Can Maximising Time in Range Using Automated Insulin Delivery and a Low Carbohydrate Diet Restore the Glucagon Response to Hypoglycaemic in Type 1 Diabetes?
Phase: NA
Conditions: Type 1 Diabetes, Type 1 Diabetes Mellitus With Hypoglycemia, Hypoglycemia, Hypoglycemia Unawareness, Glucagon Deficiency, Insulin Hypoglycemia
Sponsor: University of Edinburgh

Automated insulin delivery and Glucagon Secretion 
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Non-CTIMP Study Protocol 
Can Maximising Time in Range Using Automated Insulin Delivery and a 
Low Carbohydrate Diet Restore the Glucagon Response to 
Hypoglycaemic in Type 1 Diabetes? 
 
 
The University of Edinburgh and Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
 
Protocol authors 
Prof. Shareen Forbes 
Dr Nicola Baillie 
Dr Faye Baxter 
Funder 
The Helmsley Charitable Trust 
Funding Reference Number 
Insert funding reference before finalisation 
Chief Investigator 
Prof. Shareen Forbes 
Sponsor number 
AC19163 
REC Number 
20/SS/0117 
Project registration 
Clinicaltrials.gov: NCT04614168  
Version Number and Date 
Version 8- 28/09/22 
 
 
 
 
 
 

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CONTENTS 
 
1 
INTRODUCTION ......................................................................................................................... 6 
1.1 
BACKGROUND ......................................................................................................................... 6 
1.2 
RATIONALE FOR STUDY ........................................................................................................... 9 
2 
STUDY OBJECTIVES .................................................................................................................... 9 
2.1 
OBJECTIVES ............................................................................................................................. 9 
2.1.1 
Primary Objective ............................................................................................................... 9 
2.1.2 
Secondary Objectives .......................................................................................................... 9 
2.2 
ENDPOINTS ........................................................................................................................... 10 
2.2.1 
Primary Endpoint .............................................................................................................. 10 
2.2.2 
Secondary Endpoints ......................................................................................................... 10 
3 
STUDY DESIGN ......................................................................................................................... 10 
4 
STUDY POPULATION ................................................................................................................ 15 
4.1 
NUMBER OF PARTICIPANTS................................................................................................... 15 
4.2 
INCLUSION CRITERIA ............................................................................................................. 15 
4.3 
EXCLUSION CRITERIA ............................................................................................................. 15 
4.4 
CO-ENROLMENT .................................................................................................................... 16 
5 
PARTICIPANT SELECTION AND ENROLMENT ............................................................................ 16 
5.1 
IDENTIFYING PARTICIPANTS .................................................................................................. 16 
5.2 
CONSENTING PARTICIPANTS ................................................................................................. 16 
5.2.1 
Withdrawal of Study Participants ..................................................................................... 16 
6 
STUDY ASSESSMENTS .............................................................................................................. 17 
6.1 
STUDY ASSESSMENTS ............................................................................................................ 17 
6.2 
STORAGE AND ANALYSIS OF SAMPLES .................................................................................. 32 
7 
DATA COLLECTION ................................................................................................................... 33 
7.1 
SOURCE DATA DOCUMENTATION .................................................................................................. 35 
7.2 
CASE REPORT FORMS ................................................................................................................. 36 
8 
DATA MANAGEMENT .............................................................................................................. 36 
8.1 
PERSONAL DATA ........................................................................................................................ 36 
8.2 
DATA INFORMATION FLOW .......................................................................................................... 36 
8.3 
TRANSFER OF DATA .................................................................................................................... 36 
8.4 
DATA CONTROLLER .................................................................................................................... 36 
8.5 
DATA BREACHES ........................................................................................................................ 37 
9 
STATISTICS AND DATA ANALYSIS ............................................................................................. 37 
9.1 
SAMPLE SIZE CALCULATION .................................................................................................. 37 
9.2 
PROPOSED ANALYSES ............................................................................................................ 37 
10 
ADVERSE EVENTS ..................................................................................................................... 37 
10.1 
DEFINITIONS .......................................................................................................................... 37 

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10.2 
IDENTIFYING AES AND SAES ................................................................................................... 38 
10.3 
RECORDING AES, SAES AND SADES .......................................................................................... 39 
10.3.1 
Pre-existing Medical Conditions ................................................................................... 39 
10.3.2 
Worsening of the Underlying Condition during the Trial .............................................. 39 
10.4 
ASSESSMENT OF AES AND SAES ............................................................................................. 39 
10.4.1 
Assessment of Seriousness ........................................................................................... 39 
10.4.2 
Assessment of Causality ............................................................................................... 39 
10.4.3 
Assessment of Expectedness ........................................................................................ 39 
10.4.4 
Assessment of Severity ................................................................................................. 40 
10.5 
REPORTING OF SAES AND SADES TO THE SPONSOR ................................................................ 40 
10.6 
REPORTING OF DEVICE DEFICIENCIES ................................................................................... 41 
10.7 
MEDICAL DEVICE QUARANTINE ............................................................................................ 41 
11 
OVERSIGHT ARRANGEMENTS .................................................................................................. 41 
11.1 
INSPECTION OF RECORDS ...................................................................................................... 41 
11.2 
STUDY MONITORING AND AUDIT .......................................................................................... 42 
12 
GOOD CLINICAL PRACTICE ....................................................................................................... 42 
12.1 
ETHICAL CONDUCT ................................................................................................................ 42 
12.2 
INVESTIGATOR RESPONSIBILITIES ......................................................................................... 42 
12.2.1 
Informed Consent ......................................................................................................... 42 
12.2.2 
Study Site Staff ............................................................................................................. 42 
12.2.3 
Data Recording ............................................................................................................. 43 
12.2.4 
Investigator Documentation......................................................................................... 43 
12.2.5 
GCP Training ................................................................................................................. 43 
12.2.6 
Confidentiality .............................................................................................................. 43 
12.2.7 
Data Protection ............................................................................................................ 43 
13 
STUDY CONDUCT RESPONSIBILITIES ........................................................................................ 44 
13.1 
PROTOCOL AMENDMENTS .................................................................................................... 44 
13.2 
MANAGEMENT OF PROTOCOL NON COMPLIANCE ............................................................... 44 
13.3 
SERIOUS BREACH REQUIREMENTS ........................................................................................ 44 
13.4 
STUDY RECORD RETENTION .................................................................................................. 44 
13.5 
END OF STUDY ....................................................................................................................... 44 
13.6 
CONTINUATION OF TREATMENT FOLLOWING THE END OF STUDY ....................................... 45 
13.7 
INSURANCE AND INDEMNITY ................................................................................................ 45 
14 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ................................................. 45 
14.1 
AUTHORSHIP POLICY ............................................................................................................. 45 
15 
REFERENCES ............................................................................................................................ 46 
 

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Title                            Can Maximising Time-in-Range using Automated Insulin Delivery Restore Glucagon Secretion To 
Hypoglycaemia 
Precis 
A pilot study of 8 months at home, closed loop + low carbohydrate diet (LCD) vs control. 
Device 
Tandem t:slim X2 with Control IQ and Dexcom G6 system. 
Objectives 
This study aims to look at the glucagon response to hypoglycaemia in 24 participants with T1D t ascertain 
is maximising time in range improves glucagon response to insulin-induced hypoglycaemia. 
Study Design 
Randomised clinical feasibility trial with a 1:1 randomisation to Control IQ + LCD and routine care. 3-month 
study extension phase for routine care group where they are converted to Control IQ technology. 
End Point 
To assess if maximising TIR can restore glucagon secretions in T1D. 
Population 
Adults with c-peptide negative T1D  
Sample Size 
24 participants 
Treatment 
Groups 
Control- Group 1: Standard diabetes care with x3 20 day periods of blinded Dexcom G6 CGM. 3-month 
study extension where converted to Tandem t:slim X2 with Control IQ technology and Dexcom CGM. 
Quality of life questionnaires completed at the end of this period and glucose data collected from the CGM. 
Intervention- Group 2: Tandem t:slim X2 with Control IQ technology and Dexcom G6 CGM + LCD 
Participant 
Duration 
9 months + 3 month optional study extension for standard care group 
Protocol 
Synopsis 
After consent eligibility will be assessed. The trial will consist of 3 phases: 
Phase 1: Baseline data. All participants will complete 20 days of blinded CGM with Dexcom G6 
Phase 2: Study Run in. Group 2 will have 2 weeks using the t:slim X2 pump with Control IQ technology 
and the Dexcom G6 CGM unblinded.  
Phase 3: Study. 8 months. Group 1 will continue routine care as pre-study. They will undergo two periods 
of blinded Dexcom G6 CGM monitoring each lasting 20 days. Group 2 will continue on their allocated 
devices and LCD with close monitoring by the study team to ensure TIR is maximised. Both groups will 
undergo a hyperinsulinaemic hypoglycaemic clamp study at 0 and 8 months. Group 1 will be invited to 
take part in a 3 month study extension phase where they are converted to the study devices and complete 
quality of life questionnaires. 

