Continuous Glucose Monitoring: An Evaluation of Impact on Improving the Efficiency of Diagnostic Processes and Enhancing Patient Safety in the Management of Reactive and Spontaneous Hypoglycaemia
Phase: NA
Conditions: Hypoglycemia, Reactive, Hypoglycaemia Night, Hypoglycemia Non-Diabetic, Hypoglycemia Unawareness, Insulinoma, Insulinoma; Malignant, Pancreas, Insulin Hypoglycemia, Insulin Resistance, Spontaneous Hypoglycemia, Neuro Endocrine Tumours
Sponsor: Barts & The London NHS Trust

 
 
 
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JRMO Research Protocol for  
Interventional Studies  
 
 
 
 
Full Title  
Continuous Glucose Monitoring: An evaluation of impact on improving the efficiency of 
diagnostic processes and enhancing patient safety in the management of reactive and spontaneous 
hypoglycaemia. 
 
Short Title 
CGM use in diagnosis of spontaneous and reactive  
hypoglycaemia 
 
Sponsor 
 
Barts Health NHS Trust 
 
Contact person: 
 
Dr Mays Jawad 
Research & Development Governance 
Operations Manager 
Joint Research Management Office 
 
5 Walden Street 
 
London 
 
E1 2EF 
 
Phone: 020 7882 7275/6574 
 
Email: research.governance@qmul.ac.uk 
 
 
IRAS Number 
265405 
 
 
REC Reference 
19/LO/1518 
 
Chief Investigator 
Dr Scott A Akker 
Consultant endocrinologist 
Department of endocrinology, St Bartholomew’s 
Hospital 
Ward 6C 
West Smithfield 
London EC1A 7BE 
0207 377 7000 
s.a.akker@qmul.ac.uk 
 
List of sites 
Department of endocrinology, St Bartholomew’s 
Hospital 
Dr Scott Akker/ Dr Craig Stiles 
Ward 6C 
West Smithfield 
London EC1A 7BE 
 

 
 
 
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0207 377 7000 
c.stiles@qmul.ac.uk  
 
List of laboratories 
None 
 
List of technical departments 
None 
 
List of central facilities 
None 

 
 
 
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1. Contents 
 
1. 
Contents ......................................................................................................... 3 
2. 
Glossary ......................................................................................................... 6 
3. 
Signature page ............................................................................................... 7 
4. 
Summary and synopsis .................................................................................. 7 
5. 
Introduction ..................................................................................................... 9 
5.1 
Background ............................................................................................... 10 
5.2 
Preclinical data .......................................................................................... 10 
5.3 
Clinical data .............................................................................................. 10 
5.4 
Rationale ................................................................................................... 11 
5.5 
Risks / benefits .......................................................................................... 12 
6. 
Study objectives ........................................................................................... 12 
6.1 
Primary objective....................................................................................... 12 
6.2 
Secondary objective .................................................................................. 13 
6.3 
Primary endpoint ....................................................................................... 13 
6.4 
Secondary endpoint ..................................... Error! Bookmark not defined. 
7. 
Study population ........................................................................................... 13 
7.1 
Inclusion criteria ........................................................................................ 14 
7.2 
Exclusion criteria ....................................................................................... 14 
8. 
Study design ................................................................................................. 15 
9. 
Study procedures ......................................................................................... 16 
10. 
Assessment and management of risk ........................................................... 19 
11. 
Statistical considerations .............................................................................. 26 
11.1 Sample size .............................................................................................. 26 
11.2 Method of analysis .................................................................................... 27 
12. 
Ethics ........................................................................................................... 27 

 
 
 
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13. 
Public Involvement........................................................................................ 28 
14. 
Data handling and record keeping ................................................................ 29 
14.1 Data management ..................................................................................... 29 
14.2 Source data ............................................................................................... 29 
14.3 Confidentiality ........................................................................................... 29 
14.4 Record Retention and Archiving ................................................................ 30 
15. 
Laboratories ................................................................................................. 30 
15.1 Central and local laboratories .................................................................... 30 
15.2 Sample collection and preparation ............... Error! Bookmark not defined. 
15.3 Lab procedures ......................................................................................... 30 
15.4 Sample storage and transfer ..................................................................... 30 
16. 
Interventions and tools .................................................................................. 30 
16.1 Devices ..................................................................................................... 30 
16.2 Techniques and interventions ................................................................... 31 
16.3 Tools ......................................................................................................... 31 
16.4 Medicinal product ...................................................................................... 31 
16.5 Other biological or chemical products ........................................................ 31 
17. 
Safety reporting ............................................................................................ 31 
17.1 Adverse Events (AEs) ............................................................................... 31 
17.2 Adverse Reaction (ARs) ............................................................................ 32 
17.3 Notification and reporting of Adverse Events and Reactions ..................... 32 
17.4 Serious Adverse Events (SAEs) or reactions ............................................ 32 
17.5 Notification and reporting of Serious Adverse Events ................................ 32 
17.6 Urgent Safety Measures ............................................................................ 32 
17.7 Annual Safety Reporting ........................................................................... 33 
17.8 Overview of the Safety Reporting responsibilities ...................................... 33 
18. 
Monitoring and auditing ................................................................................ 33 
19. 
Trial committees ........................................................................................... 33 

 
 
 
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20. 
Finance and funding ..................................................................................... 33 
21. 
Indemnity ...................................................................................................... 33 
22. 
Dissemination of research findings ............................................................... 33 
23. 
References ................................................................................................... 34 
 
 

 
 
 
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2. Glossary 
 
CGM – continuous glucose monitoring 
CBG – capillary blood glucose  
 

 
 
 
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3. Signature page 
 
 
 
 
 
