned for this study.  

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14.12 
Sample Size and Power Calculations 
The study will run at seven sites. We have ensured adequate recruitment of 
participants and centres by allowing for a potential 50% uptake and 10% drop-out of 
participants among collaborative paediatric sites, with further contingency sites 
including participant identification sites (identified but not included as applicants). 
Data from the SENCE study (NCT02912728) were used to estimate the standard 
deviation of the primary endpoint. Only subjects from the two treatment arms involving 
CGM use in this study who were using an insulin pump at the time of enrolment were 
used to estimate the SD. Based on data from this study, 65 subjects are required to 
attain 90% power to detect a difference if a treatment effect of 5%, a standard deviation 
of 10.3% for an individual measurement, and a correlation of 0.3 between periods are 
assumed. Adding an additional 10% to this sample size to account for drop outs results 
in a final sample size of 72 subjects. 
 
14.13 
Deviations from the Statistical Plan 
Any deviations from the original statistical plan will be recorded and agreed by the 
Investigators. 
 
15 Case Report Forms 
The Case Report Form (CRF) is the printed, optical, or electronic document designed 
to record all the protocol required information to be reported to the Chief Investigator 
for each study subject. 
 
CRFs will be completed in accordance with GCP and ISO 14551 Guidelines. 
Corrections to the CRF will be performed by striking through the incorrect entry and 
by writing the correct value next to the data that has been crossed out; each correction 
will be initialled and explained (if necessary) by the Investigator or the Investigator’s 
authorised staff. 
 
The electronic CRF system provides an edit feature that records the identity of the 
person making the change and retains a record of the before and after values of the 
data field(s) in question. In addition, all eCRF changes require electronic review and 
sign-off by the investigator associated with the visit. 
 

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If any amendments to the protocol or other study documents are made, CRFs will be 
reviewed to determine if an amendment to these forms is also necessary. 
 
16 Data Management 
Confidentiality of subject data shall be observed at all times during the study. Personal 
details for each subject taking part in the research study and linking them to a unique 
identification number will be held locally on a study screening log in the Trial Master 
File at the investigation centre. These details will not be revealed at any other stage 
during the study, and all results will remain anonymous. The study identification 
number will be used on the case report forms and on all the blood and serum samples 
that are collected throughout the study. Names and addresses will not be used. 
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 the investigation centre. 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 at least 15 
years in line with the General Data Protection Regulation (GDPR) (EU) 2016/679. 
 
Direct access to the source data will be provided for monitoring, audits, REC review 
and regulatory authority inspections during and after the study. The fully anonymised 
data may be shared with third parties (EU or non-EU based) for the purposes of 
advancing management and treatment of diabetes.   
 
Appropriate procedures agreed by the Chief Investigator and Principal Clinical 
Investigator will be put in place for data review, database cleaning and issuing and 
resolving data queries. 
 
17 Ethics 
The study will be conducted in accordance with the Declaration of Helsinki Ethical 
Principles for Medical Research involving Human Subjects (64th WMA General 
Assembly, Fortaleza, Brazil, October 2013).   
 
17.1  Independent Research Ethics Committees (REC) 

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Prior to commencement of the study, the protocol, any amendments, subject 
information and informed consent and assent forms, any other written information to 
be provided to the subject, subject recruitment procedures, current investigator CVs, 
and any other documents as required by the relevant Research Ethics Committee will 
be submitted. Written approval will be obtained from the relevant Ethics Committee 
prior to the commencement of the study. Any additional requirements imposed by the 
REC or regulatory authority shall be followed. 
 
17.2  Informed consent of study subjects 
In obtaining and documenting informed consent, the investigator will comply with the 
applicable regulatory requirements and will adhere to ICH GCP standards and to the 
ethical principles that have their origin in the Declaration of Helsinki. Prior to the start 
of the study, the Investigator will obtain favourable ethical opinion of the written 
informed consent form, assent form and any other written information to be provided 
to subjects. 
 
Subjects and parents/guardians will be given full verbal and written information 
regarding the objectives and procedures of the study and the possible risks involved. 
The study team will avoid any coercion or undue improper inducement of the subject 
to participate and subjects and parents/guardians will be given ample time to consider 
participation in the study. 
 
If the family decides to participate in the study, the parents or legal representatives will 
be asked to sign the informed consent form before study-specific procedures are 
initiated. Whenever possible and according to local laws and recommendations of the 
local Ethics Committees, the assent of the subjects will be obtained in addition to the 
consent of the parents or legal representatives. All subjects will receive a copy of the 
informed consent/assent form, and the Project Coordinator’s office will hold copies of 
the consent/assent forms and Ethics Committee approvals and make them available 
upon request. 
 
For participants wishing to continue with the extension phase of the study, further 
written consent/assent will be obtained from parents/guardians and participants. The 
signed informed consent forms will be photocopied, originals filed in the Investigator’s 
Site File, a copy placed in the patient’s notes and a copy given to the subjects.  
 
 
All subjects will have the right to leave the study at any time, without stating any 
reason, and without any negative consequences to their subsequent medical 

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treatment. The subject 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. 
 
18 Amendments to the Protocol 
Any substantial amendments to the protocol and other documents shall be notified to, 
and approved by, the Research Ethics Committee, and the regulatory authority, prior 
to implementation as per nationally agreed guidelines. 
 
19 Deviations from Protocol 
Deviations from the protocol should not occur without prior approval of the REC or 
sponsor except under emergency circumstances, to protect the rights, safety and well-
being of subjects. If deviations do occur, they will be documented, stating the reason 
and the date, the action taken, and the impact for the subject and for the study. The 
documentation will be kept in the Investigator’s Site File. Deviations will be logged 
electronically and will require chief investigator or local principal investigator 
acknowledgement and sign-off. 
 
Deviations affecting the subject’s rights, safety and well-being or the scientific integrity 
of the study will be reported to the REC and sponsor as soon as possible in a timely 
manner, following nationally-agreed guidelines. 
 
20 Study Management 
20.1  Data and Safety Monitoring Board (DSMB) 
An independent Data Safety Monitoring Board (DSMB) will comprise an independent 
chairperson and two external experts. The DSMB aims to safeguard the interests of 
trial participants, assess the safety and efficacy of the interventions during the trial, 
and monitor the overall conduct of the clinical trial.  
 
The DSMB should receive and review the progress and accruing data of the project 
clinical trials and provide advice on the conduct of the trial. The DSMB will be informed 
of all serious adverse events and any unanticipated adverse device effects that occur 
during the study and will review compiled adverse event data at periodic intervals. 
 

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20.2  Trial Steering Committee (TSC) 
The Trial Steering Committee (TSC) will provide the overall supervision of the clinical 
trial. The TSC will comprise an independent chairperson, the Chief Investigator, and 
the leaders of work packages (WP) 2 (pilot study), WP3 (main study) and WP4 (data 
management) of the KidsAP consortium. The TSC will monitor clinical trial progress 
and conduct and advise on scientific credibility. The TSC will consider and act, as 
appropriate, upon the recommendations of the Data Safety and Monitoring Board 
(DSMB) and ultimately carries the responsibility for deciding whether a trial needs to 
be stopped on grounds of safety or efficacy.  
 
The TSC will meet (in person or conference call) at regular intervals during the 
preparation of the study and follow up to discuss the operational aspects of the study. 
The Principal Clinical Investigators may also participate. The TSC will report its 
decisions to the Ethical Board and the General Assembly of the KidsAP Consortium. 
 
20.3  Study Monitoring  
The Study Coordinator will ensure that the study is conducted in accordance with ICH 
GCP standards through site monitoring visits. A monitoring plan will be written and 
agreed prior to randomisation. 
 
 
 
21 Responsibilities 
21.1  Chief Investigator 
The Chief Investigator (CI) is the person with overall responsibility for the research and 
all ethical applications will be submitted by the CI. The CI is accountable for the 
conduct of the study and will ensure that all study personnel are adequately qualified 
and informed about the protocol, any amendments to the protocol, the study 
treatments and procedures and their study related duties. The CI should maintain a 
list of appropriately qualified persons to whom he/she has delegated specified 
significant study-related duties. 
 
21.2  Principal Clinical Investigator 

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The Principal Clinical Investigator will be responsible for the day-to-day conduct of the 
clinical aspects of the study.   
21.3  Study Coordinator 
The Study Coordinator will provide day-to-day support for the study and provide 
training through Principal Investigator meetings, site initiation and routine monitoring 
visits. 
 
22 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 
subject and confidentiality of their information shall be preserved in reports and 
publication of data. 
23 Timetable 
Inclusion of the first subject in the study is planned to take place in January 2019. The 
expected completion of the last subject is April 2021 and the planned completion of 
the Clinical Study Report is October 2021. 
 
The expected completion of the last participant in the extension phase is October 
2022.  
24 Retention of Study Documentation 
Subject notes must be kept for the maximum time period as permitted by each relevant 
institution. Other source documents and the Investigator’s Site File must be retained 
for at least 15 years, in line with the General Data Protection Regulation (GDPR) (EU) 
2016/679. The Principal Investigator will archive the documentation pertaining to the 
study after completion or discontinuation of the study. 
25 Indemnity Statements 
Indemnity for any harm arising from the conduct of research will be provided according 
to local arrangements in respective centres.  
 
 
Cambridge, UK - National Health Service indemnity cover will apply for any 
claims arising from management and conduct of research. Any liability arising 
from study design will be covered by the clinical trial insurance policy organised 
by the University of Cambridge. 

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 
Graz, Innsbruck, Vienna, Austria – Subjects will be insured according to 
Medical Device Law § 47 (StF: BGBl. Nr. 657/1996, BGBl. I Nr. 143/2009) 
 
Leipzig, Germany - Subjects will be insured according to the German Medical 
Device Law (MPG). Any liability arising from the study will be covered by the 
clinical trial insurance policy organized by the University of Leipzig.  
 
Luxembourg - Centre Hospitalier de Luxembourg indemnity will apply for any 
claims arising from the management and conduct of research. Any liability 
arising from the study design will be covered by the clinical trial insurance 
policy organised by the Centre Hospitalier de Luxembourg (Amlin Corporate 
Insurance NV).   
 

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26 References 
1. 
Todd JA. Etiology of type 1 diabetes. Immunity. 2010;32(4):457-67. 
2. 
Gale EA. The rise of childhood type 1 diabetes in the 20th century. Diabetes. 
2002;51(12):3353-61. 
3. 
Patterson CC, Gyurus E, Rosenbauer J, Cinek O, Neu A, Schober E, et al. 
Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence 
of non-uniformity over time in rates of increase. Diabetologia. 2012;55(8):2142-7. 
4. 
Wood JR, Miller KM, Maahs DM, Beck RW, DiMeglio LA, Libman IM, et al. 
Most youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet 
American Diabetes Association or International Society for Pediatric and Adolescent 
Diabetes clinical guidelines. Diabetes Care. 2013;36(7):2035-7. 
5. 
Maahs DM, Hermann JM, DuBose SN, Miller KM, Heidtmann B, DiMeglio LA, 
et al. Contrasting the clinical care and outcomes of 2,622 children with type 1 
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German/Austrian DPV registries. Diabetologia. 2014;57(8):1578-85. 
6. 
Bohn B, Karges B, Vogel C, Otto K-P, Marg W, Hofer SE, et al. 20 Years of 
Pediatric Benchmarking in Germany and Austria: Age-Dependent Analysis of 
Longitudinal Follow-Up in 63,967 Children and Adolescents with Type 1 Diabetes. 
PLOS ONE. 2016;11(8):e0160971. 
7. 
Juvenile Diabetes Research Foundation Continuous Glucose Monitoring 
Study G, Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, et al. 
Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J 
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8. 
Tsalikian E, Fox L, Weinzimer S, Buckingham B, White NH, Beck R, et al. 
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9. 
Hovorka R. Closed loop insulin delivery: from bench to clinical practice. 
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10. 
Bakhtiani PA, Zhao LM, El Youssef J, Castle JR, Ward WK. A review of 
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Obes Metab. 2013. 
11. 
Cobelli C, Renard E, Kovatchev B. Artificial pancreas: past, present, future. 
Diabetes. 2011;60(11):2672-82. 

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12. 
Hovorka R, Elleri D, Thabit H, Allen JM, Leelarathna L, El-Khairi R, et al. 
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13. 
Thabit H, Lubina-Solomon A, Stadler M, Leelarathna L, Walkinshaw E, 
Pernet A, et al. Home use of closed-loop insulin delivery for overnight glucose control 
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14. 
Leelarathna L, Dellweg S, Mader JK, Allen JM, Benesch C, Doll W, et al. Day 
and night home closed-loop insulin delivery in adults with type 1 diabetes: three-
center randomized crossover study. Diabetes Care. 2014;37(7):1931-7. 
15. 
Tauschmann M, Allen JM, Wilinska ME, Thabit H, Stewart Z, Cheng P, et al. 
Day-and-night hybrid closed-loop insulin delivery in adolescents with type 1 diabetes: 
A free-living, randomized clinical trial. Diabetes Care. 2016;39(7):1168-74. 
16. 
Thabit H, Tauschmann M, Allen JM, Leelarathna L, Hartnell S, Wilinska ME, 
et al. Home use of an artificial beta cell in type 1 diabetes. N Engl J Med. 
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17. 
Kropff J, Del Favero S, Place J, Toffanin C, Visentin R, Monaro M, et al. 2 
month evening and night closed-loop glucose control in patients with type 1 diabetes 
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18. 
Kovatchev BP, Renard E, Cobelli C, Zisser HC, Keith-Hynes P, Anderson 
SM, et al. Feasibility of outpatient fully integrated closed-loop control: first studies of 
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19. 
Del Favero S, Boscari F, Messori M, Rabbone I, Bonfanti R, Sabbion A, et al. 
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20. 
Russell SJ, Hillard MA, Balliro C, Magyar KL, Selagamsetty R, Sinha M, et al. 
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21. 
Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, et 
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Med. 2014;371(4):313-25. 
22. 
Ly TT, Roy A, Grosman B, Shin J, Campbell A, Monirabbasi S, et al. Day and 
Night Closed-Loop Control Using the Integrated Medtronic Hybrid Closed-Loop 
System in Type 1 Diabetes at Diabetes Camp. Diabetes Care. 2015;38(7):1205-11. 

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23. 
Nimri R, Danne T, Kordonouri O, Atlas E, Bratina N, Biester T, et al. The 
"Glucositter" overnight automated closed loop system for type 1 diabetes: a 
randomized crossover trial. Pediatr Diabetes. 2013;14(3):159-67. 
24. 
Nimri R, Muller I, Atlas E, Miller S, Fogel A, Bratina N, et al. MD-Logic 
overnight control for 6 weeks of home use in patients with type 1 diabetes: 
randomized crossover trial. Diabetes Care. 2014;37(11):3025-32. 
25. 
Phillip M, Battelino T, Atlas E, Kordonouri O, Bratina N, Miller S, et al. 
Nocturnal glucose control with an artificial pancreas at a diabetes camp. N Engl J 
Med. 2013;368(9):824-33. 
26. 
de Beaufort CE, Swift PG, Skinner CT, Aanstoot HJ, Aman J, Cameron F, et 
al. Continuing stability of center differences in pediatric diabetes care: do advances 
in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood 
Diabetes. Diabetes Care. 2007;30(9):2245-50. 
27. 
Holl RW, Swift PG, Mortensen HB, Lynggaard H, Hougaard P, Aanstoot HJ, 
et al. Insulin injection regimens and metabolic control in an international survey of 
adolescents with type 1 diabetes over 3 years: results from the Hvidore study group. 
Eur J Pediatr. 2003;162(1):22-9. 
28. 
Mauras N, Beck R, Xing D, Ruedy K, Buckingham B, Tansey M, et al. A 
randomized clinical trial to assess the efficacy and safety of real-time continuous 
glucose monitoring in the management of type 1 diabetes in young children aged 4 
to <10 years. Diabetes Care. 2012;35(2):204-10. 
29. 
Gaudieri PA, Chen R, Greer TF, Holmes CS. Cognitive function in children 
with type 1 diabetes: a meta-analysis. Diabetes Care. 2008;31(9):1892-7. 
30. 
Ryan CM. Why is cognitive dysfunction associated with the development of 
diabetes early in life? The diathesis hypothesis. Pediatr Diabetes. 2006;7(5):289-97. 
31. 
Ferguson SC, Blane A, Wardlaw J, Frier BM, Perros P, McCrimmon RJ, et al. 
Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive 
function. Diabetes Care. 2005;28(6):1431-7. 
32. 
Schoenle EJ, Schoenle D, Molinari L, Largo RH. Impaired intellectual 
development in children with Type I diabetes: association with HbA(1c), age at 
diagnosis and sex. Diabetologia. 2002;45(1):108-14. 
33. 
Persson S, Dahlquist G, Gerdtham UG, Steen Carlsson K. Impact of 
childhood-onset type 1 diabetes on schooling: a population-based register study. 
Diabetologia. 2013;56(6):1254-62. 

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34. 
Marzelli MJ, Mazaika PK, Barnea-Goraly N, Hershey T, Tsalikian E, 
Tamborlane W, et al. Neuroanatomical correlates of dysglycemia in young children 
with type 1 diabetes. Diabetes. 2014;63(1):343-53. 
35. 
Barnea-Goraly N, Raman M, Mazaika P, Marzelli M, Hershey T, Weinzimer 
SA, et al. Alterations in White Matter Structure in Young Children With Type 1 
Diabetes. Diabetes Care. 2013. 
36. 
Williams RM, Dunger DB. Insulin treatment in children and adolescents. Acta 
Paediatr. 2004;93(4):440-6. 
37. 
Bulsara MK, Holman CD, Davis EA, Jones TW. The impact of a decade of 
changing treatment on rates of severe hypoglycemia in a population-based cohort of 
children with type 1 diabetes. Diabetes Care. 2004;27(10):2293-8. 
38. 
Murphy HR, Wadham C, Hassler-Hurst J, Rayman G, Skinner TC, Group 
FaACaTSF. Randomized trial of a diabetes self-management education and family 
teamwork intervention in adolescents with Type 1 diabetes. Diabet Med. 
2012;29(8):e249-54. 
39. 
Skyler JS. Struggles with clinical translation of immune intervention trials. 
Diabetes Care. 2014;37(5):1173-5. 
40. 
Danne T, Kordonouri O, Holder M, Haberland H, Golembowski S, Remus K, 
et al. Prevention of hypoglycemia by using low glucose suspend function in sensor-
augmented pump therapy. Diabetes technology & therapeutics. 2011;13(11):1129-
34. 
41. 
Choudhary P, Shin J, Wang Y, Evans ML, Hammond PJ, Kerr D, et al. Insulin 
pump therapy with automated insulin suspension in response to hypoglycemia: 
reduction in nocturnal hypoglycemia in those at greatest risk. Diabetes Care. 
2011;34(9):2023-5. 
42. 
Garg S, Brazg RL, Bailey TS, Buckingham BA, Slover RH, Klonoff DC, et al. 
Reduction in duration of hypoglycemia by automatic suspension of insulin delivery: 
the in-clinic ASPIRE study. Diabetes technology & therapeutics. 2012;14(3):205-9. 
43. 
Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, et 
al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl 
J Med. 2013;369(3):224-32. 
44. 
Buckingham BA, Raghinaru D, Cameron F, Bequette BW, Chase HP, Maahs 
DM, et al. Predictive low-glucose insulin suspension reduces duration of nocturnal 
hypoglycemia in children without increasing ketosis. Diabetes Care. 
2015;38(7):1197-204. 

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45. 
Guerci B, Meyer L, Salle A, Charrie A, Dousset B, Ziegler O, et al. 
Comparison of metabolic deterioration between insulin analog and regular insulin 
after a 5-hour interruption of a continuous subcutaneous insulin infusion in type 1 
diabetic patients. The Journal of clinical endocrinology and metabolism. 
1999;84(8):2673-8. 
46. 
Ly TT, Nicholas JA, Retterath A, Davis EA, Jones TW. Analysis of glucose 
responses to automated insulin suspension with sensor-augmented pump therapy. 
Diabetes Care. 2012;35(7):1462-5. 
47. 
Hovorka R, Allen JM, Elleri D, Chassin LJ, Harris J, Xing D, et al. Manual 
closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 
2 randomised crossover trial. Lancet. 2010;375(9716):743-51. 
48. 
Elleri D, Allen JM, Kumareswaran K, Leelarathna L, Nodale M, Caldwell K, et 
al. Closed-loop basal insulin delivery over 36 hours in adolescents with type 1 
diabetes: randomized clinical trial. Diabetes Care. 2013;36(4):838-44. 
49. 
Nimri R, Muller I, Atlas E, Miller S, Kordonouri O, Bratina N, et al. Night 
glucose control with MD-Logic artificial pancreas in home setting: a single blind, 
randomized crossover trial-interim analysis. Pediatr Diabetes. 2014;15(2):91-9. 
50. 
Barnard KD, Wysocki T, Allen JM, Elleri D, Thabit H, Leelarathna L, et al. 
Closing the loop overnight at home setting: psychosocial impact for adolescents with 
type 1 diabetes and their parents. BMJ Open Diabetes Res Care. 
2014;2(1):e000025. 
51. 
Elleri D, Allen JM, Tauschmann M, El-Khairi R, Benitez-Aguirre P, Acerini CL, 
et al. Feasibility of overnight closed-loop therapy in young children with type 1 
diabetes aged 3-6 years: comparison between diluted and standard insulin strength. 
BMJ Open Diabetes Res Care. 2014;2(1):e000040. 
52. 
Stewart ZA, Wilinska ME, Hartnell S, Temple RC, Rayman G, Stanley KP, et 
al. Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes. 
N Engl J Med. 2016;375(7):644-54. 
53. 
Tauschmann M, Allen JM, Wilinska ME, Thabit H, Acerini CL, Dunger DB, et 
al. Home use of day-and-night hybrid closed-loop insulin delivery in suboptimally 
controlled adolescents with type 1 diabetes: a 3-week, free-living, randomized 
crossover trial. Diabetes Care. 2016;39(11):2019-25. 
54. 
Thabit H, Elleri D, Leelarathna L, Allen J, Lubina-Solomon A, Stadler M, et al. 
Unsupervised overnight closed loop insulin delivery during free living: analysis of 
randomised cross-over home studies in adults and adolescents with type 1 diabetes. 
Lancet. 2015;385 Suppl 1:S96. 

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55. 
Elleri D, Acerini CL, Allen JM, Hayes J, Pesterfield C, Wilinska ME, et al. 
Parental attitudes towards overnight closed-loop glucose control in children with type 
1 diabetes. Diabetes technology & therapeutics. 2010;12(1):35-9. 
56. 
Barnard KD, Wysocki T, Thabit H, Evans ML, Amiel S, Heller S, et al. 
Psychosocial aspects of closed- and open-loop insulin delivery: closing the loop in 
adults with Type 1 diabetes in the home setting. Diabet Med. 2015;32(5):601-8. 
57. 
Hovorka R. Artificial Pancreas project at Cambridge 2013. Diabet Med. 
2015;32(8):987-92. 
58. 
Thabit H, Tauschmann M, Allen JM, Leelarathna L, Hartnell S, Wilinska ME, 
et al. Home use of an artificial beta cell in type 1 diabetes. N Engl J Med. 
2015;373(22):2129-40. 
59. 
Ly TT, Maahs DM, Rewers A, Dunger D, Oduwole A, Jones TW, et al. ISPAD 
Clinical Practice Consensus Guidelines 2014. Assessment and management of 
hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2014;15 
Suppl 20:180-92. 
60. 
Wolfsdorf JI, Allgrove J, Craig ME, Edge J, Glaser N, Jain V, et al. ISPAD 
Clinical Practice Consensus Guidelines 2014. Diabetic ketoacidosis and 
hyperglycemic hyperosmolar state. Pediatr Diabetes. 2014;15 Suppl 20:154-79. 
61. 
Goodman R. The Strengths and Difficulties Questionnaire: a research note. J 
Child Psychol Psychiatry. 1997;38(5):581-6. 
62. 
Green LB, Wysocki T, Reineck BM. Fear of hypoglycemia in children and 
adolescents with diabetes. J Pediatr Psychol. 1990;15(5):633-41. 
63. 
Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J. Fear of 
hypoglycemia: quantification, validation, and utilization. Diabetes Care. 
1987;10(5):617-21. 
64. 
Gonder-Frederick LA, Schmidt KM, Vajda KA, Greear ML, Singh H, Shepard 
JA, et al. Psychometric properties of the hypoglycemia fear survey-ii for adults with 
type 1 diabetes. Diabetes Care. 2011;34(4):801-6. 
65. 
Bonsignore M, Barkow K, Jessen F, Heun R. Validity of the five-item WHO 
Well-Being Index (WHO-5) in an elderly population. Eur Arch Psychiatry Clin 
Neurosci. 2001;251 Suppl 2:II27-31. 
66. 
Johns MW. A new method for measuring daytime sleepiness: the Epworth 
sleepiness scale. Sleep. 1991;14(6):540-5. 
67. 
Palmer AJ, Roze S, Valentine WJ, Minshall ME, Foos V, Lurati FM, et al. The 
CORE Diabetes Model: Projecting long-term clinical outcomes, costs and cost-

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effectiveness of interventions in diabetes mellitus (types 1 and 2) to support clinical 
and reimbursement decision-making. Current medical research and opinion. 2004;20 
Suppl 1:S5-26. 
68. 
Palmer AJ, Roze S, Valentine WJ, Minshall ME, Foos V, Lurati FM, et al. 
Validation of the CORE Diabetes Model against epidemiological and clinical studies. 
Current medical research and opinion. 2004;20 Suppl 1:S27-40. 
69. 
McEwan P, Foos V, Palmer JL, Lamotte M, Lloyd A, Grant D. Validation of 
the IMS CORE Diabetes Model. Value in health : the journal of the International 
Society for Pharmacoeconomics and Outcomes Research. 2014;17(6):714-24. 
70. 
Beaudet A, Clegg J, Thuresson PO, Lloyd A, McEwan P. Review of utility 
values for economic modeling in type 2 diabetes. Value in health : the journal of the 
International Society for Pharmacoeconomics and Outcomes Research. 
2014;17(4):462-70. 
 
 
27 Document Amendment History 
Version 
Number 
Date 
Amendment information 
1.1 
19/12/2018 
1. Inclusion of additional exclusion criterion for 
Germany and UK only. 
1.2 
10/01/2019 
1. Clarification of inclusion criteria 
2. Section 13.4 “Smartphone” added for clarity 
3. Clarification added on analysis of primary end 
point 
1.3 
17/07/2019 
1. Change of clinical PI at Cambridge, UK 
2.0 
10/03/2020 
1. Inclusion of sub-study on sleep assessment 
2. Addition of 2 new questionnaires for caregivers 
3.0 
30/06/2020 
1. Addition of 18-month extension phase 
2. Study personnel information updated 
3. Clarification of timing of Visit 7 on the Schedule 
of study visits added 
4. Visit 8 (sleep assessment) changed to Visit 8a 
and Visit 9 (end of primary study phase) 
changed to Visit 8b for clarity  
5. Information about CamAPS FX as CE marked 
device added  
 

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1 
 
2 
 
3 
 
4 
An open-label, multi-center, randomized, 2-period cross-over study 
5 
to assess the efficacy and safety of closed loop insulin delivery in 
6 
comparison with sensor augmented insulin pump therapy with 
7 
continuous glucose monitoring (CGM) over 4 months in children 
8 
with type 1 diabetes aged 1 to 7 years in the home setting. 
9 
KidsAP02 Study 
10 
 
11 
Statistical Analysis Plan 
12 
Randomized Crossover Trial 
13 
 
14 
 
15 
Version: 3.0 
16 
Version Date: 05/05/2021 
17 
Author: Nathan Cohen/ Laura Bocchino 
18 
Protocol Version: 3.0 
19 
 
20 
 
21 
Note: The table shells are included in a separate document. 
 
22 

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Revision History 
The following table outlines changes made to the Statistical Analysis Plan.  
Version Number 
Author 
Approver 
Effective Date 
Study Stage 
1.0 
Nathan Cohen 
Peter Calhoun 
04/04/2019 
Protocol 
development 
1.1 
Nathan Cohen 
Peter Calhoun 
06/19/2019 
Enrollment 
1.2 
Nathan Cohen 
Peter Calhoun 
07/11/2019 
Enrollment 
1.3 
Nathan Cohen 
Peter Calhoun 
07/13/2020 
Follow-up 
2.0 
Nathan Cohen 
Peter Calhoun 
09/01/2020 
Follow-up 
3.0 
Laura Bocchino 
Craig Kollman 05/05/2021 
Initial SAP 
analyses 
completed 
 
 
Version Number 
Revision Description 
1.1 
Clarified when the end of the period occurs for safety analyses and that 
secondary analyses by time of day include the same subjects as the primary 
analysis 
1.2 
Clarified the scoring of the INSPIRE survey 
1.3 
Added in the questionnaires for the sleep sub-study. Changed the definition 
of daytime and nighttime to be consistent with the protocol. 
2.0 
Added in analyses for the extension phase 
3.0 
Added post-hoc secondary insulin analyses in Units/kg/day.  Added post-
hoc secondary insulin analyses in Units/kg/day by time of day.  Added in 
post-hoc tabulation of basal and bolus in Units/kg/day by time of day.  
Clarified analyses of secondary HbA1c and clinical outcomes.  
 
 
23 
 
24 
Author:  ________________________________ 
25 
 
26 
 
27 
 
28 
Senior Statistician: ________________________________ 
29 
Laura Bocchino
I am electronically signing this document
2021-05-05 16:48-04:00
Craig Kollman
I am digitally signing this document
2021-05-05 18:51-04:00

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30 
Jaeb Principal Investigator: ________________________________ 
31 
 
32 
1. Overview 
33 
This document outlines the statistical analyses to be performed for the KidsAP02 study. The 
34 
approach to sample size and statistical analyses for this study are summarized below. 
35 
This is an open-label, multicenter, randomized, two period crossover study to assess the efficacy 
36 
and safety of closed loop (CL) insulin delivery in comparison with sensor augmented/insulin 
37 
pump (SAP) therapy with continuous glucose monitoring (CGM) over four months in children 
38 
with type I diabetes aged 1-7 years. Approximately 72 subjects are expected to be randomized 
39 
and enter the trial. All participants will receive both interventions, and the order of receiving 
40 
them will be randomized based on a 1:1 ratio. Randomization will be preceded by a 2-4 week 
41 
run-in period where subjects must demonstrate competency and compliance in using the study 
42 
insulin pump and CGM device. After randomization, the subjects will enter the two four month 
43 
study periods and will test one intervention per study period.  The two periods will be separated 
44 
by a 1-4 week washout period. The study also includes an optional extension phase where the 
45 
participants continue CL system usage for an additional 18 months after completing the 
46 
randomized trial. The purpose of the extension phase will be to compare the efficacy and safety 
47 
of continued CL system use to SAP therapy as assessed during the main study. 
48 
2. Statistical Hypotheses 
49 
• Null Hypothesis: There is no difference in the true mean time spent in the target range 
50 
(3.9 to 10.0 mmol/L) over the four month period between the two treatment groups. 
51 
• Alternative Hypothesis: There is a nonzero difference in the true mean time spent in the 
52 
target range over the four month period between the two treatment groups. 
53 
3. Sample Size 
54 
The study is projected to randomize 72 subjects. The sample size was calculated assuming 90% 
55 
power, a treatment effect of 5% in the percentage of time in the target range, a standard deviation 
56 
of 10.3% for an individual measurement, and a correlation of 0.3 between periods.  
57 
4. Outcome Measures 
58 
Primary Efficacy Endpoint: 
59 
Time spent in the target range (3.9 to 10.0 mmol/L) over the four month period 
60 
Other Key Endpoints: 
61 
1) Percent Time spent with glucose levels above 10.0 mmol/L 
62 
2) HbA1c 
63 
3) Mean of glucose levels 
64 
4) Percent Time spent with glucose levels below 3.9 mmol/L 
65 
Secondary Efficacy Endpoints: 
66 
CGM Metrics 
67 

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Overall Glucose Control 
68 
1) Standard deviation of glucose levels 
69 
2) Coefficient of variation of glucose levels 
70 
Hyperglycemia 
71 
3) Percent Time spent with glucose levels above 16.7 mmol/L 
72 
Hypoglycemia 
73 
4) Percent Time spent with glucose levels below 3.5 mmol/L 
74 
5) Percent Time spent with glucose levels below 3.0 mmol/L 
75 
6) Area under the curve of glucose levels below 3.5 mmol/L 
76 
7) Area under the curve of glucose levels below 3.0 mmol/L 
77 
Insulin Delivery 
78 
8) Total insulin dose 
79 
9) Basal insulin dose 
80 
10) Bolus insulin dose 
81 
Clinical Metrics 
82 
11) BMI standard deviation score 
83 
Questionnaires 
84 
12) Strengths and Difficulties Questionnaire 
85 
o Emotional Problems Subscale 
86 
o Conduct Problems Subscale 
87 
o Hyperactivity Subscale 
88 
o Peer Problems Subscale 
89 
o Prosocial Subscale 
90 
o Total Difficulties Score 
91 
13) Hypoglycemia Fear Survey 
92 
o Behavior Subscale 
93 
o Worry Subscale 
94 
14) WHO-5 
95 
15) Epworth Sleepiness Scale 
96 
16) Pittsburgh Sleep Quality Index 
97 
o Subjective Sleep Quality Subscale 
98 
o Sleep Latency Subscale 
99 
o Sleep Duration Subscale 
100 
o Habitual Sleep Efficiency Subscale 
101 
o Sleep Disturbances Subscale 
102 
o Use of Sleeping Medication Subscale 
103 
o Daytime Dysfunction Subscale 
104 
17) Children’s Sleep Habit Questionnaire 
105 
o Bedtime Resistance Subscale 
106 
o Sleep Onset Delay Subscale 
107 
o Sleep Duration Subscale 
108 
o Sleep Anxiety Subscale 
109 
o Night Waking Subscale 
110 
o Parasomnias Subscale 
111 
o Sleep Disordered Breathing Subscale 
112 

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o Daytime Sleepiness Subscale 
113 
All metrics listed above will be outcomes in the main study. In the extension phase, the same 
114 
outcomes will be analyzed, with the exceptions of the Pittsburgh Sleep Quality Index and the 
115 
Children’s Sleep Habit Questionnaire. The primary outcome in the extension phase will be time 
116 
in range calculated over the full 18 months. 
117 
4.1 Calculation of CGM Metrics 
118 
For the primary outcome and all secondary CGM metrics, a single value will be calculated for 
119 
each subject for each period by pooling all CGM readings between the treatment initiation visit 
120 
and up to 112 days post-initiation visit or the end of treatment visit, whichever comes first. All 
121 
glucose sensor readings will be weighted equally in the pooled percentages regardless of how 
122 
they distribute across weeks. Data will not be truncated due to protocol deviations.  
123 
Baseline CGM metrics will be calculated by pooling all readings up to the last 14 available days 
124 
of CGM readings prior to randomization. 
125 
In the extension phase, CGM metrics will be calculated by pooling all readings inclusively 
126 
occurring from the day after the last visit of the main study up until the last visit of the extension 
127 
phase.  
128 
Additionally, CGM metrics will be calculated every three months during the extension phase by 
129 
inclusively pooling all CGM readings falling within each of the windows specified at each month 
130 
in the table below: 
131 
Month 
Window for Analysis 
Month 3 
Days 1-91 
Month 6 
Days 92-182 
Month 9 
Days 183-274 
Month 12 
Days 275-365 
Month 15 
Days 366-456 
Month 18 
Days 457-548 
 
132 
4.2 Calculation of BMI SD Scores 
133 
BMI standard deviation score will be calculated using the WHO growth chart.  
134 
5. Analysis Datasets and Sensitivity Analyses 
135 
5.1 Analysis Cohorts 
136 
• The primary analysis and all secondary analyses will be performed on a modified 
137 
intention-to-treat basis with each day included in the treatment group assigned by 
138 
randomization. 
139 
• A per-protocol analysis restricted to randomized participants with a minimum of 60% of 
140 
available CGM readings during the control period and 60% CL system use during the CL 
141 
period will be conducted for the primary outcome. 
142 
• Safety outcomes will be reported for all enrolled participants, regardless of whether the 
143 
study was completed. 
144 

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6. Analysis of the Primary Efficacy Endpoint 
145 
6.1 Included Subjects 
146 
In analyses conducted in the main study, only subjects with at least 168 hours of CGM data in at 
147 
least one period will be included. If a subject has more than 168 hours of data in period 1 and 
148 
then drops out of the study without any data in period 2, then he or she will be included in the 
149 
analysis.   
150 
In the extension phase, analyses will include participants with at least 168 hours of CGM data 
151 
during the SAP phase of the main study and at least 672 hours of CGM data during the extension 
152 
phase. For the analyses conducted every three months during the extension phase, at least 168 
153 
hours of CGM data will be required within a given three-month period to be included in the 
154 
tabulations of summary statistics for that particular period.  
155 
6.2 Missing Data 
156 
Missing data will not be imputed for the primary analysis in this study. 
157 
6.3 Statistical Methods 
158 
Mean ± SD or summary statistics appropriate to the distribution will be reported for the primary 
159 
outcome and each of the key secondary outcomes listed below over the four month period by 
160 
treatment intervention. Summary statistics also will be tabulated for the primary outcome during 
161 
the extension phase. For the main study, the treatment interventions will be compared using a 
162 
linear mixed model adjusting for period as a fixed effect and site as a random effect. The analysis 
163 
dataset will be three records per subject (one for baseline and one for each period). Inclusion of 
164 
the pre-randomization baseline value as a third observation for each subject in the model gives a 
165 
variance reduction analogous to adjusting for it as a covariate.  Baseline is not modeled as a 
166 
covariate in this analysis because there is no corresponding baseline for period 2, only pre-
167 
randomization.  Note that adjusting for a post-randomization period 2 baseline can introduce a 
168 
bias so that is not done here.  The model will account for correlated data from the same subject. 
169 
A 95% confidence interval will be reported for the difference between the interventions based on 
170 
the linear mixed model.  
171 
Residual values will be examined for an approximate normal distribution. If values are highly 
172 
skewed, then a ranked normal score transformation will be used instead. However, previous 
173 
experience suggests that the primary outcome will follow an approximately normal distribution. 
174 
A separate model will also be built with the inclusion of a period by treatment interaction to 
175 
assess for the presence of a carryover effect. We do not expect a carryover effect to be present. A 
176 
two-sided p-value will be reported.  
177 
For the primary endpoint and other key endpoints listed in section 4, the familywise type I error 
178 
rate (FWER) will be controlled at two-sided α = 0.05. A gatekeeping strategy will be used, where 
179 
the primary endpoint will be tested first, if passing the significance testing, other key endpoints 
180 
will be tested in the order listed below using the fixed-sequence method at α = 0.05: 
181 
• Time spent with sensor glucose levels between 3.9 to 10.0 mmol/l  
182 
• Time spent above target glucose (10.0 mmol/l) 
183 
• HbA1c 
184 

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• Average of glucose levels 
185 
• Time spent below target glucose (3.9 mmol/l) 
186 
This process continues iteratively moving to the next variable down on the list until a non-
187 
significant result (p ≥ 0.05) is observed, or all five variables have been tested.  If a non-
188 
significant result is encountered, then formal statistical hypothesis testing is terminated and any 
189 
variables below on the list are not formally tested and analysis of these variables becomes 
190 
exploratory. 
191 
 
192 
For example, in the hypothetical scenario depicted in the table below, the first three outcome 
193 
variables both have a significant result so testing continues to the fourth variable (CGM mean 
194 
glucose).  The result is not significant for that fourth variable (p = 0.33) so testing stops.  No 
195 
formal hypothesis test is conducted for the fifth variable on the list in this example scenario. 
196 
HIERARCHICAL 
ORDER 
OUTCOME VARIABLE 
TREATMENT 
ARM P-VALUE 
SIGNIFICANT? 
ACTION 
1st 
CGM % 3.9-10.0 mmol/L 
(primary outcome) 
0.001 
Yes 
Test next variable 
2nd 
CGM % above 10.0 
mmol/L 
0.02 
Yes 
Test next variable 
3rd 
HbA1c 
0.007 
Yes 
Test next variable 
4th  
CGM mean glucose 
0.33 
No 
Stop formal testing 
5th 
CGM % below 3.9 mmol/L 
Not tested 
Unknown 
N/A 
 
197 
Regardless of the results of the hierarchical testing, summary statistics appropriate to the 
198 
distribution will be tabulated by treatment arm for each hierarchical outcome.  A 95% confidence 
199 
interval for the treatment arm difference will also be calculated for all five hierarchical outcomes 
200 
listed above.  However, a confidence interval that excludes zero will not be considered a 
201 
statistically significant result if an outcome variable higher on the hierarchical list failed to reach 
202 
statistical significance. 
203 
 
204 
In the extension phase, the primary analysis will involve performing a paired t-test to compare 
205 
the mean time in range between the extension phase and the SAP period of the main study. If the 
206 
outcome is skewed, then a nonparametric test will be used instead. 
207 
7. Analysis of the Secondary Endpoints 
208 
7.1 Included Subjects 
209 
In the analyses involving HbA1c and BMI standard deviation score, all subjects with an 
210 
available measurement within the analysis windows specified in section 7.3 will be included.  
211 
For secondary CGM metrics, inclusion criteria will be the same as the primary analysis.  
212 
For the secondary insulin outcomes computed during the main study, at least 168 hours of insulin 
213 
data in at least one period will be required for inclusion. If a subject has more than 168 hours of 
214 

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insulin data in period 1 and then drops out of the study without any data in period 2, then he or 
215 
she will be included in the analysis.   
216 
For the secondary insulin outcomes calculated during the extension phase, analyses will include 
217 
participants with at least 168 hours of insulin data during the SAP phase of the main study and at 
218 
least 672 hours of insulin data during the extension phase. 
219 
7.2 Missing Data 
220 
For the secondary CGM and insulin metrics, missing data will not be imputed in this study.  
221 
In the event that a BMI standard deviation score or HbA1c is unavailable at the end of a period 
222 
but is available at a previous time point, it will be estimated using the method of direct likelihood 
223 
to incorporate information from previous measurements to calculate the maximum likelihood 
224 
estimate.  
225 
It is worth noting that all statistical methods for handling missing data rely on untestable 
226 
assumptions and there is no one correct way to handle missing data. Our goal is to minimize the 
227 
amount of missing data so that the results will not be sensitive to which statistical method is 
228 
used. 
229 
7.3 Analysis Windows 
230 
Only HbA1c and body weight measurements obtained within ±7 days of the end of treatment 
231 
visit dates during each period will be included in the analyses as the outcome. The baseline 
232 
measurements must be within ±14 days of the recruitment visit.  
233 
During the extension phase, only HbA1c and body weight measurements occurring within ±7 
234 
days of the target collection dates will be included in tabulations of summary statistics every 
235 
three months. 
236 
7.4 Statistical Methods 
237 
7.4.1 Secondary CGM Outcomes 
238 
For all secondary CGM outcomes, summary statistics appropriate to the distribution will be 
239 
tabulated by treatment group over the four month period. Analysis of all secondary CGM 
240 
endpoints will parallel the primary analysis. A ranked normal score transformation will be 
241 
applied to all highly skewed secondary outcomes.  
242 
In the extension phase, summary statistics appropriate to the distribution will be tabulated for the 
243 
secondary CGM metrics during the SAP period of the main study and during the extension 
244 
phase. Summary statistics also will be tabulated every three months. Additionally, secondary 
245 
CGM metrics will be compared between the extension phase and the SAP period of the main 
246 
study using a paired t-test. For skewed outcomes, a nonparametric test will be used instead. 
247 
7.4.2 Secondary Insulin Outcomes 
248 
For all secondary insulin outcomes, summary statistics appropriate to the distribution will be 
249 
tabulated by treatment group over the four month period. Analysis of all secondary insulin 
250 
endpoints will parallel the primary analysis. A ranked normal score transformation will be 
251 
applied to all highly skewed secondary outcomes. 
252 

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In the extension phase, summary statistics appropriate to the distribution will be tabulated for the 
253 
secondary insulin metrics during the SAP period of the main study and during the extension 
254 
phase. Additionally, secondary insulin outcomes will be compared between the extension phase 
255 
and the SAP period of the main study using a paired t-test. For skewed outcomes, a 
256 
nonparametric test will be used instead. 
257 
7.4.3 Secondary HbA1c Outcomes 
258 
For HbA1c, a longitudinal model adjusting for period as a fixed effect will be constructed to 
259 
compare treatment arms. The model will include three time points: (1) baseline, (2) period 1 
260 
outcome, and (3) period 2 outcome. Summary statistics for HbA1c will be tabulated every three 
261 
months during the extension phase. 
262 
7.4.4 Secondary Clinical Outcomes 
263 
For BMI standard deviation score, a longitudinal model adjusting for period as a fixed effect will 
264 
be constructed to compare treatment arms. The model will include three time points: (1) baseline, 
265 
(2) period 1 outcome, and (3) period 2 outcome. 
266 
7.5 Secondary Analyses by Time of Day 
267 
Summary statistics for the following outcome metrics will also be tabulated separately for 
268 
daytime (defined as 8am to less than 12am) and nighttime (defined as 12am to less than 8am) 
269 
over the four month period and during the extension phase:  
270 
• Percent time with glucose levels spent in the target range (3.9 to 10.0 mmol/L) 
271 
• Mean of glucose levels 
272 
• Standard deviation of glucose levels 
273 
• Percent time with glucose levels below 3.9 mmol/L 
274 
• Total insulin dose 
275 
For each of these outcome metrics during the main study, the same model described above for 
276 
the primary and secondary analyses will be fit with the inclusion of a treatment by time of day 
277 
interaction. The same subjects will be included as in the primary analysis. The p-value for the 
278 
interaction term will be reported. These analyses will be conducted to determine whether a 
279 
similar trend to the overall treatment effect is seen in the different times of day.  
280 
The study is not expected to have sufficient statistical power for definitive conclusions in the 
281 
secondary analyses by time of day, and statistical power will be low to formally assess for the 
282 
presence of a treatment by time of day interaction. Interpretation of the analyses by time of day 
283 
will depend on whether the overall analysis demonstrates a significant treatment effect. In the 
284 
absence of any significant treatment effects in the overall analyses, assessment of secondary 
285 
analyses by time of day will be considered exploratory and used to suggest hypotheses for 
286 
further investigation in future studies. 
287 
7.6 Questionnaire Analyses 
288 
For each questionnaire (and their corresponding subscales), total scores will be calculated and 
289 
reported at each time point. They will also be compared between treatment arms using the same 
290 
model described above for the primary outcome. The distribution of responses for each 
291 

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individual question at baseline and for each treatment arm will also be reported in separate 
292 
tables.  
293 
For the INSPIRE Survey, a mean score will be calculated instead of a total score. The mean 
294 
score will be calculated after excluding all questions where the participants give a response of 
295 
“NA”.  
296 
For the Pittsburgh Sleep Quality Index (and all of its subscales), the scoring instructions will be 
297 
used to calculate the total scores overall and by subscale. For this questionnaire, scores will be 
298 
tabulated for each parent who completes the survey. 
299 
For the INSPIRE Survey and the CL Experience Survey, a treatment arm comparison will not be 
300 
done, because the surveys are only completed at the end of the CL arm. For these questionnaires, 
301 
only summary statistics for the scores and the distribution of responses for each question will be 
302 
reported. Additionally, treatment arm comparisons will not be done for the Pittsburgh Sleep 
303 
Quality Index or the Children’s Sleep Habit Questionnaire, because they are only completed at 
304 
visit 8.  
305 
For the Strengths and Difficulties Questionnaire, no overall total score will be calculated that 
306 
involves every question. Instead, only a Total Difficulties Score is computed from the questions 
307 
comprising the Emotional Problems, Conduct Problems, Hyperactivity, and Peer Problems 
308 
subscales. 
309 
The electronic data capture system for this study will not allow the subject to submit any 
310 
questionnaires until all items are completed.  Analysis will be limited to subjects who submit a 
311 
questionnaire (no imputation). 
312 
7.7 Ancillary Analyses 
313 
Cost utility analyses and human factors analyses will be described in a separate document. 
314 
8. Safety Analyses 
315 
All safety outcomes will be tabulated by participant for all events from enrollment to the final 
316 
study visit.  
317 
8.1 Definitions 
318 
Reportable adverse events for this protocol include any untoward medical occurrence, 
319 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) 
320 
in a subject who has received an investigational device, whether or not related to the 
321 
investigational medical device. These include severe hypoglycemia (SH) and diabetic 
322 
ketoacidosis (DKA).  
323 
Hypoglycemic events will be considered severe if the event requires assistance of another person 
324 
due to altered consciousness to actively administer carbohydrate, glucagon, or other resuscitative 
325 
actions. This means that the subject is impaired cognitively to the point that he/she is unable to 
326 
treat him- or herself, is unable to verbalize his or her needs, is incoherent, disoriented, and/or 
327 
combative, or experiences seizure or coma. If plasma glucose measurements are not available 
328 
during such an event, neurological recovery attributable to the restoration of plasma glucose to 
329 

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normal is considered sufficient evidence that the event was induced by a low plasma glucose 
330 
concentration. 
331 
Definite DKA is defined as having all of the following: 
332 
• Hyperglycemia (blood glucose >200 mg/dL or >11 mmol/L) 
333 
• with either low pH (<7.3) or low serum bicarbonate (<15 mmol/L) 
334 
• and ketonemia or ketonuria  
335 
8.2 Adverse Events Summary 
336 
All episodes of SH and of DKA along with any other reportable adverse events will be listed by 
337 
treatment group.  
338 
Separate listings will be provided for pre-randomization and post-randomization adverse events. 
339 
A separate listing also will be provided for events that occur during the extension phase.  
340 
8.3 Comparison of Safety Outcomes between Treatment Groups 
341 
The following safety analyses will be performed if enough events occur for formal statistical 
342 
analyses. 
343 
For each of the following safety outcomes, mean ± SD or summary statistics appropriate to the 
344 
distribution will be tabulated by treatment group: 
345 
• Number of subjects with any DKA events 
346 
• Number of episodes of DKA events per subject and incidence rate per 100 person years 
347 
• Number of subjects with any SH events 
348 
• Number of episodes of SH events per subject and incidence rate per 100 person years 
349 
• Number of adverse events per subject 
350 
• Number of serious adverse events per subject 
351 
All of the above safety outcomes will be tabulated for all subjects (including dropouts and 
352 
withdrawals), regardless of whether CGM data are available or whether the closed loop system 
353 
was operational (if the event occurred during the CL period). Any adverse events that occurred 
354 
before the treatment initiation visit in period 1 or during the washout period will not be included 
355 
in the rate calculations or treatment group comparisons listed above. In all safety analyses, each 
356 
period will inclusively consist of all days in between the treatment initiation visit and the end of 
357 
treatment visit. If the subject drops out of the study in the middle of a period and the end of 
358 
treatment visit for that particular period does not occur, then the dropout date will be used as the 
359 
last day of the period.  
360 
The number of person-years for the incidence rate calculations in each period will be inclusively 
361 
defined as the number of person-years in between the treatment initiation visit date and the end 
362 
of treatment visit date. If the subject drops out of the study in the middle of a period and the end 
363 
of treatment visit for that particular period does not occur, then the dropout date will be used as 
364 
the last day of the period. 
365 
For each of DKA and SH (if enough events), the event rates will be compared using a repeated 
366 
measures Poisson regression model adjusting for period and whether the subject has ever had a 
367 

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prior event. Binary variables will also be compared using a repeated measures logistic regression 
368 
model adjusting for period and whether the subject has ever had a prior event.  
369 
9. Adherence and Retention Analyses 
370 
9.1 Utility Analysis 
371 
The amount of CGM use will be tabulated for each treatment arm, in addition to the amount of 
372 
closed loop system use in the CL arm. Summary statistics appropriate to the distribution and 
373 
range will be reported for the percentage of time using the CGM over the four month period (as 
374 
defined above) for each treatment group. The same will be done for the percentage of time using 
375 
the closed loop system in the CL arm. Tabulations of summary statistics will also be performed 
376 
for the percentage of time spent using the closed loop system while using the CGM in the CL 
377 
arm.  
378 
The percentage of time spent using the CGM will be calculated by dividing the total number of 
379 
CGM readings by the expected number of readings during the four-month period. The 
380 
percentage of time using the closed loop system in the CL arm will be calculated by dividing the 
381 
total amount of time that temporary basal infusion lasts no more than 30 minutes by the 
382 
maximum possible amount of time that the system could have been used. The percentage of time 
383 
using the closed loop system while using the CGM (in the CL arm) will then be computed by 
384 
dividing the time that the closed loop system was operational by the amount of time that the 
385 
CGM was available. 
386 
If a subject drops out of the study in the middle of a period, then the subject will be counted as 
387 
not using the CGM or the closed loop system at all during the remainder of the study. Thus, these 
388 
time points will be counted as zero use in the calculation of CGM use and closed loop system 
389 
use. 
390 
9.2 Protocol Adherence and Retention 
391 
The following tabulations and analyses will be performed to assess protocol adherence for the 
392 
study: 
393 
• Number of protocol and procedural deviations per subject along with the number and 
394 
percentage of subjects with each number of deviations 
395 
• Number of protocol and procedural deviations by severity with brief descriptions listed 
396 
• Flow chart accounting for all subjects at all visits post randomization to assess visit 
397 
completion rates 
398 
• A flow chart accounting for the number of subjects enrolled, the number of dropouts pre- 
399 
and post-randomization, and the number of subjects eligible to be included in the primary 
400 
analysis 
401 
• Number of and reasons for unscheduled visits 
402 
10. Baseline Descriptive Statistics 
403 
Baseline demographic and clinical characteristics of the cohort of all randomized subjects will be 
404 
summarized in a table. Descriptive statistics will be tabulated overall and by randomization 
405 
group. For continuous variables, summary statistics appropriate to the distribution will be given. 
406 
For discrete variables, number and percentage will be reported for each category. The following 
407 
baseline CGM metrics will be included in the table: 
408 

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• % Time in Range (3.9-10.0 mmol/L) 
409 
• Mean of sensor glucose levels 
410 
• Standard deviation of glucose levels 
411 
• Coefficient of variation of glucose levels 
412 
• % Time >10.0 and >16.7 mmol/L 
413 
• % Time <3.9, <3.5, and <3.0 mmol/L 
414 
• Area under the curve of glucose levels below 3.5 mmol/L and below 3.0mmol/L 
415 
11. Planned Interim Analyses 
416 
No formal interim analyses or stopping guidelines are planned for this study.  
417 
The DSMB will review data collected for the study every six months. The data to be reviewed will 
418 
include information regarding all of the following: 
419 
• Status of randomized participants 
420 
• Recruitment rates by month and by site 
421 
• Baseline demographic and clinical characteristics 
422 
• Dropped participants and reasons for discontinuing 
423 
• Reportable adverse events 
424 
12. Subgroup Analyses 
425 
No subgroup analyses are planned for this study.  
426 
13. Multiple Comparisons/Multiplicity 
427 
13.1 Primary analysis and other key secondary outcomes 
428 
For the primary endpoint and other key endpoints listed in section 4, the familywise type I error 
429 
rate (FWER) will be controlled at two-sided α = 0.05. A gatekeeping strategy will be used, where 
430 
the primary endpoint will be tested first, if passing the significance testing, other key endpoints 
431 
will be tested in the order listed below using the fixed-sequence method at α = 0.05: 
432 
• Time spent with sensor glucose levels between 3.9 to 10.0 mmol/l (70 to 180 mg/dl)  
433 
• Time spent above target glucose (10.0 mmol/l) (180 mg/dl) 
434 
• HbA1c 
435 
• Average of glucose levels 
436 
• Time spent below target glucose (3.9 mmol/l) (70 mg/dl) 
437 
Additional details are provided in section 6.3. 
438 
13.2 Other Secondary Analyses 
439 
For the other secondary endpoints listed in section 4, Benjamini-Hochberg false discovery rate 
440 
(FDR) adjusted p-values will be calculated within each subcategory below: 
441 
CGM derived indices: 
442 
• Standard deviation, and coefficient of variation of glucose levels 
443 
• Time with glucose levels <3.5 mmol/L (63 mg/dL) and <3.0 mmol/l (54 mg/dl) 
444 
• Time with glucose levels in significant hyperglycemia (glucose levels > 16.7 mmol/l) (300 
445 
mg/dl) 
446 
• AUC of glucose below 3.5 mmol/l (63 mg/dl) and below 3.0 mmol/l (54 mg/dl) 
447 

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Insulin and Other Endpoints: 
448 
• BMI standard deviation score 
449 
• Total, basal, and bolus insulin dose  
450 
Questionnaires: 
451 
• Strengths and Difficulties Questionnaire 
452 
o Emotional Problems Subscale 
453 
o Conduct Problems Subscale 
454 
o Hyperactivity Subscale 
455 
o Peer Problems Subscale 
456 
o Prosocial Subscale 
457 
o Total Difficulties Score 
458 
• Hypoglycemia Fear Survey 
459 
o Behavior Subscale 
460 
o Worry Subscale 
461 
• WHO-5 
462 
• Epworth Sleepiness Scale 
463 
Analyses by Time of Day: 
464 
• Percent time with glucose levels spent in the target range (3.9 to 10.0 mmol/L) 
465 
• Mean of glucose levels 
466 
• Standard deviation of glucose levels 
467 
• Percent time with glucose levels below 3.9 mmol/L 
468 
• Total insulin dose 
469 
During the extension phase, Benjamini-Hochberg false discovery rate (FDR) adjusted p-values 
470 
will be calculated within these subcategories: 
471 
CGM derived indices and HbA1c metrics: 
472 
• Time spent above target glucose (10.0 mmol/l) (180 mg/dl) 
473 
• HbA1c at 18 months 
474 
• Average of glucose levels 
475 
• Time spent below target glucose (3.9 mmol/l) (70 mg/dl) 
476 
• Standard deviation, and coefficient of variation of glucose levels 
477 
• Time with glucose levels <3.0 mmol/l (54 mg/dl) 
478 
• Time with glucose levels in significant hyperglycemia (glucose levels > 16.7 mmol/l) (300 
479 
mg/dl) 
480 
Insulin and Other Endpoints: 
481 
• BMI SDS 
482 
• Total, basal, and bolus insulin dose 
483 
Questionnaire Scores: 
484 
• Strengths and Difficulties Questionnaire 
485 
• Hypoglycemia Fear Survey 
486 
• WHO-5 
487 
• Epworth Sleepiness Scale 
488 

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• INSPIRE Survey 
489 
 
490 
14. Exploratory Analyses 
491 
No exploratory analyses will be performed for this study. 
492 
 
493 
15. Additional Analyses after Version 2.0 and Clarifications of Previous 
494 
Analyses 
495 
 
496 
 
497 
15.1 Post-Hoc Secondary Insulin Outcomes in Units/kg/day 
498 
Secondary insulin outcomes as previously outlined in section 7.4.2 were reported and tested in 
499 
Units/day.  Post-hoc analysis of secondary Insulin outcomes in Units/kg/day will parallel the 
500 
primary analysis. A ranked normal score transformation will be applied to all highly skewed 
501 
secondary outcomes. 
502 
Insulin outcomes measured in U/kg/day will be treated as missing for a period if either the 
503 
insulin dose or the patient’s weight is missing for that period. Previous measurements will not be 
504 
used to impute missing values 
505 
Benjamini-Hochberg false discovery rate (FDR) adjusted p-values will be calculated.  Post-hoc 
506 
secondary insulin outcomes in Units/kg/day will be added to the Insulin and Other Endpoints 
507 
subcategory previously defined in section 13.2.  Subcategory for FDR correction will now 
508 
include the following seven (7) outcomes:  
509 
• Old analyses: 
510 
o BMI standard deviation score 
511 
o Total insulin (Units/day) 
512 
o Basal insulin (Units/day) 
513 
o Bolus insulin (Units/day) 
514 
• New analyses: 
515 
o Total insulin (Units/kg/day) 
516 
o Basal insulin (Units/kg/day) 
517 
o Bolus insulin (Units/kg/day) 
518 
15.2 Post-Hoc Secondary Insulin Outcomes in Units/kg/day by Time of Day 
519 
Secondary total insulin outcome by time of day as previously outlined in section 7.5 was 
520 
reported and tested in Units/day.  Post-hoc analysis of secondary total insulin outcome in 
521 
Units/kg/day will parallel the primary analysis, with the inclusion of a treatment by time of day 
522 
interaction.  The p-value for the interaction term will be reported.  A ranked normal score 
523 
transformation will be applied to all highly skewed secondary outcomes. 
524 
Where weight is missing at a follow-up visit, insulin outcomes in U/kg/day will be treated as 
525 
missing. 
526 

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Benjamini-Hochberg false discovery rate (FDR) adjusted p-values will be calculated.  Post-hoc 
527 
secondary insulin outcomes by time of day in Units/kg/day will be added to the Analyses by Time 
528 
of Day subcategory previously defined in section 13.2.  Subcategory for FDR correction will 
529 
include the following six (6) outcomes:  
530 
• Old analyses: 
531 
o Percent time with glucose levels spent in the target range (3.9 to 10.0 mmol/L) 
532 
o Mean of glucose levels 
533 
o Standard deviation of glucose levels 
534 
o Percent time with glucose levels below 3.9 mmol/L 
535 
o Total insulin dose (Units/day) 
536 
• New analysis: 
537 
o Total insulin (Units/kg/day) 
538 
 
539 
15.3 Post-Hoc Secondary Tabulation by Time of Day 
540 
Summary statistics for the following outcome metrics will be tabulated separately for daytime 
541 
(defined as 8am to less than 12am) and nighttime (defined as 12am to less than 8am) over the 
542 
four month period:  
543 
• Basal insulin dose (Units/kg/day) 
544 
• Bolus insulin dose (Units/kg/day) 
545 
 
546 
15.4 Clarification for Secondary Outcomes 
547 
• Analysis of secondary HbA1c outcomes previously outlined in section 7.4.3. will parallel 
548 
the primary analysis. A ranked normal score transformation will be applied to all highly 
549 
skewed secondary outcomes.  
550 
 
551 
• Analysis of secondary clinical outcomes previously outlined in section 7.4.4. will parallel 
552 
the primary analysis. A ranked normal score transformation will be applied to all highly 
553 
skewed secondary outcomes.  
554 
 
555