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LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - Joint office 
for The University of Edinburgh and Lothian Health Board 
AID 
Automated insulin delivery 
BMI 
Body mass index 
BSA 
Body surface area 
CGM 
Continuous glucose monitor 
CRF 
Clinical research facility 
CTIMP 
Clinical trial of investigational medical product 
T1D 
Type 1 Diabetes 
DAFNE 
Dose Adjustment for Normal Eating- A course for adult's with Type 1 Diabetes  
to help adjusting insulin doses  
iDCL 
International Diabetes Closed Loop Trial 
DKA 
Diabetic Ketoacidosis 
DPP- 4 Inhibitors 
Dipeptidyl petidase 4 inhibitors 
EDTA 
Ethylenediaminetetraacetic Acis- a chemical used in blood collection tubes 
EGP 
Endogenous glucose production 
ERI 
Edinburgh Royal Infirmary 
ERICRF 
Edinburgh Royal Infirmary Clinical Research Facility 
GCP 
Good Clinical Practice 
GLP-1 
Glucagon-like peptide 1 
HbA1c 
Glycated Haemaglobin 
ICH 
International Conference on Harmonisation 
ISF 
Insulin sensitivity factor- how 1 unit of insulin lowers the blood glucose by  
LCD 
Low carbohydrate diet 
NEJM 
New England Journal of Medicine 
QA 
Quality assurance 
QoL 
Quality of Life 
RCT 
Randomised controlled trial 
REC 
Research Ethics Committee 
SCI-Diabetes 
Electronic patient record used Scotland-wide for people with diabetes 
SSRI 
Selective seratonin reuptake inhibitor 
TIR 
Time in range 
USB 
Universal serial bus 
 
 
 
 
 
 
 

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1 
INTRODUCTION 
1.1 
BACKGROUND 
Glucagon, the pancreatic islet alpha cell product, is a sensitive regulator of glucose 
homeostasis. In vivo in humans it is critical to the counter-regulatory response to 
hypoglycaemia (1-3). Almost all people who have had Type 1 diabetes (T1D) for 5 
years develop a specific defect in alpha cell Glucagon secretion (4). This defect 
therefore increases the risk of severe hypoglycaemia. Glucagon secretion may also 
be inappropriately high in response to hyperglycaemia, meaning that the response is 
not just absent but is dysregulated. 
 
It is not currently known if preserving glycaemic time in range in T1D leads to 
improved regulation of glucagon response to hypoglycaemia. Data from longitudinal 
studies shows that C-peptide (a widely used measure of pancreatic beta cell 
function) can be preserved in people with optimised TIR, this supports the potential 
argument that glucagon response to hypoglycaemia may also be preserved with this 
strategy. 
 
Little is known of the aetiology of this defect, however in a mouse model of neonatal 
diabetes it was shown that chronic hyperglycaemia leads to a profound change in 
islet morphology and function without a change in islet number or density (5). 
Structural and electrophysiological changes in beta cells were shown and attributed 
to chronic hyperglycaemia. In a later study the same group showed that profound 
metabolic changes, including significant glycogen accumulation, contributed to the 
insulin secretory defect of the beta cells (6). Interestingly, in both studies, reducing 
glucose levels led to the restoration of normal glucose homeostasis and a reversal of 
the morphological changes of the beta cell.  
 
Although no dynamic assessment of alpha cell function was made the near 
normalization of glucose homeostasis suggests restoration of both alpha and beta 
cell function. 
 
Glucagon is a counter-regulatory hormone which helps raise blood glucose levels 
and it plays a significant role in rescuing people from hypoglycaemia. It is therefore 
important to understand if this hormonal response, if lost, can be re-established in 
people with Type 1 Diabetes.  
 
This pilot study aims to look at the Glucagon response to hypoglycaemia in 24 
patients with T1D to ascertain whether maximizing blood glycaemic time-in-range 
(TIR) improves the Glucagon response to hypoglycemia. 
 
 
 
 
 
 
Strategies to maximise Time-in-range in Type 1 diabetes 

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Continuous Glucose Monitoring systems (CGMs) have made it possible to quantify 
glycaemic time in range (TIR), defined as blood glucose >70 and <180 mg/dl  (>3.9 
and <10.0 mmol/L) (7), this has greatly expanded the understanding of glycaemic 
control beyond HbA1c alone. Maximising TIR is emerging as a major goal of 
treatment in T1D (8). 
We aim to improve TIR by using an AID system, the t:slim X2 insulin pump with 
Control IQ technology, and the Dexcom G6 CGM in conjunction with a low 
carbohydrate diet. We are introducing a low carbohydrate diet as postprandial 
hyperglycaemia contributes significantly to overall glycaemic burden. Data from the 
Type 1 Diabetes Exchange indicate that < 30% of patients achieve glycaemic targets 
(8). 
 
1. Automated Insulin Delivery systems, AIDs 
Automated insulin delivery systems (AIDs) have been shown to improve TIR in both 
the paediatric and adult population (9, 10). This technology combines an insulin 
pump, a CGM system and an algorithm allowing automatic adjustment of insulin 
delivery based on a patient’s blood glucose. 
 
We propose using the Dexcom G6 CGM and the Tandem t:slim X2 insulin pump. The 
Tandem t:slim X2 has built in Control IQ technology, an algorithm that utilises CGM 
data to adjust insulin delivery (Tandem Diabetes Care, San Diego, US) (11).  
 
The features available with this system are:  
• 
Automated insulin correction boluses administered using CGM data. 
• 
A dedicated hypoglycaemia safety system that attenuates smoothly, or 
discontinues, insulin delivery using CGM and insulin-on-board information. 
• 
Gradually intensified control overnight. During the day the 
system targets a range of 112.5-160 mg/dl (6.2-8.9 mmol/l). It is more 
aggressive at night – the goal is to arrive at 112.5-120 mg/dl (6.2-6.7mmol/l) 
by the time the user wakes up.  
• 
Control-IQ also has an “exercise mode” that changes the target to be closer 
to 140-160 mg/dl (7.8-8.8 mmol/l). 
 
AIDs, using Control IQ and Dexcom G6, trial results.  
Positive clinical results from studies of the Tandem t:slim X2 insulin pump with 
Control-IQ advanced hybrid closed-loop technology have been reported. Data 
demonstrated that the system achieved the primary outcome of increasing TIR 
without any severe hypoglycaemic events. 
 
The iDCL study published in June 2019 (12) showed TIR for participants using 
Control-IQ technology for 6 months was 71% per day compared to 59% per day for 
participants in the control group (using sensor augmented pump therapy, i.e. open 
loop.). During the overnight period time in range with Control-IQ technology was 76 
% compared to  
59% in the control group. Time spent with glucose values above 180 mg/dL (10.0 
mmol/l) was 27% in those using Control-IQ technology compared to 39% in the 
control group. Time spent below 70 mg/dL (3.9 mmol/l) was 1.4 % with Control-IQ 
technology compared to 1.9% in the control group and time spent below 54 mg/dL 
(3.0 mmol/l) was 0.21 % compared to 0.24 % in the control group. 

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Protocol 3 of the iDCL study was released in the NEJM in October 2019 (11). This 
showed that the TIR in the closed-loop group increased from 61±17% at baseline to 
71±12% during the 6 months trial period and remained unchanged at 59±14% in the 
control group.  The results with regard to the main secondary outcomes (percentage 
of time that the glucose level was >180mg/dl ( 10.0 mmol/l)  mean glucose level, 
HbA1c, and percentage of time that the glucose level was <70 mg/dl (3.9 mmol/l) or 
<54 mg/dl (3.0 mmol/l) all favoured the closed-loop system. These results were 
demonstrated in people with and without prior experience with insulin pump therapy. 
In addition to time in range those using Control-IQ technology also saw statistically 
significant improvements in HbA1c and reductions in mean glucose. This is the most 
impressive data on AIDs to date. 
 
2. Low Carbohydrate Diet 
Maximising TIR using an AID system as described will allow us to test the hypothesis 
that chronic hyperglycemia per se plays a causative role in the development of 
defective glucagon secretion in T1D. However, it remains possible that the AID 
system may be insufficient given that post-prandial hyperglycemia still remains 
difficult to fully control with these devices (13). 
 
One additional approach that may address post-prandial hyperglycemia effectively is 
a Low Carbohydrate Diet (LCD), defined as <130g per day of carbohydrates or 25% 
carbohydrates as a proportion of calories. No randomized controlled trials (RCTs) 
exist in this field in T1D but small observational surveys confirm the safety and 
efficacy of controlling post-prandial hyperglycemia in adults with T1D using a low or 
very low carbohydrate diet (14). 
 
In this study we propose a carbohydrate portion of 30-40g carbohydrate per meal. 
This will be initiated by experienced healthcare professionals in this field. Patients will 
receive education about this diet at baseline. The ERICRF routinely uses this diet for 
post islet transplant patients.  
 
We will ensure patient safety in this arm of the trial by monitoring blood ketones daily 
and will supply the meters and test strips for this.  
 
We will supply nutritional scales to assist with carbohydrate counting and provide 
support and advice on this throughout the trial.  
 
 

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1.2 
RATIONALE FOR STUDY 
 
It is not currently known if maximizing TIR by principally reducing the exposure of the 
alpha cell to hyperglycemia is sufficient to restore glucagon secretory responses to 
insulin-induced hypoglycaemia in people with T1D. 
 
We will attempt to answer this question by maximizing glycaemic TIR using new-
generation AIDs in combination with a LCD. In addition, participants will be 
intensively followed up by study investigators to achieve maximal glycaemic TIR.  
 
This will provide proof-of-principle that restoration of the glucagon response to insulin 
induced hypoglycaemia is possible in T1D. If these findings are confirmed this study 
will drive efforts to restore the glucagon response to hypoglycaemia not only by 
optimising glycaemic TIR but also by other pharmacological measures. It will also 
drive researchers to investigate if there are compositional, structural and, or, 
functional changes in the islet after regulation of the glucagon response.  
 
Most importantly however is the impact on patients and patient care. In the short and 
the long-term restoration of this response would significantly reduce morbidity and 
mortality from hypoglycaemia impacting on quality-of-life for the patient as well as 
having significant socio-economic implications. 
 
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
Does maximizing TIR using AIDs with a LCD restore the glucagon response to insulin-
induced hypoglycaemic in people with type 1 diabetes. 
2.1.2 Secondary Objectives 
• 
Has the quality of life (QoL) improved with improved blood sugar control? 
• 
Are there fewer hypoglycaemic episodes? 
• 
Is there a lower burden of diabetes care? 
• 
Has the fear of Hypoglycaemia changed as a result of using this technology?  
• 
Has satisfaction with their diabetes treatment improved as a result of using 
this technology? 
• 
Is there an improvement in HbA1c using this technology? 
• 
Endogenous glucose production and glycerol kinetics as measured by stable 
isotope studies (glycerol isotope will be used when supply is available) 
• 
Is there a similar improvement in TIR between participants using the HCL 
system and following a LCD and those using the HCL system and following 
their pre-study diet 

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• 
Is there a difference in QoL between participants using the HCL system and 
following a LCD and those using the HCL system and following their pre-
study diet 
 
 
 
2.2 
ENDPOINTS 
2.2.1 Primary Endpoint 
The glucagon response to hypoglycaemia after a period of increased time in range 
using automated insulin delivery and a low carbohydrate diet compared with the 
glucagon response at baseline. 
 
2.2.2 Secondary Endpoints 
Treatment satisfaction, fear of hypoglycaemia and quality of life at baseline compared 
to endpoint using validated questionnaires. Changes in endogenous glucose 
production and glycerol kinetics as measured by stable isotope studies. The difference 
in time in range and QoL between participants using the HCL system and following the 
LCD and those using the HCL system alone will be compared. 
3 
STUDY DESIGN 
This is a feasibility pilot study involving 24 participants with T1D. We aim to achieve 
improved glycaemic control using new generation Automated Insulin Delivery 
systems which consist of: 
• 
Tandem t:slim X2 insulin pump 
• 
Continuous glucose monitoring using the Dexcom G6 
• 
Control IQ technology which uses an algorithm to adjust insulin delivery using 
CGM data 
 
To reduce postprandial glucose excursions the intervention arm of this study will also 
follow a low carbohydrate diet (30-40g of carbohydrate per main meal portion). 
 
Healthcare professionals who are trained in the use of these technologies will 
monitor patient data and implement pump setting changes as required during the 
study period in order to maximise TIR. Study staff will be able to obtain technical 
support from both Tandem and Dexcom throughout the trial period. 
 
Participant’s CGM data will be available to the study staff using Dexcom clarity which 
is a secure cloud based data storage system. Participant’s Tandem t:2 slim X2 data 
will be available via the t:connect Diabetes Management Application, another secure 
cloud based data storage system, which participants will upload their pump data to. 
 
Face-to-face visits will be at the Edinburgh Royal Infirmary. Each participant will be in 
the study for 9 months. Those in group 1 will be invited to take part in a 3-month 

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study extension phase where they will be converted to the study devices. Over this 
time their glucose data will be collected and at the end of the 3-months they will 
complete quality of life questioinnaires. 
 
The trial is expected to last for 14 months.  
 
 

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Study Devices 

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Control IQ 
The t:2 slim X2 is an insulin pump that contains Control-IQ Technology. This is a 
third-generation closed-loop control system containing an algorithm that has been 
implemented in two mobile platforms (DiAs and inControl) and has been tested in 30 
clinical trials by 450 adults and children with type 1 diabetes for over 280,000 hours 
of use to date. 
 
This control algorithm provides the user with automated insulin correction boluses 
and a dedicated hypoglycaemia safety system that attenuates smoothly or 
discontinues insulin delivery using CGM and insulin-on-board information. It also 
gradually intensifies control overnight. Every five minutes Control-IQ receives CGM 
glucose data in order to inform insulin delivery. If glucose is in the target range, it 
delivers the insulin according to the user’s settings. If out of range, it will give more or 
less insulin. The algorithm can use the CGM data to adjust insulin delivery based on 
the patients predicted blood glucose over the next 30 minutes. 
 
In the closed-loop group of the recently published iDCL trial the median percentage 
of time Control IQ was in closed-loop mode was 90%, this was consistent throughout 
the 6 months (11).  
 
Control IQ has FDA approval in the USA. December 2019. It launched in the UK in 
July 2020 after receiving a CE mark. 
 

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4 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
Enrolment will proceed with the goal of having 24 participants enter the trial. The participants 
will be people with type 1 diabetes recruited from the NHS Lothian diabetes pump waiting list 
and type 1 diabetes clinic. Recruitment will be staggered with each participant entering the trial 
for a 9 month period. The trial is expected to last 14 months. 
. 
4.2 
INCLUSION CRITERIA 
• 
Participants with Type 1 diabetes with C-peptide levels less than 200pmol/L. 
• 
Age 21-65. 
• 
Type 1 diabetes for 5 years or more. 
• 
HbA1c greater than or equal to 53 mol/mol. 
• 
Normal renal function. 
• 
Normal thyroid function. 
• 
Willingness to monitor blood ketones daily. 
• 
Use of freestyle libre device is permitted at study entry and may be continued in 
participants in group 1 
4.3 
EXCLUSION CRITERIA 
• 
Current use of a non-approved closed loop / AID system or those on a predictive low 
glucose suspend insulin pump. 
• 
Proliferative retinopathy  
• 
Regular use of real time CGM in the preceding 3 months. 
• 
History of Diabetic ketoacidosis in the preceding 6 months. 
• 
Severe hypoglycaemic episode requiring external assistance in the preceding 6 
months. 
• 
Inability to safely use technology used in this study (e.g. impaired vision, memory or 
dexterity that prevents safe operation of CGM or insulin pump.) 
• 
Inability to support the technology requirements for the study (e.g. unable to upload 
study device at home) 
• 
History of Haemophilia, Cystic Fibrosis, pancreatic disease or complete 
pancreatectomy, ischaemic heart disease, cardiac arrhythmia, epilepsy or 
hypoglycaemia induced seizure 
• 
History of severe reaction or allergy to adhesive necessary to this study. 
• 
Unable to adhere to study timetable. 
• 
Unable to give informed consent. 
• 
Pregnancy or planning pregnancy. We will perform a pregnancy test on all eligible 
participants at baseline.  
• 
Concurrent use of any non-insulin glucose-lowering agent (including GLP-1 agonists, 
Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas. These may lower insulin 
requirements and predispose to diabetic ketoacidosis. 
• 
Concurrent use of medication that may affect blood glucose such as SSRIs 
• 
A condition, which in the opinion of the investigator, would put the patient or study at 
risk 
 

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4.4 
CO-ENROLMENT 
 
Study staff will discuss with participants on a case-by-case basis if they are planning on 
enrolling in another study. The participant and study staff must consider the burden on the 
participant of being enrolled in more than one study. Any other study that a participant enrolled 
in would need to have no impact on their glycaemic control as this would potentially make the 
results from this study invalid. 
 
 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
Study staff, who are part of the diabetes care team in NHS Lothian, will identify potential 
participants from the type 1 diabetes clinic and the insulin pump waiting list. 
Electronic health records, Trakcare and SCI Diabetes, of potential participants will be 
screened for any exclusion criteria. If no exclusion criteria are identified study staff will write to 
the potential participant inviting them to contact the research team if they would like to know 
more about the study. Potential participants will be able to contact study staff by post or email 
to arrange a telephone call to discuss the study. If after discussion with study staff on the 
phone potential participants would like to know more about the study they will be sent the 
participant information leaflet and the consent form by post to review. 
 
5.2 
CONSENTING PARTICIPANTS 
Before completing any procedures or collecting any data that are not part of usual care written 
informed consent will be obtained. This will be obtained at the screening visit. 
The study protocol will be discussed with the potential participant by study staff over the phone. 
They will be sent the Patient Information Leaflet and Informed Consent Form to read and will 
be encouraged to discuss the study with family members, study staff and their personal doctors 
before deciding whether to participate in the study. Participants will be given a minimum of 5 
days and a maximum of 14 days to consider taking part in the study. The participant will be 
given contact details for study staff should they wish to ask further questions during this 14 day 
period. If study staff are not contacted by the potential participant within this 14 day period they 
will follow-up with a telephone call. 
 
5.2.1 Withdrawal of Study Participants 
Participants are free to withdraw from the study at any point or a participant can be withdrawn 
by the Investigator. If withdrawal occurs, the primary reason for withdrawal will be documented 
in the participant’s case report form, if possible. The participant will have the option of 
withdrawal from: 
  
(i) 
all aspects of the trial but continued use of data collected up to that point . To 
safeguard rights, the minimum personally-identifiable information possible will be 
collected. 
(ii) 
Participants can also ask for all data previously collected about them to be removed 
and not used in analysis 
(iii) 
Participants do not have to give a reason for withdrawal from the trial 

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6 
STUDY ASSESSMENTS 
6.1 
STUDY ASSESSMENTS 
Study Visit 1: Eligibility Assessment 
After informed consent has been signed the potential participant will be evaluated for 
study eligibility. This will be done through the elicitation of a medical history, 
performance of a physical examination by study staff and local laboratory testing if 
needed to screen for exclusionary medical conditions.  
 
 
The following data will be collected: 
• 
Inclusion and exclusion criteria assessment. 
• 
Demographics (date of birth, sex) 
• 
Contact information (retained at the site and not entered into study database) 
• 
Medical history 
• 
Concomitant medications 
• 
Pregnancy test if applicable 
• 
HbA1c blood test 
• 
Urine sample for albumin:creatinine ratio 
• 
Physical examination to include: Weight, height, BMI, vital signs including 
measurement of blood pressure and heart rate 
• 
Retinal screening will be arranged if this has not occurred in the previous 6 
months  
• 
Modified Clark and Gold score 
 
At the end of this visit participants will be given the following questionnaires: 
1. EQ5D 
2. Fear of Hypoglycaemic Scale 
3. Hypoglycaemic Confidence 
4. Diabetes Technology Attitudes 
5. Diabetes Specific Emotional Distress (DDS-1) 
6. Diabetes Treatment Satisfaction Questionnaire 
 
They can either complete these at the time of the visit of complete at home and 
return to study staff at the following visit. A stamped addressed envelope will be 
provided to return the forms. 
 
 
Randomisation 
 We will perform stratified random sampling according to age, gender and BMI. We 
will then provide envelopes to randomly assign final members from the various strata, 

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these envelopes will be kept in a secure, locked unit within in the clinical research 
facility. This technique ensures that observations from all relevant strata are included 
in the sample.  by stratified sampling to match for: age, gender and BMI. They will be 
assigned to one of two groups: 
 
• Group 1: Controls: standard diabetes care with blinded CGM (Dexcom G6) on three 
occasions lasting 20 days. All will be invited to a 3-month study extension phase 
where they will be converted to the study devices.  
• Group 2: New-generation AIDs (t:slim X2 insulin pump with Control-IQ technology) 
with CGM (Dexcom G6) and a low carbohydrate diet (30-40g of carbohydrate per 
main meal portion). They will also have a 20-day period of blinded CGM (Dexcom 
G6) at baseline 
 
Amendment: 28/09/22: Recruitment and retention to group 1 has been challenging 
with potential participants not wanting to engage with the study if allocated to group 
1. This has led to unbalanced study groups. Currently there are 11 participants in 
group 2 and only 3 participants in group 1 (with a further 2 participants previously 
recruited but choosing to leave the study early). In order to balance groups from now 
on participants will be approached to take part in the study and informed up-front that 
they will be allocated to group 1.  
 
Dexcom G6 clinical supplies, technical and software assistance will all be provided 
by Dexcom (see letter of support: Dr T Walker, Senior US Medical Director, 
Dexcom). 
 
Participants will be asked to choose an envelope at random at the end of the 
screening visit which will allocate them to a group. At this time arrangements for 
subsequent visits will be made. We will send those randomised to group 2 training 
materials for the insulin pump and CGM. Participants will be allocated to a group 
within 1 week of the screening visit. This will change in version 8 of the protocol 
(28/09/22), from this point participants will only be recruited to the control group 
(group 1) and not randomised. 
 
 
Visit 2- Baseline Data 
All participants will attend for a second visit at ERICRF or ERI outpatient department. 
Participants will be fitted with a Dexcom G6 CGM. They will use this, blinded, for 
twenty days to gain experience in its insertion and for the research team to gain 
baseline data on glycaemic control. They will be required to insert two CGM devices 
to cover this 20 day period with support from study staff as required. If during this 
time the CGM device falls off or is faulty a replacement CGM device will be provided 
to the participant if less than 14 days of data has been collected. As participant’s will 
not be able to view their CGM data during this time they will have to continue to 
monitor their own blood glucose as they would do normally. 
 
All participants will be asked to complete a 7-day food diary during this period of 
blinded CGM. They will be asked to include 5 week days and 2 weekend days in the 
diary. This diary can take the form of a paper diary provided by study staff or 
participants can use a mobile phone application if they prefer. They will be asked to 
document food consumed and their insulin doses. They can return this to study staff 

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by post or at the next visit. A stamped addressed envelope will be provided if 
returning the diary by post. 
 
 
 
Study Visit 3 (Group 2 only) 
Participants randomised to Group 2 will attend the ERI to meet study staff, be fitted 
with their insulin pump and CGM device. This will take place after the 20-day period 
of blinded CGM monitoring. They will return the completed food diary at this visit. 
Participants in this group will be given training in the use of the pump that is in-line 
with was is received by NHS patients commencing on insulin pump therapy. This will 
require the participant to complete online training modules prior to attending this visit. 
They will also undergo a virtual or face-to-face pump start session with study staff 
and a training representative from the pump distributer. At this training session their 
knowledge of the pump will be checked against a standard checklist and we will 
ensure that the training modules have been completed. They will also be provided 
with written materials on the use of the pump and the algorithm which are produced 
by the pump manufacturer. Ongoing support on the use of the pump will be provided 
by study staff throughout the study period as is required by the participant, this can 
be via telephone contact for face-to-face if required. The pump manufacturer also 
has an online presence, including training and troubleshooting videos that can be 
freely accessed by participants (Tandem YouTube cannel: 
https://www.youtube.com/channel/UCBpeIuXQrQC-SGGooyxOhKA and Dexcom 
online training resources: https://www.dexcom.com/en-GB/training-resources). 
 
Whilst on an insulin pump the participant will change their own insertion site every 
three days. This is routine in insulin pump use and is a marked reduction in injections 
when compared with insulin pens and needles, which is often done five to six times 
daily. They will also receive advice from the study team with respect to the low 
carbohydrate diet plans and management of insulin doses for their carbohydrate  
portions. This advice will be informed by the food diary completed by the participant. 
Participants in this group will be given blood ketone testing sticks and asked to do 
these tests daily. If blood ketones are greater than 1.5 mmol/L they will be asked to 
contact the health care professionals involved in the study or the out of hours care 
team. Participants will be given a paper record for them to record their ketone 
readings. This will change from protocol version 8 (28/09/22), from this point routine 
ketone monitoring will no longer be required. Participants will only be asked to 
monitor ketones as per standard diabetes management guidelines. 
 
Study Run- in and Visit 4 (by telephone) 
Participants in Group 2 will enter a maximum 2-week study run in period to adjust to 
their new equipment. Over this time the participants will be unblinded to their CGM 
data. The length of the run-in period will be determined on an individual basis after 
discussion between the participant and the investigators and will be based on the 
participant’s previous experience with and confidence in using the technology.  
Data will be monitored by the study staff and participants will be able to contact study 
staff by telephone or email to discuss any issues. At the end of this run-in period 
participants will meet with study staff either virtually or in person if they prefer this to 
assess: 
1. Compliance with the use of the study devices 

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2. Any skin reaction in areas where a CGM sensor or pump set site was worn 
3. Proficiency with the CGM and insulin pump technology by reviewing the 
individual items listed on the pump training checklist 
4. Eligibility to continue to in the trial, which requires: 
a. CGM readings being obtained on at least 11 of the previous 14 days- 
if completing the full 14-day run in period 
b. Successful use of the pump every day 
 
Additional visits and phone contacts for further training are at investigator discretion.  
 
The pump settings (insulin: carbohydrate ratios, basal rates and insulin sensitivity) 
will be reviewed and optimised as appropriate based on the participant’s blood 
glucose readings over the run-in period.  
 
Study Visit 5: Hypoglycaemic Clamp Study 1 
All Participants will attend the ERICRF, group 2 after the 2-week run-in period, for the 
first hypoglycaemic clamp study. This technique is safe and is considered, world-
wide, as the gold standard approach in the assessment of hypoglycaemia (15-17). 
The clamp study will last for 5-6 hours. Blood glucose data for the preceding 24 
hours will be reviewed prior to the study and if there have been any hypoglycaemic 
episodes the clamp study will be postponed.  
 
During the clamp study the participant’s blood glucose will be lowered in three steps 
to 2.5mmol/l.   
 
In the 48 hours preceding the study participants will be asked to avoid moderate/high 
intensity exercise and any medication that may affect blood glucose such as: 
salicylates and quinolone antibiotics.  
 
In the 24 hours preceding the study participants will be asked to do the following:  
• Avoid alcohol and caffeine  
• Consume a moderate carbohydrate (40-60g) evening meal the night before  
• Fast for at least 8 hours before presenting to the clinical research facility at 07:00 
(participant can continue to consume water as required)  
• Avoid hypoglycaemia- the study will be postponed if the blood glucose is <3mmol/l 
for >20 minutes  
• If on basal/bolus or open loop pump system to reduce their basal insulin the night 
before by 20%  
• If on a closed loop system to place the pump on exercise settings the morning of 
testing  
  
The clamp study will be rescheduled if the participant has donated blood in the 
preceding 12 weeks if male and the preceding 16 weeks if female. 
 
When participants arrive in the ERICRF they will have anthropological measurements 
taken to calculate their infusion rates accurately. They will also have a pregnancy test 
if applicable. 

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Two peripheral intravenous cannulas will be inserted. This first of these will be in the 
nondominant hand which will then be placed in a heated box at 55°C to aterialise 
venous blood. This will be used for blood sampling during the study. The second 
cannula will be inserted an antecubital fossa vein for the infusions. At the time of 
cannula insertion baseline bloods will be obtained for: glucose, glycerol, D2 Glucose, 
D5 Glycerol, Free Fatty Acids, lipid profile, insulin, glucagon, cortisol, adrenaline and 
noradrenaline. Note that bloods for D2-Glucose and D5-Glycerol will only be taken 
when the investigators have received supply of the isotopes. There is currently a 
delay in this supply and the investigators anticipate receiving the isotopes in January 
2022. Clamp studies carried out before receipt of the isotopes will not have these 
samples taken. 
 
 
Stable Isotope Studies 
 
 
Endogenous glucose production (EGP) and glycerol kinetics will be further assessed 
by infusion of the stable isotopes D2 Glucose and D5 Glycerol. This is a safe method 
for assessing EGP in humans (18, 19). The isotopes will be supplied by Tayside 
Pharmaceuticals (Patrick Blair Place, Dundee DD1 9SY). There are supply issues 
with the D5-glycerol but is important that study visits are allowed to continue so that 
participants can progress through the 8 months of the study. Not using the D5-
glycerol will not impact on the primary outcome of the study. The D5-glycerol supply 
issues will continue for the remainder of the study due to there being less raw 
material available from the supplier. This means that supply of the D5-glycerol will be 
intermittent and unpredictable for the remainder of the study. Visits that take place 
when D5-glycerol is available will be completed as described below. Visits taking 
place when D5-glycerol is not available will continue without using the D5-glycerol. 
The D5-glycerol is infused alongside the D2-glucose from the same infusion bag. So 
that the process for making this infusion remains unchanged the D5-glycerol will be 
replaced with 0.9% Sodium Chloride, which will not impact on the participant or the 
study results. Participants impacted by this change will be asked to sign another 
consent form. 
 
This will involve: 
1. A priming dose: 
a. D2 Glucose: 26.4 micoromol/kg 
b. D5  Glycerol: 2 micromol/kg (if available) 
2. A continuous infusion: 
a. D2 Glucose: 0.5micromol/kg/minute for the remainder of the clamp study 
b. D5 Glycerol: 0.1micromol/kg/minute for the remainder of the clamp study (if 
available) 
 
The continuous infusion of each isotope will run for 90 minutes before the clamp 
study is commenced. During this time blood samples will be drawn for Glucose, 
Glycerol, D2 Glucose and D5 Glycerol (if being infused) on three occasions. 
 

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If the participant’s blood glucose is >7mmol/l at the start of the study they will begin a 
priming infusion of Novorapid insulin 0.3U/ml at 50ml/hour until the blood glucose is 
<7mmol/l but >5mmol/l.  Once blood glucose is <7mmol/l a basal inuslin infusion will 
run at 6mU/m2/min until the start of the clamp study to maintain blood glucose in the 
euglycaemic range. 
 
Insulin infusion rates will be calculated using the participants body surface area, 
which avoids overdosing insulin in overweight participants. The body surface area 
will be calculated using the formula:   
  
BSA (m2) = √(( height (cm) x weight (kg))/ 3600  (20) 
  
After the isotopes have been infused for 90 minutes the insulin infusion will be 
increased to 60mU/m2/min. At the same time a variable rate 20% Dextrose infusion 
will also be commenced. The rate of this will be adjusted as required to obtain the 
desired blood glucose nadir.   
  
We will have three blood glucose plateaus during the clamp study each lasting for 40 
minutes: 5mmol/l, 3mmol/l and 2.5mmol/l. Throughout the clamp study blood glucose 
will be monitored every 5 minutes using near-patient testing and the participant will 
remain blinded to their blood glucose level. During each plateau blood will be drawn 
on 3 occasions at 10-minute intervals for: insulin, cortisol, adrenaline, noradrenaline, 
glucagon, glucose, glycerol, free fatty acids and the stable isotopes.  
 
During the clamp the following additional tests will be carried out:  
• Physiological measurements: Blood pressure and heart rate every 10 minutes.  
• Symptoms scoring: Participants will rate symptoms at set intervals during    
hypoglycaemia. Symptoms will be scored on a validated questionnaire, The 
Edinburgh Hypoglycaemia Scale, scoring from 1 (not at all) to 7 (very severe) on a 
visual analogue scale. At any point participants may stop the test if symptoms are 
intolerable.  
• Cognitive Function Tests: Psychometric tests known to be sensitive to 
hypoglycaemia will be applied at set time intervals during hypoglycaemia: Trail 
Making Test, Digit Span Test, Digit Symbol Substitution Test and Four Choice 
Reaction Time Test. 
 
At the end of the study the participants will be examined and assessed to ensure 
they have fully recovered from the clamp. They will be given lunch consisting of at 
least 60g of carbohydrate and post clamp advice. They may leave the CRF when 
blood glucose is stable above 5mmol/l. 
 
In total we will take not more than 300ml of blood during the clamp study. The blood 
samples will be stored in a secure and monitored environment and will be disposed 
of according to the Human Tissue Authority's code of practice after a period of 5 
years. The samples will be centrifuged before being frozen at -80 degrees Celsius. 
Serum samples will be allowed to clot at room temperature before centrifugation. 
 

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At the beginning and end of the clamp study a sample will be taken from the 
infusates to confirm the isotope concentration in these. These samples will be frozen 
until analysis.  

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Figure 1: Hypoglycaemic Clamp Study with stable isotopes 
Note in visits where the D5-glycerol is not available on the D2-glucose will be 
infused. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 2: Hypoglycaemic Clamp Study without stable isotopes  
 
 
 

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Monitoring Period 
Group 1 
Group 1 will continue on their standard diabetes care. At 4 months they will perform a 
20 day period of blinded CGM monitoring. This will require them to insert the CGM 
device on two occasions during this 20 day period. During this 20 day period this 
group will continue on their standard diabetes care, including monitoring their own 
blood glucose, as they will not be able to view the data from the CGM device. 
Participants in this group will perform a further 20 day period of blinded CGM 
monitoring prior to the second hypoglycaemic clamp study. This means that 
participants in this group will have to insert the CGM device on 6 occasions during 
the study period. In each of these periods of blinded CGM monitoring the aim will be 
to collect at least 14 days of data. Study staff will collect the CGM devices at the end 
of each 20 day blinded period so that the data can be downloaded for analysis. CGM 
devices for these two blinded periods will be delivered to the participants’ home. The 
device for the 4 month period will then be collected from the participant by study staff. 
The device used prior to the second clamp study can be given to study staff at the 
clamp study visit. During each of these blinded CGM periods participants will be 
asked to complete a 7-day food diary, to include 5 week days and 2 weekend days. 
This can be in the form of a paper diary provided by study staff or a mobile phone 
application. This can be returned to study staff at the next visit or by post, a stamped 
addressed envelope will be provided. After the second clamp study participants will 
be invited to take part in a 3-month study extension phase. During this time they will 
be converted to the study devices. They will be asked to upload their study pump 
once a week and will have ad hoc contact with the investigators over this time to 
adjust pump settings as required. At the end of the 3 months they will be sent quality 
of life questionnaires to complete along with a stamped addressed envelope to return 
these to the investigators. 
 
 
Group 2 
Participants in group 2 will be continually monitored throughout the study period to 
ensure time in range is optimised throughout the 8 months. They will be asked to 
upload their insulin pump data at least once weekly to the online platform Tandem 
t:connect. This is done using a USB device provided with the insulin pump and the 
participants own computer or laptop with internet access. Participants will be given 
training in the use of the platform and account logins as part of their pump training. 
The data from the participant’s CGM device will also be reviewed by study staff. This 
data automatically uploads to the Dexcom Clarity cloud platform without the need for 
the participant to physically attach the device to their computer. Study staff will review 
blood glucose data on Dexcom clarity daily to ensure time in range is being 
maximised.  
 
Study staff will review the uploaded  pump data at least once weekly using 
administrative log-in details and will contact participants by telephone if the data 
suggests: 
1. Adjustments are required to insulin pump settings (carbohydrate ratios, insulin 
sensitivity factor, basal rates) as they are experiencing time out of the target 
glycaemic range 
2. The participant is not changing the insulin pump set every 3 days 
3. The participant requires further education about the low carbohydrate diet or 
carbohydrate counting 

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4. The participant is experiencing multiple alarms or error codes 
 
Participants will have contact information for study staff and will be able to contact 
staff via email or telephone on an ad hoc basis throughout the study. 
 
Study Visit 6  
A scheduled mid-point telephone consultation at 3-4 months will be arranged for all 
participants. This can be a face-to-face appointment if requested by the participant. 
All participants will also have a HbA1c measured at 4 months. This will be done using 
a home testing kit provided by Exeter Clinical Laboratory International if participants 
decide to have a telephone visit Samples are collected via a fingerstick blood test, in 
the same manner as checking a blood glucose, and then posted to the reference lab 
in Exeter for sample analysis. If the participant decided to have a face-to-face visit a 
laboratory HbA1c will be taken in place of the home testing kit. 
 
Participants in group 2 will be asked to attend for repeat retinopathy screening at 3-4 
months. 
 
Study Visit 7: Hypoglycaemic Clamp Study 
All participants will undergo a second hypoglycaemic clamp study, as previously 
described, at 8 months. Participants will be given the following questionnaires to 
complete. 
1. EQ5D 
2. Fear of Hypoglycaemic Scale 
3. Hypoglycaemic Confidence 
4. Diabetes Technology Attitudes 
5. Diabetes Specific Emotional Distress (DDS-1) 
6. Diabetes Treatment Satisfaction Questionnaire 
7. Gold Score 
 
Participants will return their study devices. They will be given the opportunity to 
discuss the study with study staff and provide any feedback. 
 
Study Visit 8 (Group 1 only) 
Participants in group 1 who have agreed to take part in the 3-month study extension 
phase will attend for training on using the Dexcom CGM along with the Tandem t:slim 
X2 insulin pump. This session will take a variable amount of time depending on if the 
participant was on an insulin pump prior to the study.  
 
After this visit participants will have ad hoc telephone contact with investigators to 
review insulin pump setting or provide advice regarding the devices. They will be 
asked to upload their pump once weekly to the t:connect platform. They will be sent 
the following questionnaires to complete at home after 3 months (+/- 2 weeks) which 
they will return to the investigators in a stamped addressed envelope: 
 
1. EQ5D 
2. Fear of Hypoglycaemic Scale 

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3. Hypoglycaemic Confidence 
4. Diabetes Technology Attitudes 
5. Diabetes Specific Emotional Distress (DDS-1) 
6. Diabetes Treatment Satisfaction Questionnaire 
7. Gold Score 
 
 
All participants will undergo repeat retinopathy screening at the end of the trial 
period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1: Study Procedures 
 
 
 

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Figure 3: Study Flowchart 

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6.2 
STORAGE AND ANALYSIS OF SAMPLES 
The blood tests set out in the table below will be required during the study. The volumes 
represent the volume required during the whole trial. 
Test 
Container 
Volume 
Required (ml) 
Number of Tests 
Total Volume 
Screening Visit 
HbA1c 
EDTA 
1ml 
1 
 
HbA1c spot 
Testing kit 
0.5ml 
1 
 
FBC 
EDTA 
2ml 
1 
 
Urea and Electrolytes 
LithHep 
5ml 
1 
 
Thyroid Function 
LithHep 
5ml 
1 
 
Pregnancy Test 
(urine) 
n/a 
n/a 
1 
n/a 
Total Volume 
 
 
 
13.5ml 
Clamp Study 1 
Glucagon 
EDTA 
3ml 
10 
30ml 
Cortisol 
Serum 
3ml 
10 
30ml 
Adrenaline 
LithHep 
3ml 
10 
30ml 
Noradrenaline 
LithHep 
3ml 
10 
30ml 
Insulin 
LithHep 
3ml 
10 
30ml 
Glucose 
Fluoride 
1ml 
48 
48ml 
Glucose (near-patient 
test) 
n/a 
0.5ml 
48 
24ml 
Glycerol 
Plasma 
2ml 
13 
26ml 
Free Fatty Acids 
Fluoride 
2ml 
10 
20ml 
D2 Glucose 
Plasma 
1ml 
13 
13ml 
D5 Glycerol (only in 
study visits when supply 
available) 
Plasma 
1ml 
13 
13ml 
Lipid profile 
Serum 
4ml 
1 
4ml 
Pregnancy Test 
(urine) 
n/a 
n/a 
1 
n/a 
Total Volume 
 
 
 
298ml 
4 Month Test 
HbA1c Spot (telephone 
visit) 
Testing kit 
0.5ml 
1 
0.5ml 
HbA1c (face-to-face 
visit) 
EDTA 
1ml 
1 
1ml 
Clamp Study 2 
Glucagon 
EDTA 
3ml 
10 
30ml 
Cortisol 
Serum 
3ml 
10 
30ml 
Adrenaline 
LithHep 
3ml 
10 
30ml 
Noradrenaline 
LithHep 
3ml 
10 
30ml 
Insulin 
LithHep 
3ml 
10 
30ml 
Glucose 
Fluoride 
1ml 
48 
48ml 
Glucose (near-patient 
test) 
n/a 
0.5ml 
48 
24ml 
Glycerol 
Plasma 
2ml 
13 
26ml 
Free Fatty Acids 
Fluoride 
2ml 
10 
20ml 
D2 Glucose 
Plasma 
1ml 
13 
13ml 
D5 Glycerol 
Plasma 
1ml 
13 
13ml 
Lipid profile 
Serum 
4ml 
1 
4ml 

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The measurement of blood glucose during the clamp study is critical for the safety of 
the participants and integral to the study itself. Without this we would not know if a 
participant was at the desired blood glucose level. Measurement of glucagon during 
the clamp study is key to determining the primary outcome of the trial- the glucagon 
response to hypoglycaemia. Other hormones that are involved in the body’s 
response to hypoglycaemia will also be measured during the clamp study 
(adrenaline, noradrenaline and cortisol). While these are not directly related to the 
primary outcome of the trial they are linked as the intervention may show an 
improvement in these responses. An improvement in these responses is also linked 
to improvement in awareness of hypoglycaemia, which is a secondary outcome 
measure for the trial for those with IAH. This trial is looking at time in range as a 
measure of blood glucose control in type 1 diabetes. This is an emerging tool for 
measuring control in diabetes that has only been made possible in recent years 
through new technologies such as CGM. Traditionally HbA1c is used as a measure 
of blood glucose control. That is why participants will have this measured at baseline, 
midpoint and endpoint. The HbA1c blood spot samples will not be analysed locally. 
They will be sent to a reference lab in Exeter for analysis (Exeter Clinical Laboratory 
International, Royal Devon and Exeter NHS Trust, Exeter).  
 
The blood taken during the screening visit and the lipid profile taken during the clamp 
studies are part of the standard monitoring of people with type 1 diabetes. 
 
During the trial period participant blood samples will be stored in the ERICRF. The 
blood samples will be stored in a secure and monitored environment and will be 
disposed of according to the Human Tissue Authority's code of practice after a period 
of 5 years.  
 
 
7 
DATA COLLECTION 
During the trial data will be collected by study staff. The following data will be 
collected at these time points: 
1. Selection of potential participants prior to consent: 
a. Review of electronic health care records, Trakcare and SCI Diabetes, 
for exclusion criteria  
b. This data will be reviewed by study staff who are part of the 
participant’s healthcare team 
2. Eligibility Assessment (after obtaining written informed consent): 
a. Inclusion and exclusion criteria assessment. 
b. Demographics (date of birth, sex, race and ethnicity) 
Pregnancy Test 
(urine) 
n/a 
n/a 
1 
n/a 
HbA1c Spot 
Testing kit 
0.5ml 
1 
0.5ml 
HbA1c 
EDTA 
1ml 
1 
1ml 
Total Volume 
 
 
 
299.5ml 
 
Volume for all tests (maximum): 
611ml 

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c. Contact information (retained at the site and not entered into study 
database) 
d. Medical history 
e. Concomitant medications 
f. Pregnancy test if applicable 
g. HbA1c blood test 
h. Bloods test for : Renal function and thyroid function 
i. 
Urine sample for albumin:creatinine ratio 
j. 
Physical examination to include: Weight, height, BMI, vital signs 
including measurement of blood pressure and heart rate 
k. Modified gold score 
l. 
Retinal screening will be arranged if this has not occurred in the 
previous 6 months  
3. Baseline: 
a. CGM Data: 
i. All participants will have blinded CGM data collected over a 20 
day period (aiming to capture at least 14 days of data) 
ii. This data will be collected automatically by the device after 
being fitted by the participant before being uploaded to a 
secure cloud-based platform 
b. All participants will complete the study questionnaires: 
i. Quality of life: EQ5D, Diabetes Specific Emotional Distress 
(DDS-1) 
ii. Treatment satisfaction: Diabetes treatment satisfaction 
questionnaire 
iii. Technology: Diabetes technology attitudes 
iv. Fear of hypoglycaemia: Hypoglycaemia confidence, Fear of 
Hypoglycaemic Scale 
c. All participants- first hypoglycaemic clamp study 
4. Trial period 
a. Participants in group 2 will have data collected from their insulin pump 
and CGM device 
b. Insulin pump data will be uploaded by the participant at least once per 
week to the secure platform Tandem t:connect 
c. CGM data will be automatically uploaded to the secure cloud-based 
platform Dexcom Clarity 
 
 
5. Midpoint 
a. Participants in group 1 will undergo a further 20 day period of blinded 
CGM data collection 
b. All participants will have blood taken for HbA1c 
6. Endpoint: 
a. Participants in group 1 will undergo a further 20 day period of blinded 
CGM data collection 
b. All participants will complete the study questionnaires: 

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i. Quality of life 
ii. Treatment satisfaction 
iii. Technology 
iv. Fear of hypoglycaemia 
c. All participants- second hypoglycaemic clamp study 
7. Study extension phase (3 months) 
a. Participants in group 1 who agree to the extension phase will have 
data collected from their pump and CGM device 
b. Insulin pump data will be uploaded once weekly to the to the secure 
Tandem t:connect 
c. CGM data will be automatically uploaded to the secure cloud-based 
platform Dexcom Clarity 
d. The following questionnaires will be completed: 
i. EQ5D 
ii. Fear of Hypoglycaemic Scale 
iii. Hypoglycaemic Confidence 
iv. Diabetes Technology Attitudes 
v. Diabetes Specific Emotional Distress (DDS-1) 
vi. Diabetes Treatment Satisfaction Questionnaire 
vii. Gold Score 
 
 
Participants will be given different options for completing the questionnaires related 
to the trial. They can be completed while at a visit with study staff, can be taken 
home and returned to staff by post or handed to study staff at the next visit.  
 
7.1 
 Source Data Documentation 
Source documents for the study: 
• 
Electronic health records- Trakcare and SCI Diabetes 
• 
Participant case report forms 
• 
Study questionnaires 
• 
Dexcom G6 glucose data on Dexcom Clarity 
• 
Tandem pump and control IQ data on t:connect 
• 
Food diary 
• 
Ketone recording sheet 
 

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7.2 
Case Report Forms 
Participant data will be collected on paper case report forms. The case report form will be 
identified using the participant’s unique study identifier and not identifiable information such as 
name or CHI. The case report form will be stored in locked and secure rooms in the ERICR 
/ERI outpatient department. Any electronic information collected will be stored on an NHS 
computer with password-controlled access. All patient identifiers will be removed and allocated 
a study ID number.  This will be stored on a secure NHS server for 6 years. 
.  
8 
DATA MANAGEMENT 
8.1 
Personal Data 
The following personal data will be collected as part of the research: 
• 
Name 
• 
Address 
• 
Date of birth 
• 
Contact telephone number(s) 
• 
Email address 
• 
CHI number 
 
Personal data will be stored by the research team in the Edinburgh Royal Infirmary 
under lock and key. Data will only be accessible by study staff. The code break will 
be kept on a password protected NHS computer.  
Personal data will be stored for 12-24 months. 
8.2 
Data Information Flow 
Data collected by study staff will be held on secure password protected NHS computers in the 
Edinburgh Royal Infirmary and in a locked cupboard in the Edinburgh Royal Infirmary. Only 
study staff will have access to this data. Anonymised reports on the study will be sent during 
the trial period to the Helmsley Charitable Trust, Tandem and Dexcom. The headquarters of 
these companies are based in the United States. 
 
8.3 
Transfer of Data 
Data collected or generated by the study (including personal data) will not be transferred to 
any external individuals or organisations outside of the Sponsoring organisation(s).  
Reports containing anonymised data will be sent during the trial period to the Helmsley 
Charitable Trust, Tandem and Dexcom.  
 
8.4 
Data Controller 
A data controller is an organisation that determines the purposes for which, and the manner in 
which, any personal data are processed. 
The University of Edinburgh and NHS Lothian are joint data controllers along with any other 
entities involved in delivering the study that may be a data controller in accordance with 
applicable laws (e.g. the site). 
 

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8.5 
Data Breaches 
Any data breaches will be reported to the University of Edinburgh and NHS Lothian Data 
Protection Officers who will onward report to the relevant authority according to the appropriate 
timelines if required. 
9 
STATISTICS AND DATA ANALYSIS 
9.1 
SAMPLE SIZE CALCULATION 
Sample size is based on previous work by Cranston et al ‘Restoration of 
hypoglycaemic awareness in patients with long-duration insulin dependent diabetes’ 
which was published in the Lancet in 1994. They used a similar sample size in this 
study. 
 
9.2 
PROPOSED ANALYSES 
In primary analyses, the glucagon response to insulin induced hypoglycaemia at 0 and 8 
months will be compared to the individual’s baseline glucagon responses within each group. In 
further exploratory analyses, the participants in the highest tertile of glycaemic TIR as a group 
over the 8 months will be compared to those in the lowest tertile over the 8 months as a  
group. The rate of appearance (Ra) of the stable isotopes will be used as a marker of 
endogenous glucose production. Analysis of tracee:tracer ratio will be made by mass 
spectrometry. The TIR of participants completing the study 3-month extensions will be 
compared to that of group 2 during the study. 
We predict minimizing exposure of alpha cells to hyperglycemia with AID +/- VLCD should 
significantly enhance glucagon. 
10 
ADVERSE EVENTS 
10.1 DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a clinical trial 
participant, which does not necessarily have a causal relationship with the study 
intervention. 
An adverse reaction (AR) is any untoward and unintended response that has 
occurred due to the intervention  
A serious adverse event (SAE), serious adverse reaction (SAR). Any AE or AR 
that: 
• 
results in death of the clinical trial participant; 
• 
     is life threatening*; 
• 
requires in-patient hospitalisation^ or prolongation of existing hospitalisation; 
• 
results in persistent or significant disability or incapacity; 
• 
consists of a congenital anomaly or birth defect; 
• 
results in any other significant medical event not meeting the criteria above. 
 
*Life-threatening in the definition of an SAE or SAR refers to an event where 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. 

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^Any hospitalisation that was planned prior to enrolment will not meet SAE criteria. 
Any hospitalisation that is planned post enrolment will meet the SAE criteria. 
 
Adverse Device Effect (ADE) is an adverse event related to the use of a medical 
device. This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, the 
installation, the operation, or any malfunction of the investigational medical device.  
An ADE includes any event that is a result of a use error or intentional misuse. Use 
error refers to an act or omission of an act that results in a different device response 
than intended by the manufacturer or expected by the user. An unexpected 
physiological response of the subject does not in itself constitute a use error.  
 
Serious Adverse Device Effect (SADE) is an adverse event effect that has resulted 
in any of the consequences characteristics of a SAE (as defined above). This 
includes device deficiencies that might have led to a SAE if:  
•  Suitable action had not been taken  
•  Intervention had not been made  
•  If circumstances had been less fortunate  
 
Anticipated Serious Adverse Device Effect (ASADE) is a serious adverse device 
effect..  
 
Unanticipated Serious Adverse Device Effect (USADE) is a serious adverse 
device effect which by its nature, incidence, severity or outcome is not expected in 
terms of what is known about the device.  
 
We will reference the manufacturer manuals for each device to identify anticipated 
and unanticipated adverse device effects. The manual for the Dexcom G6 can be 
found here: https://s3-us-west-2.amazonaws.com/dexcompdf/G6-CGM-Users-
Guide.pdf  and the manual for the tandem t:slim X2 with Control IQ can be found 
here: https://www.tandemdiabetes.com/docs/default-source/product-documents/t-
slim-x2-insulin-pump/k%c3%a4ytt%c3%b6opas-(t-slim-x2--pumppu-control-iq-
teknologialla)cf14759775426a79a519ff1100a9fd393f6fb39775426a79a519ff1200a9f
d39.pdf?sfvrsn=18a507d7_66. 
 
Device Deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. Device deficiencies include 
malfunctions, use errors and inadequate labelling.  
 
10.2 IDENTIFYING AEs AND SAEs 
Participants will be asked about the occurrence of AEs/SAEs at every visit during the 
study.  Open-ended and non-leading verbal questioning of the participant will be 
used to enquire about AE/SAE occurrence.  Participants will also be asked if they 
have been admitted to hospital, had any accidents, used any new medicines or 
changed concomitant medication regimens.  If there is any doubt as to whether a 
clinical observation is an AE, the event will be recorded. 
AEs and SAEs may also be identified via information from support departments e.g. 
laboratories. 

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10.3 RECORDING AEs, SAEs and SADEs 
When an AE/SAE occurs, it is the responsibility of the Investigator, or another 
suitably qualified physician in the research team who is delegated to record and 
report AEs/SAEs, to review all documentation (e.g. hospital notes, laboratory and 
diagnostic reports) related to the event.  The investigator will record all relevant 
information in the CRF/AE logs. 
Information to be collected includes dose, type of event, onset date, Investigator 
assessment of severity and causality, date of resolution as well as treatment 
required, investigations needed and outcome.   
10.3.1 Pre-existing Medical Conditions 
Pre-existing medical conditions (i.e. existed prior to informed consent) should be 
recorded as medical history and only recorded as adverse events if medically judged 
to have worsened during the study.  
10.3.2 Worsening of the Underlying Condition during the Trial 
Medical occurrences or symptoms of deterioration that are expected due to the 
participant’s underlying condition should be recorded in the patient’s medical notes 
and only be recorded as AEs on the AE log if medically judged to have unexpectedly 
worsened during the study. Events that are consistent with the expected progression 
of the underlying disease should not be recorded as AEs.  
10.4 ASSESSMENT OF AEs AND SAEs 
 
Each AE must be assessed for seriousness, causality, severity and expectedness by 
the Principal Investigator or another suitably qualified physician in the research team 
who has been delegated this role.  
Where there are two assessments of causality (e.g. between PI and Chief 
Investigator (CI)), the causality assessment by the Investigator cannot be 
downgraded. In the case of a difference of opinion, both assessments are recorded 
and the ‘worst case’ assessment is used for reporting purposes.  
10.4.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 10.1. 
10.4.2 Assessment of Causality 
The Investigator will make an assessment of whether the AE/SAE is likely to be 
related to the study intervention or medical device according to the definitions below.   
 
• 
Unrelated: where an event is not considered to be related to the study 
intervention or device. 
 
• 
Possibly Related: The nature of the event, the underlying medical condition, 
concomitant medication or temporal relationship make it possible that the AE 
has a causal relationship to the study intervention or device.  
10.4.3 Assessment of Expectedness  

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10.4.3.1 IMP 
If the AE is judged to be related to the study intervention, the PI will make an 
assessment of expectedness. 
The event may be classed as either: 
Expected: the type of event is expected in line with the study intervention 
Unexpected: the type of event was not listed in the protocol or related 
documents/literature as an expected occurrence. 
 
10.4.3.2 Medical Device 
If the AE is judged to be related to the device, the investigator will make an 
assessment of expected based on knowledge of the reaction and any relevant 
product information. The event will be classed as either: 
Expected: the reaction is consistent with the effects of the device that are known. 
Unexpected: the reaction is not consistent with the effects that are known  
 
The above will be assessed in relation to the manufacturer user guides for each 
device. 
 
10.4.4 Assessment of Severity 
The Investigator will make an assessment of severity for each AE and record this on 
the CRF/AE log or SAE form according to one of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with every day activities. 
Moderate: an event that is sufficiently discomforting to interfere with normal everyday 
activities. 
Severe: an event that prevents normal everyday activities. 
Note: the term ‘severe’, used to describe the intensity, should not be confused with 
‘serious’ which is a regulatory definition based on participant/event outcome or action 
criteria.  For example, a headache may be severe but not serious, while a minor 
stroke is serious but may not be severe. 
 
10.5 REPORTING OF SAEs and SADEs TO THE SPONSOR 
Once the Investigator becomes aware that an SAE/SADE has occurred in a study 
participant, the information will be reported to the ACCORD Research Governance 
within 24 hours. If the Investigator does not have all information regarding an SAE, 
SADE they should not wait for this additional information before notifying ACCORD.  
The SAE  report form (and SADE report form where appropriate) can be updated 
when the additional information is received. Reports will be complete as far as 
possible and will be signed and dated by the Investigator.  
The SAE form (and SADE report form where appropriate) will be transmitted via 
email to safety@accord.scot. Only forms in a pdf format will be accepted by 
ACCORD via email. Where missing information has not been sent to ACCORD after 
an initial report, ACCORD will contact the Investigator and request the missing 
information. The Investigator must respond to these requests in a timely manner.   

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Once an SAE or SADE report is received by ACCORD it will be entered onto the 
ACCORD PhV database by the Research Governance Coordinator or designee.  
All safety reports transmitted to ACCORD (including any follow-up information and 
correspondence) will be kept by the Investigator in the Trial Master File (TMF).  
 
10.6 REPORTING OF DEVICE DEFICIENCIES  
Device deficiencies will be documented on the ACCORD Medical Device Deficiency 
Form and will be reported to the sponsor in accordance with section 10.5 above.   
On receipt of device deficiency reports, the Research Governance Coordinator, or 
designee, will assess the report to ensure the correct assessment has been made. In 
the case of the event meeting SAE, SADE or USADE criteria, the Research 
Governance Coordinator, or designee will ensure that all the correct reporting 
procedures have been followed.  
The Research Governance Coordinator, or designee, will complete and return the 
Cover Sheet and Return Receipt or send an email to confirm receipt of the Device 
deficiency report within 1 working day. If this email/fax is not received within 1 
working day of sending the report to ACCORD, the Investigator must telephone 
ACCORD on +44 (0)131 242 3330 to check that the report has been received by 
ACCORD  
The Investigator is responsible for reporting device deficiencies to the relevant NHS 
Medical Physics department.  
Device deficiency reports emailed or faxed to ACCORD and any follow-up 
information and correspondence will be kept by the Investigator in the TMF.  
10.7 MEDICAL DEVICE QUARANTINE 
If the event is defined as serious i.e. a SAE or device deficiency that could have led 
to SADE or USADE the Investigator must quarantine the device as soon as possible 
e.g. segregating the device from other equipment and labelling as not for use with 
contact details attached.  
Until the  Sponsor has been given the opportunity to carry out an investigation, all 
items (together with relevant packaging materials) should be quarantined. They 
should not be repaired, or discarded or returned to the manufacturer without 
agreement from the sponsor.  
Investigators should contact the manufacturer to obtain information relating to the 
procedure for returning the device, where considered appropriate.  
The device should be cleaned and decontaminated where appropriate, securely 
packaged, and clearly labelled, including the manufacturer reference number if 
needed.  
 
 
11 
OVERSIGHT ARRANGEMENTS 
11.1 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring and audits 
on behalf of the sponsor, REC review, and regulatory inspection(s).  In the event of audit or 
monitoring, the Investigator agrees to allow the representatives of the sponsor direct access to 
all study records and source documentation. In the event of regulatory inspection, the 
Investigator agrees to allow inspectors direct access to all study records and source 
documentation. 

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11.2 STUDY MONITORING AND AUDIT 
The ACCORD Sponsor Representative will assess the study to determine if an 
independent risk assessment is required.  If required, the independent risk 
assessment will be carried out by the ACCORD Quality Assurance Group to 
determine if an audit should be performed before/during/after the study and, if so, at 
what frequency. 
 
Risk assessment, if required, will determine if audit by the ACCORD QA group is required. 
Should audit be required, details will be captured in an audit plan. Audit of Investigator sites, 
study management activities and study collaborative units, facilities and 3rd parties may be 
performed. 
 
12 
GOOD CLINICAL PRACTICE 
12.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH GCP). 
 
Before the study can commence, all required approvals will be obtained and any 
conditions of approvals will be met. 
12.2 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments.  In accordance with the principles of ICH GCP, 
the following areas listed in this section are also the responsibility of the Investigator.  
Responsibilities may be delegated to an appropriate member of study site staff.   
12.2.1 Informed Consent 
The Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out. The decision of a participant to participate in clinical 
research is voluntary and should be based on a clear understanding of what is involved. 
Participants must receive adequate oral and written information – appropriate Participant 
Information and Informed Consent Forms will be provided. The oral explanation to the 
participant will be performed by the Investigator or qualified delegated person, and must cover 
all the elements specified in the Participant Information Sheet and Consent Form. 
The participant must be given every opportunity to clarify any points they do not understand 
and, if necessary, ask for more information. The participant must be given sufficient time to 
consider the information provided.  It should be emphasised that the participant may withdraw 
their consent to participate at any time without loss of benefits to which they otherwise would 
be entitled. 
The participant will be informed and agree to their medical records being inspected by 
representatives of the sponsor(s).The Investigator or delegated member of the trial team and 
the participant will sign and date the Informed Consent Form(s) to confirm that consent has 
been obtained. The participant will receive a copy of this document and a copy filed in the 
Investigator Site File (ISF) and participant’s medical notes (if applicable). 
12.2.2 Study Site Staff 

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The Investigator must be familiar with the protocol and the study requirements.  It is the 
Investigator’s responsibility to ensure that all staff assisting with the study are adequately 
informed about the protocol and their trial related duties. 
12.2.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the CRF at each 
Investigator Site.  
12.2.4  Investigator Documentation 
The Principal Investigator will ensure that the required documentation is available in local 
Investigator Site files ISFs.  
12.2.5 GCP Training 
For non-CTIMP (i.e. non-drug) studies all researchers are encouraged to undertake GCP 
training in order to understand the principles of GCP. However, this is not a mandatory 
requirement unless deemed so by the sponsor.  GCP training status for all investigators should 
be indicated in their respective CVs.  
12.2.6 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records must be identified in a 
manner designed to maintain participant confidentiality.  All records must be kept in a secure 
storage area with limited access.  Clinical information will not be released without the written 
permission of the participant.  The Investigator and study site staff involved with this study may 
not disclose or use for any purpose other than performance of the study, any data, record, or 
other unpublished information, which is confidential or identifiable, and has been disclosed to 
those individuals for the purpose of the study..  Prior written agreement from the sponsor or its 
designee must be obtained for the disclosure of any said confidential information to other 
parties. 
12.2.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the requirements 
of the appropriate data protection legislation (including the General Data Protection Regulation 
and Data Protection Act) with regard to the collection, storage, processing and disclosure of 
personal information.  
Computers used to collate the data will have limited access measures via user names and 
passwords. 
 
Published results will not contain any personal data and be of a form where individuals are not 
identified and re-identification is not likely to take place. 
 
Dexcom clarity uses standard internet access to a specific set of IP addresses. No interface 
with clinic medical records is required for a clinic to operate. Data traffic is secured using TLS  
1.2. Data is encrypted at rest using AES-256 encryption. Data is redundantly backed up across 
wide geographic separation. Published results will not contain any personal data that could 
allow identification of individual participants. 
 
 
 
The Tandem t:connect application utilizes a stand-alone relational database that is setup 
specifically for each Clinical Trial. The original pump data that is extracted from the device is 
validated with a Checksum value before uploading, uploaded via a secure web service (SSL) 
and stored in a database table in its original XML form for archival purposes; this essentially 
serves as a Read-Only data store. The pump XML data is then read, transformed and stored 
into respective database tables which maintain integrity through the use of indexes and 

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relational key constraints. The database’s integrated Security Roles and Users control access 
to the data, allowing only the Application, secure Web Services and authorized support 
personnel to access the data. Data access is logged using a combination of integrated database 
logs and custom code. 
 
13 
STUDY CONDUCT RESPONSIBILITIES 
13.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of an urgent safety measure, must be reviewed and 
approved by the Chief Investigator.   
Amendments will be submitted to a sponsor representative for review and authorisation before 
being submitted in writing to the appropriate REC, and local R&D for approval prior to 
participants being enrolled into an amended protocol. 
13.2 MANAGEMENT OF PROTOCOL NON COMPLIANCE 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the sponsors and 
therefore will not be implemented, except where necessary to eliminate an immediate hazard 
to study participants. If this necessitates a subsequent protocol amendment, this should be 
submitted to the REC, and local R&D for review and approval if appropriate. 
Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to the 
sponsors every 3 months. Each protocol violation will be reported to the sponsor within 3 days 
of becoming aware of the violation.  All protocol deviation logs and violation forms should be 
emailed to QA@accord.scot 
Deviations and violations are non-compliance events discovered after the event has occurred.  
Deviation logs will be maintained for each site in multi-centre studies.  An alternative frequency 
of deviation log submission to the sponsors may be agreed in writing with the sponsors. 
 
13.3 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or 
delegates, the co-sponsors (seriousbreach@accord.scot) must be notified within 24 hours.  It 
is the responsibility of the co-sponsors to assess the impact of the breach on the scientific value 
of the trial, to determine whether the incident constitutes a serious breach and report to research 
ethics committees as necessary.  
13.4 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 5 years from the protocol defined end of 
study point. When the minimum retention period has elapsed, study documentation will not be 
destroyed without permission from the sponsor. 
13.5 END OF STUDY 
The end of study is defined as the last participant’s last visit.   

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The Investigators or the co-sponsor(s) have the right at any time to terminate the study for 
clinical or administrative reasons.  
The end of the study will be reported to the REC, and R+D Office(s) and co-sponsors within 90 
days, or 15 days if the study is terminated prematurely. The Investigators will inform participants 
of the premature study closure and ensure that the appropriate follow up is arranged for all 
participants involved. End of study notification will be reported to the co-sponsors via email to 
resgov@accord.scot 
A summary report of the study will be provided to the REC within 1 year of the end of the study. 
 
13.6 CONTINUATION OF TREATMENT FOLLOWING THE END OF 
STUDY 
Participants recruited to the study will be on the NHS Lothian insulin pump waiting list. At the 
end of the study participants will have to return their study devices, Tandem t:slim X2 insulin 
pump and Dexcom G6 CGM, to the study team. They will continue with their pump process as 
per the NHS Lothian pump waiting list. The pump used in this trial is one of the pumps offered 
by NHS Lothian and so participants may choose to continue with this pump. Dexcom CGM is 
not currently available through NHS Lothian. If participants wish to continue with this they would 
have to self-fund the CGM device, they would need to do this in order to use the Control IQ 
algorithm. At the end of the study participants following the low carbohydrate diet may choose 
to revert back to their pre-study diet. 
 
13.7 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance or 
indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
• 
The Protocol has been designed by the Chief Investigator and researchers employed 
by the University and collaborators.  The University has insurance in place (which 
includes no-fault compensation) for negligent harm caused by poor protocol design 
by the Chief Investigator and researchers employed by the University. 
• 
Sites participating in the study will be liable for clinical negligence and other negligent 
harm to individuals taking part in the study and covered by the duty of care owed to 
them by the sites concerned.  The co-sponsors require individual sites participating 
in the study to arrange for their own insurance or indemnity in respect of these 
liabilities. 
• 
Sites which are part of the United Kingdom's National Health Service will have the 
benefit of NHS Indemnity. 
• 
Sites out with the United Kingdom will be responsible for arranging their own 
indemnity or insurance for their participation in the study, as well as for compliance 
with local law applicable to their participation in the study. 
14 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
14.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team. Anonymised data will 
be shared with the Helmsley Charitable Trust, Tandem and Dexcom. The company 

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headquarters for these organisations are based in the United States. The study team intend to 
also disseminate anonymised data through presentation at conferences, publication in peer 
reviewed journals and the completion of a thesis. 
 
 
 
15 
REFERENCES 
 
1. 
McNeilly AD, McCrimmon RJ. Impaired hypoglycaemia awareness in type 1 
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