 
4. Summary and synopsis 
 
Short title 
CGM use in diagnosis of spontaneous hypoglycaemia 
Methodology 
Clinical trial studying a novel intervention in clinical practice 
Research sites 
St Bartholomew’s hospital 
Objectives / aims 
Objectives 
1) Use CGM (blinded to the patient and investigator) in 
advance of standard investigations (where possible) 
in order to record whether patient symptoms 
correlate with recorded hypoglycaemia. This may 
exclude hypoglycaemia as a cause of symptoms 
and allow the patient to avoid a prolonged inpatient 
investigation. 
2) Use CGM technology (blinded to the patient and 
investigator) alongside standard investigations for 
patients with both reactive and spontaneous 
hypoglycaemia to see If there is additional value in 
using two methods in detecting hypoglycaemic 
episodes. 
3) Use CGM (blinded to the patient and investigator) to 
record frequency of hypoglycaemia after medical 
treatment has been initiated in order to assess its 
effectiveness in detecting hypoglycaemic episodes 
of which the patient may not have been aware, 
potentially reducing the need for painful finger prick 
glucose testing.  
4) Use CGM (unblinded) to titrate medication to abolish 

 
 
 
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hypoglycaemia in order to improve outpatient 
management and improve patient safety. The 
Dexcom system has an alarm to alert patients to 
hypoglycaemia which will be used in the unblinded 
phase. 
Aims 
There will be two main arms to the study; 
1) Investigation of patients suspected of having 
hypoglycaemia (spontaneous or reactive) alongside 
standard investigations 
2) Management of patients with confirmed hypoglycaemia 
who are medically managed to see if continuous glucose 
monitoring can play a role in abolishing asymptomatic 
hypoglycaemia through optimisation of medicines. 
 
Number of 
participants 
30 
Inclusion and 
exclusion criteria 
Inclusion Criteria 
Able and willing to give informed consent. No vulnerable 
adults will be included. 
Either conventional gender, or non-binary. 
Age >18 years 
Any ethnicity 
Any socio economic group 
Medical condition as detailed above – arm 1 under 
investigation for possible/probable hypoglycaemia 
Arm 2 – on medical therapy for established hypoglycaemia 
 
Exclusion criteria 
Unwilling or unable to give consent 
Unable to speak sufficient English to give consent and 
understand study requirements 
Age<18 or >90 years 
Lack of capacity to consent 
Underlying hepatic condition 
Current excessive alcohol consumption (men regularly 
consuming >50 units/week, women >35 units/week) 
Diabetes Mellitus 
Current use of Diabetic medication or insulin 
Currently pregnant 
Any patient on haemo or peritoneal dialysis 
 
Statistical 
methodology and 
analysis (if 
applicable) 
 
Study duration 
1 year 
 

 
 
 
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5. Introduction 
Suspected reactive and spontaneous hypoglycaemia can be a challenging problem 
to investigate. Definitive diagnosis currently relies upon the patient experiencing 
symptoms, reporting them accurately and then a series of complex investigations.  
Current standard of care tests 
Current ‘gold standard’ testing when reactive hypoglycaemia is suspected is with an 
extended oral glucose tolerance test or mixed meal test. Where spontaneous 
hypoglycaemia is suspected and where facilities exist, the ‘gold standard’ test is an 
admission to Hospital for a 72 hour fast with twice daily laboratory measurements of 
plasma glucose, insulin and c-peptide. Finger prick glucose measurements are taken 
throughout the day to check for asymptomatic hypoglycaemia. Additional laboratory 
measurements are made if the patient becomes symptomatic. The prolonged fast is 
terminated when a diagnostic laboratory glucose measurement of <2.2mmol/L is 
reached. Where a 72 hour fast is not possible, attempts are made to test insulin and 
glucose after three separate 15 hour fasts but this risks out of hospital 
hypoglycaemia and all its potential sequelae. These investigations attempt to mimic 
the situations which precipitate the hypoglycaemia but, in particular for reactive 
hypoglycaemia, often fail to do so.  
Pathophysiology and significance of hypoglycaemia 
Symptomatic reactive hypoglycaemia is recognized in some patients with insulin 
resistance before the development of type 2 diabetes and is increasingly recognized 
as a complication of significant weight loss following bariatric surgery. Spontaneous 
hypoglycaemia is most commonly caused by an insulinoma which is a very rare 
diagnosis outside the context of MEN1 (1-4/million patients). In patients with MEN1, 
insulinoma is the second most common functioning pancreatic islet cell tumour (10-
30%) (1) and typically occurs before the age of 40. In MEN1, the management of an 
insulinoma is the most challenging as: 1) Hypoglycaemia may be under reported as 
long term exposure to hypoglycaemia can result in hypoglycaemic autonomic failure 
with blunting or loss of the body’s sympathetic response (loss of hypoglycaemic 
awareness) and an inability to counter-regulate subsequent or more serious events 
(2), including the possibility of sudden death (probably through cardiac arrhythmia) 
(3-5). 2) The chances of successful surgical resection and cure are lower as almost 
all MEN1 patients have multiple pancreatic lesions, many of which are smaller than 
the resolution of current imaging modalities. It can be difficult or impossible to know 
which lesion is producing insulin and extensive surgery can lead to pancreatic 
insufficiency to a degree that leaves the patient with extremely difficult to manage 
diabetes. As such patients are therefore often given medical therapies; these 
however are difficult to monitor for effectiveness, especially if there is loss of 
hypoglycaemic awareness.  
Current testing limitations 
Finger-prick glucose testing is currently the only viable way of home testing. 
Asymptomatic nocturnal hypoglycaemia is of most concern as repeat episodes are 
likely to lead to cumulative long term consequences of cerebral hypoglycaemia. 
Finger prick testing is unpopular amongst patients – it is painful and requires disposal 

 
 
 
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of ‘medical sharps’. It also only provides a ‘snapshot’ of the patient’s glycaemic state 
and so will, by its very nature; only provide this ‘snapshot’ when the patient is awake 
and able to use it.  
Continuous glucose monitoring 
CGM technology has transformed the monitoring of patients with diabetes mellitus 
who are insulin treated, particularly those affected by asymptomatic hypoglycaemia. 
The Dexcom system, which we  will use for this study has performed favourably 
against competitors in the hypoglycaemic ranges in a head to head comparison study 
(6) and in a study examining the accuracy of the G6 device specifically (7). When 
using concomitant gold standard YSI glucose measurements as reference, for blood 
glucoses of <54mg/dL (3mmol/L) the G6 device was within 30% of the reference 
value 93.5% of the time and within 20%  85% of the time. For blood glucoses 54-
69mg/dL (3-3.9mmol/L) these figures were 94.4 and 97.7% respectively (7).. Each 
system is composed of an implantable sensor (which can easily be placed by the 
patient) with a small probe that sits just under the skin and a chip which sits outside, 
all held in place by a dressing. Dexcom devices have enabled the instantaneous 
measurement of a surrogate of the capillary blood glucose simply by waving a mobile 
device (a proprietary device, or more recently a mobile phone or tablet) over the 
sensor. In addition to providing a ‘stat’ CBG reading, these devices can give quarter-
hourly CBG readings for the entire life time of a sensor, data which can be 
downloaded onto a mobile device for later analysis. The Dexcom G6 device also 
allows the real time CBG readings to be shared ‘live’ with up to five people, providing 
additional safety and reassurance. In the context of reactive and spontaneous 
hypoglycaemia titration of anti-hypoglycaemia medication could be made through 
virtual consultations during the monitoring period.  
 
 
5.1 
Background  
See above 
 
 
5.2 
Preclinical data  
 
 
 
5.3 
Clinical data  
Case Vignette: A 20 year old lady with mild learning difficulties was recently found to 
have spontaneous hypoglycaemia and primary hyperparathyroidism on presentation 
to hospital. There is a family history of MEN1. Results confirmed an inappropriately 
high insulin and C-peptide in the presence of hypoglycaemia 8 hours into a fast; 
results in keeping with an insulinoma. The patient had no apparent hypoglycaemia-
awareness. MRI showed three lesions in the pancreas, each in keeping with an islet 
cell tumour. Medical treatment was started (diazoxide) and titrated to abolish 
recorded hypoglycaemia while in hospital. At home however, with more physical 
activity, her mother reported ongoing symptoms of hypoglycaemia and a CGM device 
was used to monitor the situation. This recorded significant and prolonged nocturnal 
hypoglycaemia (Figure 1) as well as several episodes during the week when awake. 
With the home glucose records shared via the cloud, the medications were uptitrated 
and octreotide started with considerable improvement in nocturnal hypoglycemic 

 
 
 
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CGM readings (Figure 2). This allowed the patient, her mother and ourselves to be 
reassured that the clinical situation was now much safer.  
 
 
5.4 
Rationale 
 
Prompt diagnosis of hypoglycaemia is important as, untreated, it can lead to weight 
gain, symptomatic hypoglycaemia and increases the risk of sudden death through 
arrhythmia. At present, diagnosis of hypoglycaemia depends upon the reporting of 
symptoms and capture of hypoglycaemic range CBGs through finger prick glucose 
measurement. If the clinical suspicion of hypoglycaemia is strong enough, then 
patients will be admitted for a supervised 72 hour fast, where blood glucose is 
checked regularly through finger prick measurements and venous phlebotomy. 
Patients can lose hypoglycaemic awareness, however, and so symptoms are not 
always a reliable way to diagnose the problems. 72 hour fasts are labour intensive for 
the medical and nursing teams and may require the patient to take time off work or 
away from caring duties. A robustly tested CGM test may allow us to determine if 
blinded CGM testing can be used to obviate the need for inpatient testing. It may also 
provide useful diagnostic information by relating the proximity of hypoglycaemic 
episodes to food intake, adding to weight to diagnoses of reactive or spontaneous 
hypoglycaemia.   
CGM has revolutionized the lives and medical management of type 1 Diabetes 
patients with hypoglycaemic unawareness and we hope that it can produce similarly 
excellent results in the field of reactive/spontaneous hypoglycaemia. 
 
Once spontaneous hypoglycaemia has been diagnosed, treatment with medical 
therapy is often the first step. The goal is to try and make the patient hypoglycaemia 
free. This is tricky if the patient has no hypoglycaemia awareness, but can be 
overcome during the day with regular fingerprick glucose checks – though patients 
frequently complain that this is painful. At night, however, patients are asleep and 

 
 
 
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cannot check their blood glucose this way and so there is a paucity of data about 
their glycaemic state at night – the very time that they are fasting and hypoglycaemia 
is more probable. CGM can therefore tell us about their glycaemic status all day, 
without painful finger prick testing and also during the night whilst the patient is 
asleep. This information can then help doctors titrate their anti-hypoglycaemia 
medication with the aim of abolishing their hypoglycaemic episodes. 
 
 
5.5 
Risks / benefits  
 
Risks/inconveniences 
 
Patients will have a glucose monitoring probe inserted, this sits on the abdominal wall 
and protrudes just under the skin, sampling the glucose in the interstitial fluid. There 
is sometimes a very small amount of discomfort associated with this (84% of users 
state it is painless in company's literature) and sometimes a very small amount of 
inconvenience associated with wearing it if it catches on clothing - but it is very slim 
and rarely interferes with normal day-to-day activities. 
CGM sensor/transmitter is fully waterproof and can be worn in showers/baths and 
also to the gym. 
CGM system is safe to travel with. We will provide a letter explaining the system's 
components if study participants wish to fly in order to clear airport security. 
Patient will wear a glucose monitoring sensor and data will wirelessly download to 
their mobile device or a proprietary glucose data receiver device. If the patient does 
not have a suitable mobile device then we will lend them a glucose data receiver. 
 
CGM probe is inserted through the skin and so there is a theoretical risk of local 
infection if the skin is not cleaned prior to insertion as recommended. 
There is a theoretical risk of the probe component breaking off under the skin. 
 
 
Benefits 
 
Discovery of hypoglycaemia earlier than would otherwise be the case. 
Easier detection of asymptomatic hypoglycaemia in patients with known 
hypoglycaemia and therefore optimal titration of their medication. 
Elimination of dangerous asymptomatic hypoglycaemia. 
 
6. Study objectives 
 
 
6.1 
Primary objective 
1) Use CGM (blinded to the patient and investigator) in advance of standard 
investigations (where possible) in order to record whether patient symptoms correlate 
with recorded hypoglycaemia. This may exclude hypoglycaemia as a cause of 
symptoms and allow the patient to avoid a prolonged inpatient investigation. 
2) Use CGM technology (blinded to the patient and investigator) alongside standard 
investigations for patients with both reactive and spontaneous hypoglycaemia to 
evaluate the relative efficacy of the two methods in detecting hypoglycaemia 
episodes. 
3) Use CGM (blinded to the patient and investigator) to record frequency of 
hypoglycaemia after medical treatment has been initiated in order to assess its 

 
 
 
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effectiveness in detecting hypoglycaemic episodes of which the patient may not have 
been aware, potentially reducing the need for painful fingerprick glucose testing. 
4) Use CGM (unblinded) to titrate medication to abolish hypoglycaemia in order to 
improve outpatient management and improve patient safety. The Dexcom system 
has an alarm to alert patients to hypoglycaemia which will be used in the unblinded 
phase. 
 
6.2 
Secondary objective 
 
To determine whether CGM systems accurately record hypoglycaemia and can be 
used in this context  
 
6.3 
Primary endpoint 
 
Arm 1 - 
Outpatient - CGM findings reflect patient's fingerprick glucose readings 
                  - Episodes of true hypoglycaemia (as decided by finger prick glucose 
testing) are captured by the CGM device 
 
       - CGM detects hypoglycaemia whilst patient is asleep 
Inpatient - 72 hour fast - CGM device calls hypoglycaemia when fingerprick/lab 
glucoses also do 
 
Arm 2 - 
Blinded phase - CGM findings reflect patient's fingerprick glucose readings - any 
episodes of true hypoglycaemia (as decided by fingerprick glucose testing) are 
captured by CGM device 
unblinded phase - CGM recordings help with titration of anti hypoglycaemic 
medications and this reduces overall incidence of hypoglycaemic episodes or 
duration of time spent in hypoglycaemic range 
For patients experiencing asymptomatic hypoglycaemic episodes, a reduction in 
asymptomatic hypoglycaemic episodes and regaining of hypoglycaemic symptoms. 
For patients with symptomatic hypoglycaemia, a reduction in symptomatic episodes. 
 
7. Study population 
 
Clinicians in the endocrinology department at St Bartholomew's hospital will be 
notified of this study and encouraged to refer forward suitable patients from their 
clinics. 
 
Arm 1 
Patients referred to the endocrinology department at St Bartholomew's hospital for 
investigation of suspected hypoglycaemia by either GPs or other clinical teams in the 
same or external NHS trusts will be referred onwards to the study team by the doctor 
that sees them for their routine clinical care. 
Arm 2 
Patients known to the endocrinology department at St Bartholomew's hospital with 
hypoglycaemia that are medically managed or who are to start medical management 
will be referred to the study team by the doctor that sees them for their routine clinical 
care. 
Some patients who are found to have hypoglycaemia through arm 1 of this study will 
be automatically offered the chance to partake in arm 2 if they are to have medical 
treatment. 
 

 
 
 
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No vulnerable groups will be included – all patient will be able to give valid consent on their own behalf 
All patients will be able to understand sufficient English to give informed consent on their own behalf. 
 
Inclusion Criteria 
Able and willing to give informed consent. No vulnerable adults will be included. 
Either conventional gender, or non-binary. 
Age >18 years 
Any ethnicity 
Any socio economic group 
Medical condition as detailed above – arm 1 under investigation for possible/probable 
hypoglycaemia 
Arm 2 – on medical therapy for established hypoglycaemia 
 
Exclusion criteria 
Unwilling or unable to give consent 
Unable to speak sufficient English to give consent and understand study 
requirements 
Age<18 
Lack of capacity to consent 
Underlying hepatic condition 
Current excessive alcohol consumption (men regularly consuming >50 units/week, 
women >35 units/week) 
Diabetes Mellitus 
Current use of Diabetic medication or insulin 
Currently pregnant 
Any patient on haemo or peritoneal dialysis 
 
Length of study participation 
Arm 1 - investigation of hypoglycaemia - maximum of 10 days of monitoring (5 days 
as an outpatient, max 5 days as an inpatient). 
Arm 2 - evaluating anti hypoglycaemic drugs - maximum of 10 days of initial 
monitoring (investigator and patient blinded to CGM results), then up to a maximum 
of a further 20 days (unblinded) monitoring, likely to be far less than this though. 
 
 
 
7.1 
Inclusion criteria 
Able and willing to give informed consent. No vulnerable adults will be included. 
Either conventional gender, or non-binary. 
Age >18 years 
Any ethnicity 
Any socio economic group 
Medical condition as detailed above – arm 1 under investigation for possible/probable 
hypoglycaemia 
Arm 2 – on medical therapy for established hypoglycaemia 
 
7.2 
Exclusion criteria 
 
Unwilling or unable to give consent 
Unable to speak sufficient English to give consent and understand study 
requirements 
Age<18 
Lack of capacity to consent 
Underlying hepatic condition 

 
 
 
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Current excessive alcohol consumption (men regularly consuming >50 units/week, 
women >35 units/week) 
Current use of Diabetic medication or insulin 
Currently pregnant 
Any patient on haemo or peritoneal dialysis 
 
 
 
 
8. Study design 
 
Arm 1 
Patients will be recruited to the study via the endocrine outpatient clinic, or via 
referral to St Bartholomew’s hospital for inpatient management of hypoglycaemia. 
 
For those originating from the outpatient department, patients will receive a CGM kit, 
finger prick testing meter and glucose monitoring diary. 
5 days prior to admission to hospital the patient will start the continuous glucose 
monitoring and will also record their finger prick glucose reading in their glucose 
monitoring diary at any point they experience symptoms they ascribe to 
hypoglycaemia. 
 
During their admission to hospital for investigation into suspected hypoglycaemia 
(either patients from outpatients, or direct admissions), patients will continue/start 
continuous glucose monitoring, alongside standard of care twice daily venous 
glucose, insulin and c-peptide measurements and routine finger prick testing. As per 
standard of care, extra finger prick glucoses and venous glucose/insulin/c-peptide 
testing will be performed when the patient experiences symptoms that they associate 
with hypoglycaemia. 
 
Arm 2 
Patients who have been diagnosed with spontaneous hypoglycaemia which requires 
medical therapy will be given a CGM kit and a finger prick glucose monitoring device 
and glucose monitoring diary. Patients will take the standard medical therapy and 
perform finger prick glucose testing when they experience symptoms that they 
attribute to hypoglycaemia. These values will be recorded in the glucose monitoring 
diary. After (up to) 10 days of blinded CGM monitoring, the diary and CGM data will 
be reviewed. A member of the endocrine team (consultant or registrar with consultant 
approval) will then make changes to the medical therapy in order to abolish any 
remaining episodes of hypoglycaemia. Patients will then wear the CGM device in 
unblinded mode for up to a further 20 days (though likely to be far less) in order to 
facilitate further medication titrations. Patients will be asked to confirm low CGM 
glucose readings during this time with a finger prick glucose measurement. 
 
The study organisers will observe the glucose data obtained from the CGM and 
match it with finger prick glucose readings (from glucose monitoring diaries) and lab 
glucose data to check for concordance.  
CGM data (in conjunction with glucose monitoring diaries) will be scrutinised and 
compared against drug regimens to see which doses needed to be altered, or where 
additional medication is required. 
 

 
 
 
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Patients will complete a modified Clarke and Gold hypoglycaemia questionnaire at 
the start of arm 2. They will complete an adapted questionnaire prior to surgery for 
their hypoglycaemia (if indicated) or at 6 months after the start of arm 2 – whichever 
comes first. 
9. Study procedures 
Arm 1 
 
Patients will be recruited either through attendance at endocrinology outpatients at St 
Bartholomew’s hospital or through inpatient transfer to St Bartholomew’s hospital – 
both with suspected diagnoses of hypoglycaemia. 
If attending the outpatients department with suspected hypoglycaemia and thought to 
be suitable for the study, then the patient will meet a member of the study team after 
their outpatient appointment or they will be offered an appointment to discuss the 
study at a mutually convenient time. Informed consent will be obtained during this 
meeting. 
Once a date has been set for their admission to hospital for standard of care 
investigation of hypoglycaemia (usually including an oral glucose tolerance test or 
mixed meal test, but certainly including a 72 hour fast), an appointment will be made 
with the patient for 5 days prior to this date. 
At this appointment, the patient will be provided with a finger prick glucose monitoring 
kit (and instructed in how to use it), a glucose monitoring diary to record finger prick 
glucose measurements and a CGM device. A CGM probe will be fitted during the 
consultation and checks made to ensure that it is working. 
 
The patient will then proceed with their standard of care admission five days later. 
CGM monitoring will continue for the duration of their admission. The CGM device 
will be removed at discharge or after 5 days of admission, whichever comes first. 
 
For patients who are transferred to St Bartholomew’s directly for investigation of their 
hypoglycaemia, informed consent will be obtained at the earliest convenient point in 
their admission and the CGM device applied in preparation for the standard of care 
investigations. The CGM device will be removed at discharge or after 5 days of 
admission, whichever comes first. 
 
 
Schedule of study interventions  
 
Study intervention  
Visit 1 
Visit 2 
Visit 3 
Establishment of possible 
hypoglycaemia diagnosis 
x 
 
 
Meet with study team to learn 
about study and give Informed 
consent 
Either x 
Or x 
 
Placement of CGM device, 
receive finger prick glucose 
meter and diary 
 
x 
 
Admission to hospital for 
standard of care investigations 
Return CGM receiver device if 
not proceeding to arm 2 
 
 
x 
 
 
Arm 2 

 
 
 
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For patients with confirmed hypoglycaemia, where it is planned that they will receive 
medical management, we will seek informed consent for their entry into arm 2 of the 
study. 
This might take place;  
 
at the conclusion of inpatient investigations for hypoglycaemia prior to 
initiation of anti-hypoglycaemia medication (on an inpatient or outpatient 
basis) 
 
after an endocrinology outpatient appointment for a patient with confirmed 
hypoglycaemia 
 
In the first instance, patients will be fitted with a CGM device and given a finger prick 
glucose monitoring kit and glucose monitoring diary. Each patient will be asked to 
complete a modified Clarke and Gold hypoglycaemia questionnaire. 
A further appointment will then be made to discuss the results of the initial CGM and 
to titrate the drug regimen. This appointment could be face to face or by telephone. 
 
If periods of hypoglycaemia persist then alterations to the drug regime will be made 
and the patient will continue to wear the CGM device, but both they and the 
investigators will be unblinded to the CGMs allowing further titrations to the anti-
hypoglycaemia medications to be made by telephone. Patients will be asked to take 
a finger prick glucose reading to confirm any low CGM readings. 
 
At the conclusion of the patient’s study participation, they will be asked to return the 
CGM receiver.  
At 6 months, or prior to surgery to cure the hypoglycaemia (whichever comes first) 
the patient will attend the hospital to complete an adapted version of the modified 
Clarke and Gold hypoglycaemia questionnaire. 
 
Schedule of study interventions  
 
Study intervention  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Meet with study team to 
learn about study and 
give Informed consent 
x 
 
 
 
 
Placement of CGM 
device, receive finger 
prick glucose meter and 
diary 
Complete hypoglycaemia 
questionnaire 
Either x  
Or x 
 
 
 
Review of CGM data and 
titration of medication and 
unblinding of CGM device  
 
Either x 
Or x 
 
 
Subsequent medication 
titration by telephone 
 
 
Either x 
Or x 
 
Return CGM receive 
device 
 
 
 
x 
 
Complete adapted  
hypoglycaemia 
questionnaire 
 
 
 
 
x 
 
Study Drugs/device 
 

 
 
 
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The drugs used to treat hypoglycaemia will be those that are current standard of care 
and the doses/indications will not vary from standard practice. 
 
We will use a Dexcom G6 continuous glucose monitoring device to record patient’s 
blood glucose to aid diagnosis of hypoglycaemia prior to and during standard of care 
hospital investigations. The device’s software will be modified by Dexcom to disable 
hypoglycaemia alarm functions, visible blood glucose readout (on the receiver 
device) and the ability to view blood glucose remotely. 
For the unblinded component of arm 2 these functions will be restored 
 
Concomitant medications 
 
Patients will continue to take all other prescribed medications. 
 
Criteria for discontinuation 
 
Patients that become pregnant, or develop a critical illness during the study will be 
withdrawn as Dexcom devices are unreliable in these circumstances. 
 
Procedure for data collection 
Arm 1 – CGM data from each Dexcom device will be downloaded at the end of the 
inpatient investigations. 
Finger prick Glucose monitoring diaries will be collected from patients. 
 
Arm 2 – CGM Data from each Dexcom device will be downloaded at the end of the 
blinded phase and analysed. Subsequently, CGM data will be viewed remotely and 
downloaded. 
Finger prick Glucose monitoring diaries will be collected from patients. 
Hypoglycaemia questionnaires will be completed with patients 
 
Follow-up procedures  
Patients with confirmed hypoglycaemia will remain under standard endocrinology 
follow up irrespective of whether they choose to partake in arm 2 of the study. 
 
Patients completing arm 2 will remain under standard endocrine follow up at St 
Bartholomew’s hospital, unless they decide to transfer their care elsewhere. 
 
Participant withdrawal  
Participants may withdraw at any time. Any data that has been collected up to that 
point will be retained. 
 
End of study definition  
The end of the study (specifically - the end of collecting new CGM data) for each 
individual patient will be when, 
 
Arm 1 – The patient completes the inpatient CGM monitoring period and are 
found not to have hypoglycaemia, OR they complete the inpatient CGM 
monitoring period, are scheduled for anti hypoglycaemic treatment but do 
not wish to proceed to arm 2 investigations.  
 
Arm 2 – The patient completes the initial blinded monitoring phase and 
analysis shows that no further drug titration is required OR the patient goes 
into the subsequent unblinded monitoring phase and drug titration abolishes 
most/all of the hypoglycaemic episodes OR the 30 days of CGM monitoring 
elapses – whichever occurs first. Patients will be asked to complete a 

 
 
 
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hypoglycaemia questionnaire prior to surgery to cure hypoglycaemia, or at 6 
months after the start of arm 2. 
 
 
10. Assessment and management of risk 
11. Safety Information 
Adapted From Dexcom’s website https://www.dexcom.com/safety-information  
Our annotations are in bold, italics and underlined 
Dexcom G6 Continuous Glucose Monitoring System  
Indications for Use 
The Dexcom G6 Continuous Glucose Monitoring System (Dexcom G6 System) is a 
real time, continuous glucose monitoring device indicated for the management of 
diabetes in persons age 2 years and older. 
The Dexcom G6 System is intended to replace fingerstick blood glucose testing for 
diabetes treatment decisions. Interpretation of the Dexcom G6 System results should 
be based on the glucose trends and several sequential readings over time. The 
Dexcom G6 System also aids in the detection of episodes of hyperglycemia and 
hypoglycemia, facilitating both acute and long-term therapy adjustments. 
The Dexcom G6 System is also intended to autonomously communicate with digitally 
connected devices, including automated insulin dosing (AID) systems. The Dexcom 
G6 System can be used alone or in conjunction with these digitally connected medical 
devices for the purpose of managing diabetes. 
Contraindication 
No MRI/CT/Diathermy – MR Unsafe  
Don’t wear your CGM (sensor, transmitter, receiver, or smart device) for magnetic 
resonance imaging (MRI), computed tomography (CT) scan, or high-frequency 
electrical heat (diathermy) treatment. 
The G6 hasn’t been tested in those situations. The magnetic fields and heat could 
damage the components of the G6, which may cause it to display inaccurate G6 
sensor glucose readings (G6 readings) or may prevent alerts. Without G6 readings or 
alarm/alert notifications, you might miss a severe low or high glucose event. 
Warnings 
Don't Ignore Low/High Symptoms  
Don't ignore how you feel. If your glucose alerts and readings don't match what you're 

 
 
 
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feeling, use your blood glucose meter to make diabetes treatment decisions or, if 
needed, seek immediate medical attention.When in doubt, get your meter out. 
NB – we will be blinding patients to their continuous glucose monitoring (except in 
the latter half of arm 2) and will ask patients to check their finger-prick glucose if 
they experience hypoglycaemic symptoms. 
Don’t Use If…  
Do not use the G6 if you are pregnant, on dialysis, or critically ill.  
NB – pregnant patients or those on renal dialysis will be screened out of our study 
Precaution  
Avoid Sunscreen and Insect Repellent  
Some skin care products, such as sunscreens and insect repellents, can make the 
plastic used in your G6 crack. Before using your G6, make sure there are no cracks in 
your receiver, transmitter, and transmitter holder. If you find a crack, please contact 
Technical Support. Do not allow these skin care products to contact your G6. After 
using skin care products, wash your hands before touching your G6. If any skin care 
products get on your G6, immediately wipe with a clean cloth. 
Start Up Safety Statements 
Warnings  
Use Meter During Startup  
When you start a new sensor, you won’t get any readings or alarm/alerts until you 
enter your sensor code or two calibrations. Use your meter to make treatment 
decisions during the 2-hour sensor warmup period.  
NB – Patient will be blinded to CGM data (except for latter part of arm 2). Data 
from the first 2 hours of CGM will be discarded. 
Precautions 
Use Correct Sensor Code  
When you start a new sensor, you must enter a code into your display device to use 
the G6 without fingerstick calibrations. Each sensor has its own code printed on the 
back of the adhesive patch. Do not use a code from a different sensor or make up a 
code. If you do not enter the correct code, your sensor will not work as well and could 
be inaccurate. If you lost the sensor code, you may calibrate the G6 using fingersticks.  
Calibration Safety Statements 
Calibration is not required if users enter a sensor code. If users do not enter a sensor 
code, the following warnings and precautions apply. 
Warnings  
Don’t Wait – Calibrate!  
If you have not used the calibration code, you must manually calibrate your G6 using 

 
 
 
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values obtained from a blood glucose meter and fingersticks daily. You must calibrate 
immediately when the G6 notifies you. If you haven’t calibrated when notified, your 
G6 may not be accurate, so use your glucose meter to make treatment decisions until 
you calibrate your G6. 
Use Fingersticks  
Use fingertips to calibrate from your BG meter. Blood from other places may be less 
accurate and not as timely.  
 
Precautions  
Be Accurate, Be Quick.  
Enter the exact BG value displayed on your meter within five minutes of using your 
meter. Don’t enter the G6 reading as a calibration.  
System/Hardware/Software Safety Statements 
Warnings  
Wire Breaks Off  
Don’t ignore broken or detached sensor wires. A sensor wire could remain under your 
skin. If this happens, please contact our 24/7 Technical Support.  
If a sensor wire breaks off under your skin and you can’t see it, don’t try to remove it. 
Contact your HCP. Also seek professional medical help if you have symptoms of 
infection or inflammation – redness, swelling, or pain – at the insertion site. 
Where to Insert: Belly or Buttocks?  
All patients can use their bellies (abdomen). Patients 2 to 17 years old can also choose 
their upper buttocks. Look for a place on your belly or upper buttocks where you have 
some padding.  
The sensor is not tested or approved for other sites. Talk to your HCP about the best 
site for you. 
Where to Store  
You can store your sensors at room temperature or in your refrigerator – as long as 
it’s between 36° F and 86° F. Don’t store sensors in the freezer.  
Follow G6 instructions. If you don’t, you could have a severe low or high glucose 
event. 
Precautions  
Don’t Use if Expired  
Don’t use expired sensors, because they may give incorrect results. Check the 
package label for the expiration date. It’s in YYYY-MM-DD (Year-Month-Day) 
format. 
Check Package  
Don’t use sensor if its sterile package has been damaged or opened, because it might 
cause an infection. 

 
 
 
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Clean and Dry Skin  
Clean and dry your hands and your insertion site before inserting your sensor.  
Wash your hands with soap and water, not gel cleaners, and then dry them before 
opening the sensor package. If your hands are dirty when you insert the sensor, you 
may get germs on the insertion site and get an infection.  
Clean your insertion site with alcohol wipes to prevent infections. Don’t insert the 
sensor until your skin is dry. If your insertion site is not clean and completely dry, you 
run the risk of infection or the transmitter holder not sticking well.  
Make sure you don’t have insect repellent, sunscreen, perfume, or lotion on your 
skin.  
Where to Insert: Things to Check  
Keep the safety guard on until you put the G6 applicator against your skin. If you 
remove the safety guard first, you may hurt yourself by accidentally pushing the 
button that inserts the sensor before you mean to.  
Change your insertion site with each sensor. Using the same site too often might not 
allow the skin to heal, causing scarring or skin irritation.  
Sensor placement is important. Choose a site:  
• At least 3 inches from insulin pump infusion set or injection site  
• Away from waistband, scarring, tattoos, irritation, and bones  
• Unlikely to be bumped, pushed, or laid on while sleeping  
Transmitter Safety Statements 
Warnings  
Inspect  
Don’t use a damaged or cracked transmitter. A damaged transmitter could cause 
injuries from electrical shocks and may make the G6 not work correctly.  
Use as Directed  
The transmitter is small and may pose a choking hazard. Don’t put it in your mouth or 
let children hold it without adult supervision.  
 
Precautions  
Reuse – Don’t Throw Away  
When ending a session, don’t throw away the transmitter. The transmitter is reusable 
until the G6 notifies you that the transmitter battery is about to expire.  
Don’t Share  
Never share your transmitter. The G6 is a prescription-only medical device and is 
meant for your use only. The transmitter is tied to the G6 readings. If used by more 
than one person, the G6 readings, reports, alarm/alerts, etc., may be wrong.  
 
System Safety Statements 
Precautions  
Treatment Decisions  
Use your G6 reading and trend arrow to make treatment decisions. 

 
 
 
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Use Correct Transmitter, Receiver, and Sensor  
G6 components are not compatible with any previous Dexcom products. Do not mix 
transmitters, receivers, and sensors from different generations. 
Going Through Security Check Point 
When wearing your G6, ask for hand-wanding or full-body pat-down and visual 
inspection instead of going through the Advanced Imaging Technology (AIT) body 
scanner (also called a millimeter wave scanner) or putting any part of the G6 in the 
baggage x-ray machine.  
You can wear the G6 for the walk-through metal detector. If you do, use your meter 
for treatment decisions until you leave the security area.  
Because we haven’t tested every x-ray and scanner, we don’t know if they damage the 
G6.  
Not sure what kind of machine it is? Be safe – either ask the TSA officer, request 
hand-wanding, or request full-body pat-down. 
Interfering Substance Risks 
In previous generations of Dexcom CGM systems (G4/G5), acetaminophen could 
affect your sensor readings, making them look higher than they really were. However, 
with the G6, you can take a standard or maximum acetaminophen dose of 1 gram 
(1,000mg) every 6 hours and still use the G6 readings to make treatment decisions. 
Taking higher than the maximum dose of acetaminophen (e.g. > 1 gram every 6 hours 
in adults) may affect the G6 readings and make them look higher than they really are.  
Receiver and Smart Device Safety Statements 
Precautions  
Keep Transmitter Close to Display Device  
Keep your transmitter and display device within 20 feet with no obstacles (like walls 
or metal) between them. Otherwise, they might not be able to communicate. If water 
is between your transmitter and the display device – for example, if you’re showering 
or swimming – keep them closer to each other. The range is reduced because 
Bluetooth® doesn’t work as well through water. 
Get Alarm/Alerts on Display Device You Use  
To get your alarm/alerts, set them on the display device you use. Your receiver won’t 
get the alarm/alerts you set on your app. Likewise, your app won’t get the alarm/alerts 
you set on your receiver.  
NB – patients will not receive alarms/alerts except for those in the unblinded phase 
of arm 2.  
Is It On?  
If the receiver or smart device is turned off (shut down), it will not show G6 readings 
or alarm/alerts. Make sure your display device is turned on. 
Smart Device Safety Statements  

 
 
 
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Warnings 
Check Settings 
NB – patients will not receive glucose alarms/alerts except for those in the 
unblinded phase of arm 2.  
When using your smart device, you should confirm that your volume is turned up, 
your phone is not muted, and you do not have headphones plugged in. If your volume 
is not turned up, the device is muted, or headphones are plugged in, you will not hear 
the sound of any notifications, including important alarms. When you have 
headphones connected to your Android®, alarm/alerts will sound through the 
headphones and the speaker. On your Apple, they will sound only in the headphones. 
Some notifications are silent during the first visual and vibrate notification and then 
make a sound on the second notification. If you don’t clear the alert, it repeats at half 
volume after 5 minutes and at full volume after 10 minutes. 
Your alarm and important alerts sound and display information even when your 
volume is low or muted. Specifically, if your smart device is on mute, only these 
notifications make a sound:  
Glucose Alarm/Alerts:  
• Urgent Low  
• Urgent Low Soon  
• Low Glucose  
• High Glucose  
• Rise Rate  
• Fall Rate  
• No Readings Alert  
System Alerts:  
• Calibration Required (after 2-hour sensor warmup, only appears when a sensor code 
is not active)  
• Calibration Error (only appears when a user enters a calibration; calibration is not 
required)  
• Sensor Expired  
• Replace Sensor  
• Transmitter (not working)  
• No Storage Error  
• App Stopped  
There’s one exception: On Apple® devices, Signal Loss doesn’t sound when your 
volume is low or muted.  
Bluetooth: Your transmitter talks to your app with Bluetooth. Make sure your smart 
device Bluetooth is on. If not, you will not get alarm/alerts or CGM information.  
Notifications:  
• Make sure your smart device settings allow Dexcom app notifications to show on 
your Lock screen. This will allow you to see notifications without unlocking your 
phone.  
• Apple: During G6 setup, enable Dexcom app notifications or you won’t get 
alarm/alerts. Battery: The app must always be running in the background and may 

 
 
 
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drain your smart device battery. Keep the battery charged.  
Compatibility: Before upgrading your smart device or its operating system, check 
dexcom.com/compatibility. Automatic updates of the app or your device operating 
system can change settings or shut down the app. Always update manually and verify 
correct device settings afterward.  
Time: Let the date and time on your smart device automatically update when you 
travel across time zones or switch between standard and daylight saving times. Don’t 
manually change your smart device time, because it can make the time on the trend 
screen wrong and the app may stop displaying data.  
 
Precautions  
Check Peripheral Devices  
Do you use headphones with your smart device? What about Bluetooth speakers or a 
smart watch? When using peripherals, keep in mind you may get your alarm/ alerts on 
only one device or peripheral, not all. After connecting any peripheral devices, make 
sure that your smart device settings allow you to continue receiving alarms or alerts.  
Receiver Safety Statements 
Warnings  
Don’t Use if Damaged  
Don’t use a receiver that is damaged or cracked. A damaged receiver could cause 
injuries from electrical shocks and may make the G6 not work correctly.  
Use Cable as Directed  
Use USB cable only as directed, and store safely. Misuse of the USB cable can be a 
strangulation risk.  
Follow G6 instructions. If you don’t, you could have a severe low or high glucose 
event. 
  
Precautions  
Test Speaker and Vibrations  
You have to hear or feel alarm/alerts to react to them, so test your receiver speaker 
and vibrations regularly.  
To make sure the speaker and vibrations work, plug in the receiver to charge. The 
Speaker Test screen appears for a few seconds. Follow the directions on the screen to 
test the speaker and vibrations. If you hear and feel them, great! But if it doesn’t beep 
and vibrate – perhaps it got wet or was dropped – contact Technical Support and use 
your app until the receiver is fixed.  
Keep Clean and Dry  
Don’t submerge your receiver in water and don’t get dirt or water in the USB port. 
That could damage it.  
Dexcom Share Safety Statements 
Important User Information 

 
 
 
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Dexcom Share (Share) lets you send your sensor information from your app to your 
Followers’ smart devices! Read the indications, warnings, and precautions below to 
find out how you can safely use this app feature. 
Share and Managing Your Diabetes Safety Statements 
Indications  
Keep Followers Informed  
Use Share to send your sensor information from your smart device to your Followers’ 
smart devices.  
Use as Secondary Notice  
The information on your smart device is sent directly from your G6 transmitter. After 
it is on your device, Share sends it to your Followers. So your Followers’ information 
is always older than yours. Use your current information to manage your diabetes, not 
your Followers’ possibly outdated information.  
Your Followers can use the information they get to reach out to you and support you 
in managing your diabetes. The information they get is not meant to be used for 
treatment decisions, analysis, or teaching. Followers can’t change your information. 
NB sharing will be disabled during the study, except during the unblinded phase of 
arm 2 
Risk mitigation strategies discussed above. 
Trial subjects will be counselled on the above side effects and how to manage them. 
The endocrine team at St Bartholomew’s hospital is contactable 24 hours/day – either 
through the ward team in 5B ward (0900-1700) or through an on-call endocrine 
registrar (1700-0900) for all endocrine patient and GP enquiries. 
 
We will include side effect occurrences as part of our monthly study management 
meetings and will introduce additional methods if it becomes clear that these are 
required. 
 
12. Statistical considerations 
 
This is a non-randomised study with a small (30 patients) population, no statistician 
involvement will be required. 
 
 
12.1 
Sample size 
 
30 patients 
 
This is intended to be a pilot study to test the feasibility of using CGM for this 
purpose. It may in future complement (or in some instances replace) inpatient 
investigation of hypoglycaemia. 
The inpatient investigation of hypoglycaemia is relatively uncommon, even within 
tertiary centres. Spontaneous hypoglycaemia requiring medical treatment is similarly 
uncommon, even in tertiary centres. 

 
 
 
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12.2 
Method of analysis  
 
P<0.05 will be considered statistically significant 
 
Arm 1 
Positive and negative predictive value of CGM diagnosis of hypoglycaemia as an 
outpatient or an inpatient vs 72 hour fast (considered the ‘gold standard’)  
 
Arm 2 
In each patient, comparison of number of episodes of hypoglycaemia by finger prick 
glucose vs CGM vs symptoms during CGM blinded phase. 
Severity of hypoglycaemia excursions 
 
Amount of time spent in the hypoglycaemic range after medication titration – as 
measured by area under the curve on a time vs glucose graph generated by CGM 
machine. Comparisons of mean hypoglycaemic frequency and time within 
hypoglycaemic range within patients (blinded vs unblinded phase) using paired T 
test. 
 
 
Change in hypoglycaemia questionnaire score before/after CGMs monitoring and 
medication titration 
Regain of symptomatic hypoglycaemia in patients with asymptomatic hypoglycaemia, 
reduction of symptomatic hypoglycaemia in other patients. 
 
 
 
 
 
13. Ethics 
 Informed consent 
Patients will be offered the chance to partake in the study should their treating 
consultant feel that they meet the inclusion criteria. Declining an invitation to take part 
in the study or leaving at any time means that the patient will default back to standard 
of care investigations. