Conditions: Type 1 Diabetes
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 38
Healthy volunteers: no

Brief summary:
The aims of the study are to see if additional insulin doses for the fat and protein in a meal, given at different times, improve blood glucose levels and are safe and acceptable to children with Type 1 diabetes using multiple daily insulin injections.

Detailed description:
The study design is a repeated measures study involving the provision of a standard high protein/high fat evening test meal on 3 different evenings within a 7-day period in the same study subject. The children/adolescents will be instructed to give an insulin dose for the carbohydrate before the meal (calculated using their optimal insulin to carbohydrate (ICR) - 20%). In addition they will have an additional dose for the fat and protein content either before (together with the dose for the carbohydrate in the meal \[control meal\]), 1 hour after, or 2 hours after the meal. These will be carried out in a random order in each subject. Continuous glucose monitoring (CGM) will be carried out for the whole 7 day period. Questionnaires will assess the acceptability to young people and their parents of the extra insulin doses.

After an initial contact in the clinic, and provision of patient information leaflets, the research nurse or dietitian will telephone the patient and family after a week to answer any questions they may have about the study. If they are keen to participate, an appointment will be arranged for consent and to commence the study (Visit 1).

At Visit 1 the investigators will obtain informed consent and commence a week-long run-in period for participants to optimise insulin to carbohydrate ratio at the evening meal. During this week subjects will be requested to test capillary blood glucose (BG) levels at 7 points throughout the day (pre-meals, 2 hrs after meals and bed). They will be asked to eat a fat and protein free meal on one of these days. If necessary, adjustments to the insulin to carbohydrate ratio (ICR) or long-acting insulin doses will be made over the telephone by an experienced member of their clinical team. This is to decrease the likelihood of a correction bolus for a high BG level being required at the evening meal during the study week.

At the end of the run-in week, participants will then attend the outpatient clinic or day care ward research facility at the Oxford Children's Hospital or the Horton Hospital outpatient clinic in Banbury or the Royal Berkshire Hospital in Reading (Visit 2). At this visit, the subcutaneous glucose sensor will be inserted by the research nurse and children and young people and their families will be trained on its use prior to the study commencing. CGM records glucose levels every 5 minutes over 7 days and thus provides much more information than routine capillary BG testing. It also alarms to alert patients of high and low glucose levels. Children and young people will also record their BG levels from routine finger pricks, pre-prandially and before bed and on waking in the morning.

Also at Visit 2, the study dietitian will review BG readings and food diary from the previous week and optimise ICR doses of rapid acting insulin. This ratio will then be used to calculate insulin doses for the study meals. On three evenings over the next 7 days, the children will eat a standard high protein/high fat meal. The evenings will not be set, but will depend on the child and family schedule. The child and family will be able to choose which days during the study period on which they complete the study meals but will be advised to avoid days when the participant has undertaken lots of exercise, has had frequent hypoglycaemic episodes or has been unwell.

The standard meal will be a portion controlled gluten-free meal provided and delivered by Wiltshire Farm Foods consisting of a meat-based main course and dessert. These will be kept frozen until used by participants and prepared according to manufacturer instructions. These meals come in two sizes which allow portion sizes to be adjusted for different ages of child, but the proportions of fat, protein and carbohydrate will be kept constant for each child, and by definition the meals will be high in protein and high in fat.

Insulin doses with the standard meal will be given according to calculations carried out by the dietitian and administered in one of three ways.

The three evenings in random order will be as follows:

1. Insulin units based on ICR minus 20%, and fat/protein dose given together immediately before the meal \[control meal\].
2. Insulin units based on ICR minus 20%, given immediately before the meal plus extra insulin for fat/protein units given 1 hour after the meal.
3. Insulin units based on ICR minus 20% given immediately before the meal plus extra insulin for fat/protein units given 2 hours after the meal.

Full written instructions will be provided to the family for all aspects of the insulin dosing for the study meals. During the study on the standardised meal days children will be instructed not to eat any food after the meal during the evening, and not to correct any later BG levels unless they are dangerously high (BG over 16 mmol/l with ketones over 0.5 mmol/l). If BG levels go low at any time (BG less than 4 mmol/l) children will be instructed to treat the hypoglycaemia according to their usual management. This data will be analysed separately. Children and families will be asked to complete diaries during the trial week.

At the end of the study period (the day after the third meal), children will come back to the research facility or clinic for the end of study visit (visit 3). A research nurse or dietitian will remove the CGM sensor and download the data onto a secure laptop. Children and their families will then be asked to complete a short questionnaire about the acceptability of using the extra insulin doses, and their perceptions as to whether there were any beneficial or adverse effects.

The study dietitian will calculate standard outcomes from each patient's sensor download and pass on anonymously to the study statistician to analyse the data.

Arms:
arm 1: Insulin dose (insulin Aspart, NovoRapid) for the fat and protein in a high-fat, high-protein meal is given at the same time as the insulin for the carbohydrate content BEFORE the meal. The dose is calculated on an individual basis according to the usual insulin to carbohydrate ratio for that child. arm 2: Insulin dose (insulin Aspart, NovoRapid) for the fat and protein in a high-fat, high-protein meal is given one hour after the meal. The dose is calculated on an individual basis according to the usual insulin to carbohydrate ratio for that child. arm 3: Insulin dose (insulin Aspart, NovoRapid) for the fat and protein in a high-fat, high-protein meal is given two hours after the meal. The dose is calculated on an individual basis according to the usual insulin to carbohydrate ratio for that child.

Interventions: intervention 1: Insulin, Asp(B28)-
Intervention descriptions: intervention 1: This insulin dose is sometimes given for fat and protein content of food in children using insulin pumps, in prolonged boluses. The investigators are replicating this in children using multiple insulin injections at various times related to the meal

Protocol document:
Prot_SAP_000.pdf: 
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Trial Title:  Investigation of Appropriate Timing of Additional Insulin Dosing for Fat and Protein in 
Children with Type 1 Diabetes using Multiple Daily Injections 
 
Internal Reference Number / Short title:   Fat and Protein Study 
Ethics Ref: 15/SC/0658 
EudraCT Number: 2015-003666-85 
Date and Version No: 1st April 2017 – version 4.0 
 
Chief Investigator: 
Dr Rachel Besser, Consultant in Paediatric Diabetes, Oxford University 
Hospitals NHS Trust 
Investigators:  
Ms Anne-Marie Frohock, Diabetes Dietitian, Oxford Health NHS Trust 
Jane Bowen-Morris, Lead Diabetes Research Nurse, Oxford University 
Hospitals NHS Trust. 
Clare Megson, Loraine Bunton and Alison West, Diabetes Research 
Nurses, Oxford University Hospitals NHS Trust 
Dr Chandan Yaliwal, Consultant in Paediatrics, Royal Berkshire Hospital 
NHS Trust, Reading UK 
Jason Oke, Senior Statistician, Nuffield Department of Primary Care 
Health Sciences, University of Oxford 
Sponsor:  
Oxford University Hospitals NHS Trust  
Funder: 
NovoNordisk Research Foundation 
Chief Investigator Signature:   
 
None of the investigators have any conflict of interest with this research proposal 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
 


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TABLE OF CONTENTS 
1. 
KEY TRIAL CONTACTS ............................................................................................................................. 4 
2. 
SYNOPSIS ............................................................................................................................................... 5 
3. 
ABBREVIATIONS ..................................................................................................................................... 6 
4. 
BACKGROUND AND RATIONALE ............................................................................................................ 7 
5. 
OBJECTIVES AND OUTCOME MEASURES ............................................................................................... 8 
6. 
TRIAL DESIGN ......................................................................................................................................... 9 
7. 
PARTICIPANT IDENTIFICATION ............................................................................................................ 13 
7.1. 
Trial Participants .......................................................................................................................... 13 
7.2. 
Inclusion Criteria .......................................................................................................................... 13 
7.3. 
Exclusion Criteria ......................................................................................................................... 13 
8. 
TRIAL PROCEDURES ............................................................................................................................. 14 
8.1. 
Recruitment ................................................................................................................................. 14 
8.1. 
Screening and Eligibility Assessment ........................................................................................... 14 
8.2. 
Informed Consent ........................................................................................................................ 14 
8.3. 
Randomisation, blinding and code-breaking ............................................................................... 15 
8.4. 
Baseline Assessments .................................................................................................................. 15 
8.5. 
Subsequent Visits ........................................................................................................................ 15 
8.6. 
Sample Handling .......................................................................................................................... 16 
8.7. 
Discontinuation/Withdrawal of Participants from Trial Treatment ............................................ 16 
8.8. 
Definition of End of Trial ............................................................................................................. 17 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ................................................................................. 17 
9.1. 
IMP Description ........................................................................................................................... 17 
9.2. 
Storage of IMP ............................................................................................................................. 17 
9.3. 
Compliance with Trial Treatment ................................................................................................ 17 
9.4. 
Accountability of the Trial Treatment ......................................................................................... 17 
9.5. 
Concomitant Medication ............................................................................................................. 17 
9.6. 
Post-trial Treatment .................................................................................................................... 17 
10. 
SAFETY REPORTING ......................................................................................................................... 17 
10.1. 
Definitions ............................................................................................................................... 17 
10.2. 
Causality .................................................................................................................................. 20 
10.3. 
Procedures for Recording Adverse Events .............................................................................. 20 
10.4. 
Reporting Procedures for Serious Adverse Events .................................................................. 21 
10.5. 
Expectedness ........................................................................................................................... 21 


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10.6. 
SUSAR Reporting ..................................................................................................................... 21 
10.7. 
Safety Monitoring Committee ................................................................................................. 21 
10.8. 
Development Safety Update Reports ...................................................................................... 21 
11. 
STATISTICS ....................................................................................................................................... 22 
11.1. 
Description of Statistical Methods .......................................................................................... 22 
11.2. 
The Number of Participants .................................................................................................... 22 
11.3. 
The Level of Statistical Significance ......................................................................................... 22 
11.4. 
Criteria for the Termination of the Trial .................................................................................. 22 
11.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. ...................................... 23 
11.6. 
Inclusion in Analysis ................................................................................................................. 23 
11.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ........................ 23 
12. 
DATA MANAGEMENT ...................................................................................................................... 23 
12.1. 
Source Data ............................................................................................................................. 23 
12.2. 
Access to Data ......................................................................................................................... 23 
12.3. 
Data Recording and Record Keeping ....................................................................................... 24 
13. 
QUALITY ASSURANCE PROCEDURES ............................................................................................... 24 
14. 
SERIOUS BREACHES ......................................................................................................................... 24 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 24 
15.1. 
Declaration of Helsinki............................................................................................................. 24 
15.2. 
Guidelines for Good Clinical Practice ...................................................................................... 24 
15.3. 
Approvals ................................................................................................................................. 24 
15.4. 
Reporting ................................................................................................................................. 25 
15.5. 
Participant Confidentiality ....................................................................................................... 25 
15.6. 
Expenses and Benefits ............................................................................................................. 25 
15.7. 
Other Ethical Considerations ................................................................................................... 25 
16. 
FINANCE AND INSURANCE .............................................................................................................. 25 
16.1. 
Funding .................................................................................................................................... 26 
16.2. 
Insurance ................................................................................................................................. 26 
17. 
PUBLICATION POLICY ....................................................................................................................... 26 
18. 
REFERENCES .................................................................................................................................... 26 
19. 
APPENDIX A:  SCHEDULE OF PROCEDURES ..................................................................................... 27 
20. 
APPENDIX B:  AMENDMENT HISTORY ............................................................................................. 28 
 
 
 


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1. KEY TRIAL CONTACTS 
 
Chief Investigator 
Dr Rachel Besser  
Consultant in Paediatric Diabetes 
Oxford Children’s Hospital 
Headington 
Oxford OX3 9DU 
 
rachel.besser@ouh.nhs.uk 
phone 01865 231673 
fax 01865 234211 
 
Sponsor 
 
Oxford University Hospitals NHS Trust 
Research and Development Department 
Joint Research Office 
Block 60, Churchill Hospital 
Headington 
Oxford. OX3 7LE 
Email: OUHTMA@nhs.net 
Fax: 01865 572242 
Statistician 
Jason Oke,  
Senior Statistician,  
Nuffield Department of Primary Care Health Sciences,  
University of Oxford 
Oxford  
 
jason.oke@phc.ox.ac.uk 
phone  
 
 
 
 
 


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2. SYNOPSIS 
 
Trial Title 
Investigation of Appropriate Timing of Additional Insulin Dosing for Fat and 
Protein in Children with Type 1 Diabetes using Multiple Daily Injections 
Internal ref. no. (or 
short title) 
Fat/Protein Study 
Clinical Phase  
Phase 4 
Trial Design 
Controlled observational study 
Trial Participants 
Children aged 6 to under 18 years of age with type 1 diabetes (T1DM) 
Planned Sample Size 
40 
Treatment duration 
1 week 
Follow up duration 
No follow-up at the end of the trial period 
Planned Trial Period 
1 year 
 
Objectives 
Outcome Measures 
Primary 
 
To determine whether additional 
insulin boluses for the fat and 
protein content of a meal given 
before, one or two hours after a 
meal optimise post-prandial 
blood glucose levels in children 
with Type 1 diabetes using 
multiple daily injections? 
Continuous subcutaneous glucose profiles 
will be examined to determine –  
 
mean post-prandial glucose excursion 
for 8 hours following the test meal 
 
Secondary 
 
To examine other indices of BG 
control following additional 
insulin boluses for the fat and 
protein content of a meal given 
before, one or two hours after a 
meal in children with Type 1 
diabetes using multiple daily 
injections? 
Continuous subcutaneous glucose profiles 
will be examined to determine –  
 
peak BG level 
 
peak BG excursion from baseline (pre-
meal BG level) 
 
time of peak BG level from baseline 
measurement 
 
Rate of BG excursion from baseline to 
peak 
 
mean post-prandial glucose excursion 
for 5 and 12 hours following the test 
meal 
 
area under the curve at time-points 0-3 
hours, 3-5 hours, 5-8 hours, 8-12 hours 
post-meal 
 
Time from baseline BG at which BG 
returns to baseline level 
Investigational 
Medicinal Product(s) 
Insulin 
Formulation, Dose, 
Route of Administration 
Insulin Aspart (NovoRapid) given in a dose according to the protocol, 
subcutaneously 


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3. ABBREVIATIONS 
 
AE 
Adverse event 
AR  
Adverse reaction 
BG 
Blood Glucose 
CGM 
Continuous subcutaneous glucose monitor 
CHO 
Carbohydrate 
CI 
Chief Investigator 
CRF 
Case Report Form 
CT 
Clinical Trials 
CTA 
Clinical Trials Authorisation 
DMC/DMSC 
Data Monitoring Committee / Data Monitoring and Safety Committee 
DSUR 
Development Safety Update Report 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICR 
Insulin to carbohydrate ratio 
IMP 
Investigational Medicinal Product 
IRB 
Independent Review Board 
MDI 
Multiple Daily Injections 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
NRES 
National Research Ethics Service  
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SMPC 
Summary of Medicinal Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 


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TMF 
Trial Master File 
TSG 
Oxford University Hospitals Trust / University of Oxford Trials Safety Group 
 
4. BACKGROUND AND RATIONALE 
Type 1 Diabetes incidence in children is increasing in the UK and internationally.  Blood glucose (BG) 
control is improved with intensive insulin therapy including multiple daily injections and insulin pump 
therapy, and long-term complications are known to be related to blood glucose control [1].  Post-
prandial BG levels have been linked with the risk of cardiovascular disease, one of the major 
complications of diabetes [2]. 
 
In order to keep BG levels as normal as possible, all children in our clinic on intensive insulin 
management are taught to match insulin dose to the carbohydrate quantity in food.  We and others have 
previously demonstrated that children and their families can learn to count the quantity of carbohydrate 
in food [3], and that the link between carbohydrate quantity and insulin dose does affect the post-
prandial BG level [4].   
There is increasing evidence that the fat and protein content of food affects BG levels in addition to the 
known effect of the carbohydrate content of the food. Pankowska’s group were the first to routinely 
count fat and protein in food, and to use this value to calculate additional insulin doses given as 
prolonged boluses in children using insulin pumps to maintain good BG control, demonstrating that 
those children who used such doses and boluses were more likely to achieve target levels of control [5].  
Subsequent studies by the same group and others have refined the technique to demonstrate improved 
PPBG levels in children using insulin pumps [6,7].   
A recent study by Smart et al has shown that the post-prandial BG levels can remain high for several 
hours after high fat and high protein meals when insulin is given purely for the carbohydrate content [8].  
Furthermore, the effect is additive, with high protein and high fat meals causing high post-prandial BG 
levels which had not returned to pre-prandial levels up to 6 hours after a meal [8].   
A recent systemic review of ten studies examining insulin bolus dose and delivery patterns required for 
high fat and/or high protein meals has generated recommendations for clinical practice [9].  Although all 
the studies included have been conducted in patients using insulin pumps (adults and children) the 
authors have extrapolated their conclusions to make recommendations for changes to insulin dose 
calculations and delivery options in both CSII and MDI therapy. 
It is suggested that for high fat meals containing over 40g fat that insulin doses should initially be 
increased by 30-35% on the usual dose calculated using their ICR with the extra insulin given as a 
separate injection 1 hr after the meal.  This dose should be monitored and increased according to 
individual response [9]. 
They also recommend that for meals containing 30g fat and 40g protein that the insulin dose calculated 
with usual insulin:carbohydrate ratios should be increased by 15-20% but do not suggest a delivery 
method for this extra insulin [9].  It should be noted that all these recommendations are intended for an 
adult population. 


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The review recognises gaps in knowledge and evidence base to support specific recommendations and 
algorithms to calculate insulin doses and delivery patterns according to the fat and protein content of 
meals.  Furthermore, they identified significant inter-individual variability in post-prandial glycaemic 
response to high fat and protein meals which may be a confounding factor to research and meaningful 
conclusions in this area [9]. 
We therefore plan to investigate how to appropriately administer additional insulin for the fat and 
protein content of high protein and high fat meals to children on multiple daily injections (MDI) to 
improve BG levels up to 12 hours after a meal.   
In line with our previous studies (3,4) and as indicated from a power calculation, we will recruit forty 
patients from the Oxfordshire Children’s Diabetes Service aged from 6 to under 18 years and obtain full 
informed consent.  There will be a run-in period of 7 days during which time the children’s insulin to 
carbohydrate ratios will be optimised. 
The children will then be asked to wear continuous subcutaneous glucose monitors (CGM) which are a 
well-recognised and validated method of monitoring BG levels over several days.  The particular version 
we will use for this study lasts for 7 days. 
During the 7 day study period, the children will be asked to consume a standard high-fat, high-protein 
test meal on 3 separate evenings.  They will asked to give insulin for the carbohydrate (CHO) content of 
the meal before the meal on all 3 days.  Additional insulin will be calculated for the fat and protein 
content on the basis of the Pankowska equation [6] and recommendations from the most recent 
systemic review of current research [9] and will be given in a random order, either before, 1 hour after, 
or 2 hours after the first insulin dose before meal. The child and family will be able to choose which days 
during the study period on which they complete the study meals but will be advised to avoid the day that 
the CGM sensor was inserted, days when the participant has undertaken lots of exercise, is 
hypoglycaemic immediately before the meal, or has had frequent hypoglycaemic episodes earlier in the 
day or has been unwell. 
BG levels will be monitored using the CGM for the evening and overnight until the next morning.   
5. OBJECTIVES AND OUTCOME MEASURES 
Objectives 
Outcome Measures  
Timepoint(s) 
of 
evaluation of this 
outcome measure 
(if applicable) 
Primary Objective 
To determine whether additional 
insulin boluses for the fat and 
protein content of a meal given 
before, one or two hours after a 
meal optimise post-prandial blood 
glucose levels in children with Type 1 
diabetes using multiple daily 
Continuous subcutaneous glucose profiles 
will be examined to determine –  
 
mean post-prandial glucose excursion 
for 8 hours following the test meal 
 
Continuous Glucose 
Monitoring profiles 
during the 12 hours 
following the test 
meals 


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injections? 
Secondary Objectives 
To examine other indices of BG 
control following additional insulin 
boluses for the fat and protein 
content of a meal given before, one 
or two hours after a meal in children 
with Type 1 diabetes using multiple 
daily injections? 
Continuous subcutaneous glucose profiles 
will be examined to determine –  
 
peak BG level 
 
peak BG excursion from baseline (pre-
meal BG level) 
 
time of peak BG level 
 
timing of peak BG excursion 
area under the curve at time-points 0-3 
hours, 3-5 hours, 5-8 hours, 8-12 hours 
post-meal 
Continuous Glucose 
Monitoring profiles 
during the 12 hours 
following the test 
meals 
Tertiary Objectives 
1.  To assess the acceptability of 
giving additional insulin doses for fat 
and protein to children using MDI 
2.  To assess the safety of giving 
additional insulin doses for fat and 
protein to children using MDI 
1.  Questionnaires to parents and children 
during and at the end of the study 
2.  All episodes of hypoglycaemia (BG less 
than 4 mmol/l) or hyperglycaemia (BG >12 
mmol/l) either on CGM or self-monitoring 
of BG 
 
Collection of data 
during and at the 
end of the study 
 
6. TRIAL DESIGN 
6.1. Summary –  
The study design is a repeated measures study involving the provision of a standard high protein/high fat 
evening test meal on 3 different evenings within a 7-day period in the same study subject.  The 
children/adolescents will be instructed to give an insulin dose for the carbohydrate before the meal 
(calculated using their optimal insulin to carbohydrate ratio (ICR)).  In addition they will have an extra 
dose for the fat and protein content either before (together with the dose for the carbohydrate in the 
meal [control meal]), 1 hour after, or 2 hours after the first insulin dose given before the meal.  These 
will be carried out in a random order in each subject.  Glucose monitoring will be carried out using CGM 
for the whole 7 day period. 
 
 


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6.2. Study Flow Chart -  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 - Screening (may be carried out in routine clinic 
appointment) 
Eligibility, informed consent 
Provide blood glucose and food diary for a 7 day run in period  
HbA1c if not done within 3 months 
Dietitian to order study meals for delivery to participant’s home 
Visit 2 (generally one week after screening visit) 
 
Final assessment of ICR 
 
Insertion of CGM 
 
Randomisation of order of insulin delivery 
 
Study instructions, including insulin doses, and record 
sheet given to family 
 
Staff 24hour contact details provided to family in case 
of problems  
Participant wears CGM at home  
Eats standard test meal on 3 nights 
during week 
Visit 3(one week after visit 1) 
 
Removal of CGM 
 
Show patients download if interested to see it 
 
Child and parent to complete acceptability 
questionnaires 
 
End of study 
 
Give family expense claim form 
 Contact by  dietitian during week running up to Visit 1 
 
first at 3 days 
 
second at 5-6 days  to optimise ICR 


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6.3. Detail –  
The clinical diabetes team in each participating hospital will identify children in the service who are using 
multiple daily injections to manage their diabetes and who would be eligible for the study.  In addition, in 
Oxford, an e-mail will be sent to all patients signed up to the e-mail service to alert them that the study is 
open to recruitment.  The study will also be advertised in the Oxford 3 monthly newsletter and families 
could volunteer if they are interested in their children taking part.  There will also be a poster made for 
both the Oxford and Reading clinics to advertise the study.  Once the family has expressed an interest in 
hearing more about the study, the relevant information sheets will be handed to the patients in clinic or 
sent by post.   
After the initial contact, the research nurse or dietitian will telephone the patient and family after a week 
to answer any questions they may have about the study.  If they are keen to participate, an appointment 
will be arranged for consent and to commence the study (Visit 1).  If the patient or family do not wish to 
take part at this point this would be documented on the approach log.   
At Visit 1 we will obtain informed consent (see section 7.2) and commence a week-long run-in period for 
participants to optimise insulin to carbohydrate ratio at the evening meal.  During this week subjects will 
be requested to test BG levels at 7 points throughout the day (pre-meals, 2 hrs after meals and bed).  
They will be asked to eat a fat and protein free meal on one of these days.  If necessary, adjustments to 
the insulin to carbohydrate ratio (ICR) or long-acting insulin doses will be made over the telephone or via 
email by an experienced member of their clinical team.  This is to decrease the likelihood of a high or low 
BG level at the evening meal during the study week which would require the meal to be abandoned.   
At the end of the run-in week, participants will then attend the outpatient clinic or day care ward 
research facility at the Oxford Children’s Hospital or the Horton Hospital outpatient clinic in Banbury or 
the Royal Berkshire Hospital in Reading (Visit 2).  At this visit, the subcutaneous glucose sensor will be 
inserted by the research nurse and children and young people and their families will be trained on its use 
prior to the study commencing.  CGM records BG levels every 5 minutes over 7 days and thus provides 
much more information than routine BG testing. These systems are regularly used by the Paediatric 
Diabetes team in clinical care and are well accepted by patients.  The CGM records will enable 
researchers to calculate the area under the curve for post-prandial BG response to determine if there are 
significant differences between the test insulin dosing schedules.  Children and young people will also 
record their BG levels from routine finger pricks, pre-prandially and before bed and on waking in the 
morning. 
We considered using a blinded CGM system which does not reveal current blood glucose levels in order 
to reduce participant and parental anxiety, however the only system like this on the market does not 
alarm on hypoglycaemia which is an essential safety measure for this study and this option was therefore 
rejected. 
Also at Visit 2, the study dietitian will review BG readings and food diary from the previous week and 
optimise ICR doses of rapid acting insulin.  This ratio will then be used to calculate insulin doses for the 
study meals according to the following algorithm based on the Pankowska (Warsaw) equation [6] and 
recommendations from the latest systemic review of current research [9] 


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Insulin dose for carbohydrate = g CHO x ICR 
Insulin dose for fat and protein = FPU x (0.3 x ICR)  
TOTAL Insulin dose = (g carbs x ICR) + (FPU x (0.3 x ICR)) 
Where FPU = fat-protein unit and 1 FPU = 100kcal from fat and protein 
On three evenings over the next 7 days, the children will eat a standard high protein/high fat meal.  The 
evenings will not be set, but will depend on the child and family schedule.  The study meal will not be 
eaten on the evening that the CGM is inserted as sensor accuracy takes 24 hours to maximise accuracy.  
The child and family will be able to choose which days during the study period on which they complete 
the study meals but will be advised to avoid days when the participant has undertaken lots of exercise, is 
hypoglycaemic immediately before the meal or has had frequent hypoglycaemic episodes, or has been 
unwell.   
The standard meal will be a portion controlled gluten-free meal provided and delivered by Wiltshire 
Farm Foods consisting of a meat-based main course and dessert.  These will be kept frozen until used by 
participants and prepared according to manufacturer instructions.  These meals come in two sizes which 
allow portion sizes to be adjusted for different ages of child, but the proportions of fat, protein and 
carbohydrate will be kept constant for each child, and by definition the meals will be high in protein and 
high in fat.  
Insulin doses with the standard meal will be given according to calculations carried out by the dietitian 
and administered in one of three ways.  
The three evenings in random order will be as follows -  
1. Insulin units based on ICR and fat/protein dose given together immediately before the meal 
[control meal]. 
2. Insulin units based on ICR given immediately before the meal plus extra insulin for fat/protein 
units given 1 hour after the first meal dose. 
3. Insulin units based on ICR given immediately before the meal plus extra insulin for fat/protein 
units given 2 hours after the first meal dose.   
Participants will be asked not to give a correction dose before the meal if the BG level is between 7-
12mmol/l as this would interfere with the analysis.  They will be asked, if possible, not to carry out the 
test meals if their pre-meal BG is greater than 12 mmol/l But  If they have to do the test meal with a high 
pre-meal BG (above 12 mmol/l) they will be instructed to give their usual correction bolus in addition to 
the prescribed insulin dose for the test meal.  This data will be analysed separately.  If BG is below 
4mmol/l (hypoglycaemic) or above 16mmol/l participants will be asked to abandon the study evening 
and repeat on another evening.  Full written instructions will be provided to the family for all aspects of 
the insulin dosing for the study meals.   
During the study on the standardised meal days children will be instructed not to eat any food after the 
meal during the evening, and not to correct any later BG levels unless they are dangerously high (BG over 
16 mmol/l with ketones over 0.5 mmol/l).  If BG levels go low at any time (BG less than 4 mmol/l) 
children will be instructed to treat the hypoglycaemia according to their usual management, and omit 


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any further study doses of insulin if the hypoglycaemia occurs after a first study dose and a second is 
due. This data will be analysed separately.  Children and families will be asked to complete diaries during 
the trial week. 
At the end of the study period (the day after the third meal), children will come back to the research 
facility or clinic for the end of study visit (visit 3).   A research nurse or dietitian will remove the CGM 
sensor and download the data onto a secure laptop.  Children and their families will then be asked to 
complete a short questionnaire about the acceptability of using the extra insulin doses, and their 
perceptions as to whether there were any beneficial or adverse effects.   
The study dietitian will calculate standard outcomes from each patient’s sensor download and pass on 
anonymously to the study statistician to analyse the data.  
 
7. PARTICIPANT IDENTIFICATION 
7.1. Trial Participants 
Children and young people aged between 6 and under 18 years with Type 1 diabetes on multiple insulin 
injection regimes who are under regular out-patient review by the Oxfordshire Children’s Diabetes 
Service or the Royal Berkshire Children’s Diabetes Service.   
7.2. Inclusion Criteria 
 
Diagnosis of Type 1 diabetes (for at least a year)  
 
Aged 6 to under 18 years.  
 
On multiple daily insulin injections, including basal long-acting insulin and rapid-acting insulin 
before each meal. 
 
HbA1c < 75 mmol/mol (9.0%) 
 
Participant and/or parent/legal guardian willing and able to give informed consent for 
participation in the study. 
 
Family have a freezer in which to safely store the test meals. 
 
In the Investigator’s opinion, is able and willing to comply with all trial requirements. 
7.3. Exclusion Criteria 
The participant may not enter the trial if ANY of the following apply: 
 
HbA1c greater than 75 mmol/mol (9.0%) 
 
Child unwilling to agree to second insulin injection at a meal-time 
 
Untreated coeliac disease or other concomitant condition likely to affect BG control 
 
Food allergies (other than controlled Coeliac Disease) 


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 
Vegetarians, vegans or patients with religious dietary restrictions (as the standard meal contains 
meat) 
 
Participant taking any glucose-containing medication concurrently 
8. TRIAL PROCEDURES 
8.1. Recruitment 
The clinical diabetes team in each participating hospital will identify children in the service who are using 
multiple daily injections to manage their diabetes and who would be eligible for the study.  In addition, in 
Oxford, an e-mail will be sent to all eligible patients’ families signed up to the e-mail service to alert them 
that the study is open to recruitment.  In Oxford, the study will be advertised generally in the routine 3 
monthly newsletter which is available in the clinic, with details of who to contact for more information 
about the study.  Once the family has expressed an interest in hearing more about the study, the 
participant and parent information sheet will be given to eligible children and young people and their 
parents at their routine diabetes clinic visit or sent in the post if interest has been expressed.   
The information sheets will provide contact details of the researchers if the potential participants want 
more information before making a decision.  After allowing a week for the child and parent to read the 
information sheets, the research nurse or dietitian will telephone the family asking if they have any 
further questions about the study, to provide further information, and enquire if the child and family are 
willing to consent.  If they are willing to participate, an appointment will then be made to obtain 
informed consent.   
8.1. Screening and Eligibility Assessment 
The HbA1c level taken at the preceding clinic (maximum of 3 months before approach) will be used to 
assess eligibility.  If the clinic visit was more than 3 months before the start of the study, a further HbA1c 
level will be measured by rapid analysis at the time of the first visit.  All other screening and eligibility 
assessments can be carried out on the telephone by the research nurse or research dietitian.   
8.2. Informed Consent 
Informed consent will be undertaken by a nurse or doctor on the research or clinical team who has had 
GCP training with specific training in informed consent and has been authorised to do so by the Chief 
Investigator.  Verbal and written information will be given to potential participants detailing no less than: 
the exact nature of the study; what it will involve for the participant; the implications and constraints of 
the protocol; and any risks involved in taking part. It will be clearly stated that the participant is free to 
withdraw from the study at any time for any reason without prejudice to future care, and with no 
obligation to give the reason for withdrawal. Information will be presented to children and young people 
both verbally and in written form in an age- appropriate manner. Written assent will be sought from 
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The participant will be allowed as much time as wished to consider the information and will be given the 
opportunity to question the doctor or nurse, their consultant, their GP or other independent parties to 
decide whether they will participate in the study.  
Written Informed Consent will then be obtained by means of parent/legal guardian dated signature and 
dated signature of the person who presented and obtained the Informed Consent.  A copy of the signed 
Informed Consent will be given to the participant.  The original signed form will be retained at the study 
site. For children >8 years of age a dated signature will be sought on an assent form.  Young people over 
the age of 16 will be able to sign their own consent form. 
The parent/legal guardian or young person over the age of 16 must personally sign and date the latest 
approved version of the informed consent form before any trial specific procedures are performed. 
8.3. Randomisation, blinding and code-breaking 
Randomisation is required only for the order of the insulin dosing.  The study statistician will provide the 
randomisation codes and the study dietitian will make up sealed envelopes with all the instructions 
inside for the schedule for the participant according to the randomised order of treatment.  This 
schedule will form part of the study diary for each participant.  The envelopes will be kept in the research 
office in Oxford until they are needed, when the next one will be taken for the next participant entering 
the study at any of the participating sites.  The envelope will be opened by the research nurse or dietitian 
at the first study visit when the CGM is being inserted.  As the same research team will be working at all 
sites there is no requirement for separate codes for each site. 
Unblinding will not be required as this is not a blinded study.  Participants and researchers will know the 
order of the insulin doses for the test meal from the start of the study.   
8.4. Baseline Assessments 
At visit 1, after the informed consent and assent forms have been signed, the dietitian will collect details 
of the insulin to carbohydrate ratios currently being used at the evening meal-time.  A record book will 
be provided to the child and family to record their blood glucose levels, carbohydrate quantities and 
insulin doses for the run-in week. During the run in week the participant will be requested to record 
blood glucose levels before and 2 hours after meals, snacks and before bed. They will also be asked to 
record CHO intake and insulin doses given.  
After 3 days the dietitian will telephone to obtain BG levels and work out whether any adjustments need 
to be made to the ratios.  A further telephone call will be made on day 5-6, with further adjustment if 
necessary.  After this first visit, the study meals will be ordered by the dietitian or nurse to be delivered 
to the participant’s home.   
 
8.5. Subsequent Visits 
Visit 2 – Study visit 


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 
A review of the BG levels in the preceding week will be carried out by the study dietitian, in order 
to determine whether any further adjustments in insulin dose need to be made.   
 
The CGM will be inserted.   
 
Randomisation of the insulin dose order will be carried out and final dose calculations will be 
done by the dietitian according to the equations in section 5.3. 
 
Full written instructions will be provided to the participants, including insulin doses and timings 
for the three study meals, contact details and what to do if BG levels should be high (greater 
than 16mmol/L) or low (less than 4mmol/L).   
 
There will also be instructions about what they should do in the event of a sensor malfunction.   
 
The child and family will be informed that they can call the research team during office hours at 
any stage to discuss events during the week of the study, and they will be provided with contact 
details.  If any advice is required outside office hours, they will be advised to contact their clinical 
diabetes team in the usual way.   
Visit 3: End of study visit - The participant will return to their original outpatient or day-care setting and 
the CGM sensor will be removed by the study nurse and data downloaded onto the web-based system 
Diasend which is regularly used in clinics.  Participants and their family will have the opportunity of 
viewing the download from the sensor.  The participant and parent will be asked to complete the short 
questionnaires about the acceptability of the additional insulin doses. 
8.6. Sample Handling 
No samples will be taken during the trial.  The only sample for eligibility is the HbA1c finger-prick sample 
which will be taken and managed routinely according to protocols in the relevant clinical service.   
8.7. Discontinuation/Withdrawal of Participants from Trial Treatment 
Each participant has the right to withdraw from the trial at any time.  In addition, the Investigator may 
discontinue a participant from the trial at any time if the Investigator considers it necessary for any 
reason including: 
 
Pregnancy 
 
Ineligibility (having been overlooked at screening) 
 
Significant protocol deviation 
 
Significant non-compliance with treatment regimen or trial requirements 
 
Severe hypoglycaemia occurring during the trial week, whether or not this is as a result of the 
evening meal dose of insulin 
 
Withdrawal of Consent 
 
Loss to follow up 
Any CGM data available up to the time of patient withdrawal or exclusion will be included in the data 
analysis.  
The reason for withdrawal will be recorded in the CRF. 
If the participant is withdrawn due to an adverse event, the Investigator will arrange for follow-up visits 
or telephone calls until the adverse event has resolved or stabilised. 


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8.8. Definition of End of Trial 
The end of trial is the date of the last visit of the last participant. 
 
9. INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
9.1. IMP Description 
The trial IMP is Insulin Aspart (NovoRapid).  This is provided to the participant as part of normal standard 
care. The trial medication will be dispensed according the standard procedures at each site and is being 
used in its normal indication and standard therapeutic dose. The only change in this study is the insulin 
dosage around the evening meal.    
9.2. Storage of IMP 
No specific storage requirement above those stated for standard care are required for the IMP in this 
trial. There will be no temperature monitoring for the IMP.  
9.3. Compliance with Trial Treatment 
Participants and their families will be asked to complete a diary including the actual insulin doses given.  
This will be viewed at the end of the study and data may be removed from analysis if significant non-
compliance has occurred, for example the advised dose was not given, or the timing was not accurate to 
within 15 minutes.   
9.4. Accountability of the Trial Treatment 
IMP is supplied as part of normal standard care and therefore no accountability records will be 
maintained for the trial.   
9.5. Concomitant Medication 
Any glucose-containing medication is contraindicated. 
9.6. Post-trial Treatment 
Not relevant for this trial 
10. SAFETY REPORTING 
10.1. 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal 
product has been administered, including occurrences which are not 


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necessarily caused by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
The phrase "response to an investigational medicinal product" means 
that a causal relationship between a trial medication and an AE is at 
least a reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional 
or the Sponsor as having a reasonable suspected causal relationship to 
the trial medication qualify as adverse reactions. 
Serious 
Adverse 
Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
 results in persistent or significant disability/incapacity 
 consists of a congenital anomaly or birth defect. 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
Serious Adverse Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to one of the trial treatments, based on the information provided. 
Suspected 
Unexpected 
Serious Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out: 
 in the case of a product with a marketing authorisation, in the 
summary of product characteristics (SmPC) for that product 
 in the case of any other investigational medicinal product, in the 
investigator’s brochure (IB) relating to the trial in question. 
 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, 
the following note of clarification is provided: “Severe” is often used to describe intensity of a specific 


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event, which may be of relatively minor medical significance. “Seriousness” is the regulatory definition 
supplied above. 
Any pregnancy occurring during the clinical trial and the outcome of the pregnancy should be recorded 
and followed up for congenital abnormality or birth defect, at which point it would fall within the 
definition of “serious”. 
 
 


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10.2. 
Causality 
The relationship of each adverse event to the trial medication must be determined by a medically 
qualified individual according to the following definitions: 
Related: The adverse event follows a reasonable temporal sequence from trial medication 
administration. It cannot reasonably be attributed to any other cause. 
Not Related: The adverse event is probably produced by the participant’s clinical state or by other 
modes of therapy administered to the participant. 
10.3. 
Procedures for Recording Adverse Events 
As insulin is a well-known IMP, not all non-serious AEs will be recorded.  Mild hypoglycaemia responding 
to treatment does not need to be reported as an AE, but will be recorded on the daily diary as well as on 
the CGM records.   
Children with Type 1 diabetes are always at risk of hypoglycaemia which may result in hospitalisation.  It 
is not anticipated that the project would increase the risk of severe hypoglycaemia (a low blood glucose 
level that is associated with unconsciousness or convulsion) but a child/young person may have one of 
these episodes during the study.  The participants will all be wearing a continuous glucose monitor with 
an alarm if the BG becomes low or high.  The alarm will therefore warn the participant and family if the 
BG level falls below a certain level, reducing the risk of severe hypoglycaemia. However severe 
hypoglycaemia resulting in unconsciousness or convulsions would be reported immediately as a SAE (see 
below).   
The child and family will be informed that they can call the research team during office hours at any 
stage to discuss events during the week of the study, and they will be provided with contact details.  If 
any advice is required outside office hours, they will be advised to contact their clinical diabetes team in 
the usual way.  
It is not anticipated that the CGM will cause any adverse effects.  However infection or inflammation at 
the insertion site would be reported at the end of the trial as an AE.  If the sensor stops working or needs 
to be replaced for any reason during the trial week, this does not need to be reported as an AE, but the 
participant or family will contact the research team to have it re-sited. 
 
The following information will be recorded for all reportable AEs: description, date of onset and end 
date, severity, assessment of relatedness to trial medication, other suspect drug or device and action 
taken.  Follow-up information should be provided as necessary. 
AEs considered related to the trial medication as judged by a medically qualified investigator or the 
Sponsor will be followed either until resolution, or the event is considered stable. 
It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient 
severity to require the participant’s removal from treatment.  A participant may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE.  If either of these occurs, 
the participant must undergo an end of trial assessment and be given appropriate care under medical 
supervision until symptoms cease, or the condition becomes stable. 


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10.4. 
Reporting Procedures for Serious Adverse Events 
All SAEs (other than those defined in the protocol as not requiring reporting) must be reported on the 
Oxford University Hospitals NHS Trust SAE reporting form to OUH study team within 24 hours of the Site 
Study Team becoming aware of the event by email or fax. 
Once the SAE has been received the OUH study team will forward the report to the R&D office 
immediately. SAE reports should be faxed or emailed to: (01865) 572242 or ouhsae.reports@nhs.net 
R&D will perform an initial check of the report, request any additional information, and ensure it is 
reviewed by the Medical Monitor on a weekly basis.  It will also be reviewed at the next Trial Safety 
Group meeting.  All SAE information must be recorded on an SAE form and faxed, or scanned and 
emailed, to R&D.  Additional and further requested information (follow-up or corrections to the original 
case) will be detailed on a new SAE Report Form and faxed/emailed to R&D. 
10.5. 
Expectedness 
Expectedness will be determined according to the Summary of Product Characteristics.   
10.6. 
SUSAR Reporting 
All SUSARs will be reported by the CI to the relevant Competent Authority and to the REC and other 
parties as applicable. For fatal and life-threatening SUSARS, this will be done no later than 7 calendar 
days after the Sponsor or delegate is first aware of the reaction. Any additional relevant information will 
be reported within 8 calendar days of the initial report. All other SUSARs will be reported within 15 
calendar days. 
Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the same 
Sponsor, whether or not the event occurred in the current trial. 
10.7. 
Safety Monitoring Committee 
The Oxford University Hospitals Trust / University of Oxford Trials Safety Group (TSG) will conduct a 
review of all SAEs for the trial reported during the quarter and cumulatively. The aims of this committee 
include: 
 
To pick up any trends, such as increases in un/expected events, and take appropriate action 
 
To seek additional advice or information from investigators where required 
 
To evaluate the risk of the trial continuing and take appropriate action where necessary 
10.8. 
Development Safety Update Reports 
The CI will submit (in addition to the expedited reporting above) DSURs once a year throughout the 
clinical trial, or on request, to the Competent Authority (MHRA in the UK), Ethics Committee, Host NHS 
Trust and Sponsor. 
 
 


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11. STATISTICS 
This section has been written by our statistician. 
11.1. 
Description of Statistical Methods 
Descriptive statistics will be used to describe the group demographics and outcomes.  
 
The continuous glucose records will be analysed methodically by the CI, research dietitian and 
statistician.  Data to be obtained include –  
• 
pre-meal BG level 
• 
peak BG level 
• 
peak BG excursion from baseline at 3, 5, 8 and 12 hours following the meal 
• 
time of peak BG level 
• 
time of peak BG excursion 
• 
area under the curve at time-points 0-4 hours, 4-6 hours, 6-8 hours, 8-12 hours post-
meal 
The relationship between the insulin timing and the mean change in postprandial blood glucose levels 
will be analysed and described. 
Comparisons using paired t tests for normally distributed data, and Mann-Whitney U tests for non-
parametric data will be used to examine the differences in areas under the postprandial BG curves and 
the postprandial BG levels by insulin timing.  
11.2. 
The Number of Participants 
We estimate that using a three-treatment, three period cross-over design, 36 people will achieve 80% 
power to detect a 2 mmol/L difference in mean 5 hour postprandial glucose excursion at the 5% 
significance level. Although we do not anticipate any losses to follow-up or withdrawals due to side-
effects from the study we will aim to recruit 40 to ensure power is maintained if this does arise.  This 
power calculation has been carried out by our study statistician. 
In order to allow for drop-outs, we have made the decision to recruit 40 patients.   
Previous intervention studies of fat/protein interventions in children using insulin pumps have used 24-
42 patients with significant differences in BG levels at the 0.04 and 0.03 levels of significance (5-8). 
11.3. 
The Level of Statistical Significance 
P<0.05 will be used to demonstrate statistical significance. 
11.4. 
Criteria for the Termination of the Trial 
We would only anticipate 10 episodes of severe hypoglycaemia in 340 patients per year.  Therefore the 
likelihood of a severe hypo occurring during this study under normal circumstances would be very small.   
So if we assume there is no increase in risk then we would only expect to see 2 severe hypos in one of 
the two arms in 3 out of every 10,000 trials, for a single hypo in either arm this increases to about 1 in 
every 100 trials. Therefore we would terminate the trial if we had 2 severe hypos occurring on any arm 
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11.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. 
We will use boxplots to identify outlying, unusual or spurious data using pre-defined decision rules (e.g. 
upper or lower quartiles +- 1.5*IQR). In the case of implausible or unlikely outcome data we will look 
back at CRF’s to rule out data handling errors. If outliers cannot be resolved then we will exclude this 
particular result from the main analysis.  We intend to use a complete case analysis  but we will conduct 
to a sensitivity analysis  to assess the impact of any missing data using appropriate multiple imputation 
methods. 
11.6. 
Inclusion in Analysis 
All data available from all participants will be used for the analyses.  If a child has become hypoglycaemic 
(BG <4.0mmol/l) during the profile period then subsequent data will be analysed separately.  If any child 
has had to treat a high BG level with additional insulin (except for a correction dose at the evening meal), 
then subsequent profile data will be analysed separately.  However in either instance, the data up to the 
event will be included in all analyses.  The two other meals would still be eligible for the study analyses if 
there were no similar events.   
If there have been any protocol breaches, such as further food during the evening after the main meal, 
then all the subsequent data will not be used in the analysis for that meal.  Education of the participants 
and parents will be vital to ensure that such eventualities are rare.   
11.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
The trial protocol will be made available to reviewers of any publication arising from this study. Any 
amendments to the original protocol or additional analysis not previously specified in the protocol will 
also be made available to reviewers. 
12. DATA MANAGEMENT 
12.1. 
Source Data 
Source documents will be the hospital records for the basic demographics and HbA1c level.  During the 
trial they will be the patient diaries, both during the run-in week and for the trial week.  This is where 
data is first recorded, and from which participants’ CRF data are obtained.  
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no 
other written or electronic record of data).  All documents will be stored safely in confidential conditions. 
On all trial-specific documents, other than the signed consent, the participant will be referred to by the 
trial participant number/code, not by name. 
12.2. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
 


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12.3. 
Data Recording and Record Keeping 
All trial data will be entered on to paper CRFs and/or a to an Excel spreadsheet (Microsoft Office).   
The participants will be identified by a unique trial specific number and/or code in any database.  The 
name and any other identifying detail will NOT be included in any trial data electronic file. 
All study data will be held until the last participant has reached the age of 21 or up to 5 years from the 
end of the trial, whichever is the later date. 
13. QUALITY ASSURANCE PROCEDURES 
Regular monitoring will be performed by authorised individuals from the sponsor according to GCP. 
14. SERIOUS BREACHES 
The Medicines for Human Use (Clinical Trials) Regulations contain a requirement for the notification of 
"serious breaches" to the MHRA within 7 days of the Sponsor becoming aware of the breach. 
A serious breach is defined as “A breach of GCP or the trial protocol which is likely to affect to a 
significant degree –  
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial”. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In 
collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if appropriate, the 
Sponsor will report it to the REC committee, Regulatory authority and the NHS host organisation within 
seven calendar days. 
15. ETHICAL AND REGULATORY CONSIDERATIONS 
15.1. 
Declaration of Helsinki 
The Investigator will ensure that this trial is conducted in accordance with the principles of the 
Declaration of Helsinki. 
15.2. 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this trial is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
15.3. 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to an appropriate Research Ethics Committee (REC), regulatory authorities 
(MHRA in the UK), and host institution(s) for written approval. 


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The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
15.4. 
Reporting 
The CI shall submit once a year throughout the clinical trial, or on request, an Annual Progress Report to 
the REC, host organisation and Sponsor.  In addition, an End of Trial notification and final report will be 
submitted to the MHRA, the REC, host organisation and Sponsor. 
15.5. 
Participant Confidentiality 
The trial staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by a participant ID number on all trial documents and any electronic database, with the 
exception of the CRF, where participant initials may be added.  All documents will be stored securely and 
only accessible by trial staff and authorised personnel. The trial will comply with the Data Protection Act, 
which requires data to be anonymised as soon as it is practical to do so. 
15.6. 
Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. 
The test meals will be provided by the service, and a funding application has been made for these.  In 
addition, if funding is granted, each child will be offered a £10 high street voucher in return for their help 
with the study.   
15.7. 
Other Ethical Considerations 
The use of Children  
The participation of children and young people is indispensable for this study because there is a lack of 
research on the appropriate dietary management of children and adolescents with Type 1 diabetes using 
MDI.  Adult data cannot be extrapolated to children because of their very different life-styles, body size, 
insulin requirements and dietary differences.   Evidence based dietary interventions for children need to 
be examined in the paediatric population. In particular, the acceptability for giving additional insulin 
injections at meal-times may be very different in children compared to adults.   
Consent 
It is important that both the child and parent/legal guardian has an adequate opportunity to ask 
questions, and to fully understand the implications of the study before agreeing to take part. Children’s 
wishes will not be over-ridden. The leaflets and discussion will make it clear that withdrawal from the 
study can occur at any time with no disadvantage in terms of normal medical care. 
16. FINANCE AND INSURANCE 


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16.1. 
Funding 
Part-funding for the study has been received from the NovoNordisk Research Foundation.  Additional 
funding has been provided by the OUH Research Capability Funding to employ a Dietitian for one day per 
week for a year.  A research nurse is employed within the department.   
16.2. 
Insurance 
 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If you are harmed 
whilst taking part in a clinical trial as a result of negligence on the part of a member of the trial team this 
liability cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS Trust, 
therefore, cannot agree in advance to pay compensation in these circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 
17. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authors will acknowledge that the study was funded by 
the body which provided the funding.  Authorship will be determined in accordance with the ICMJE 
guidelines and other contributors will be acknowledged. 
Study results will be disseminated to research participants by the usual clinic newsletter and by 
presenting the results to the Parents’ support group (Oxfordshire Young Diabetics) open meeting, and to 
similar groups in other participating hospitals.   
18. REFERENCES 
1.   The Diabetes Control and Complications Trial Research Group. Effect of intensive treatment of 
diabetes on the development and progression of long-term complications in insulin-dependent 
diabetes mellitus. N Engl J Med 1993: 329; 977-86. 
2 American Diabetes Association.  Postprandial blood glucose levels; consensus statement.  Diabetes 
Care 2001: 24; 775-8 
3. Smart CE, Ross K, Edge JA, King BR, McElduff P, Collins CE.  Can children with Type 1 diabetes and their 
caregivers estimate the carbohydrate content of meals and snacks?  Diabetic Medicine 2010 
Mar;27(3):348-53. 
4.  Smart CE, Ross K, Edge JA, Collins CE, Colyvas K, King BR.  Children and adolescents in intensive insulin 
therapy maintain postprandial glycaemic control without precise carbohydrate counting.   Diabetic 
Medicine, 2009: 26; 279-285. 
5.  Application of novel dual wave meal bolus and its impact on glycated hemoglobin A1c level in children 
with type 1 diabetes.  Pańkowska E, Szypowska A, Lipka M, Szpotańska M, Błazik M, Groele L..  Pediatr 
Diabetes. 2009 Aug;10(5):298-303 
6.  Does the fat-protein meal increase postprandial glucose level in type 1 diabetes patients on insulin 
pump: the conclusion of a randomized study.  Pańkowska E, Błazik M, Groele L.  Diabetes Technol 
Ther. 2012 Jan;14(1):16-22 


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7. Benefit of supplementary fat plus protein counting as compared with conventional carbohydrate 
counting for insulin bolus calculation in children with pump therapy.  Kordonouri O, Hartmann R, 
Remus K, Bläsig S, Sadeghian E, Danne T.  Pediatr Diabetes. 2012 Nov;13(7):540-4. 
8. Both dietary protein and fat increase postprandial glucose excursions in children with type 1 diabetes, 
and the effect is additive.  Smart CE, Evans M, O'Connell SM, McElduff P, Lopez PE, Jones TW, Davis 
EA, King BR.  Diabetes Care. 2013 Dec;36(12):3897-902 
9. Impact of Fat, Protein and Glycaemic Index on Postprandial Glucose Control in Type 1 Diabetes: 
Implications for Intensive Diabetes Management in the CGM Era.  Bell KJ, Smart CE, Steil GM, Brand-
Miller JC, King B, Wolpart HA.  Diabetes Care. 2015;38:1008-1015 
19. APPENDIX A:  SCHEDULE OF PROCEDURES 
 
Procedures 
 
 
Visit 1 
Day 0 
Telephone 
call day 3-4 
Telephone 
call Day 5-
6 
Visit 2 
Day 7-10 
Visit 3 
Day 14-16 
Screening 
 
 
Baseline 
 
Informed consent/assent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
HbA1c measurement if 
not done in last 3 months 
X 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
Provide diaries for run-in 
week 
X 
 
 
 
 
Dietitian to order 
standard meals 
X 
 
 
 
 
Assessment ICR 
 
X 
 
X 
 
Optimise ICR 
 
 
x 
 
 
Randomisation 
 
 
 
X 
 
Insert CGM 
 
 
 
X 
 
Explain trial insulin doses 
 
 
 
X 
 
Provide diaries and all 
instructions for trial week 
 
 
 
X 
 
Provide contact details for 
trial week 
 
 
 
X 
 
Remove CGM and show 
download to family 
 
 
 
 
X 
Questionnaires to 
participant and 
 
 
 
 
X 


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parent/carer 
Adverse event 
assessments 
 
 
 
 
X 
 
 
20. APPENDIX B:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued 
Author(s) 
of 
changes 
Details of Changes made 
1 
2 
20/11/15 
AM Frohock 
Minor typographical errors 
Additional Research Nurses added 
Confirmed 
protocol 
met 
REC 
recommendations to remove patient 
initials from all data collection 
2 
3 
21/6/16 
AM Frohock 
Adjusted the original calculation used 
in the protocol.  This reduces the 
amount 
of 
additional 
insulin 
administered for fat and protein and 
therefore 
reduces 
the 
risk 
of 
hypoglycaemia in future participants.  
(Page 8 and Page 11) 
We also changed guidance for 
completing 
the 
study 
evenings 
following hypoglycaemic episodes 
immediately before the study meal – 
stating that in this incidence the meal 
should be abandoned.  This also 
reduces the risk of hypoglycaemia 
afterwards.  (Page 12) 
Minor changes were made to the 
flowchart to remove giving the 
voucher at visit 3 – this will now 
happen once all participants have 
completed the study at the end 
(Page 10) 
 
3 
4 
1/4/17 
AM Frohock 
Change of Chief Investigator 
3 
4 
1/4/17 
AM Frohock 
Clarification that the second insulin 
dose should be given at a time 
interval after the first insulin dose as 
there had been ambiguity from 
participants about the meaning of 
‘after the meal’ 
Change in management of correction 
doses pre-evening meal.  It has 


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become clear that it will be very 
difficult to analyse change in BG level 
from 
pre-meal 
levels 
once 
a 
correction dose of insulin is given.  So 
we have asked participants only to 
correct if BG above 12mmol/l and if 
possible to avoid doing the study on 
evenings when BG is above 12 
mmol/l before the meal if possible.  
They should definitely not complete 
the meal if BG is above 16mmol/l  
 
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee or MHRA.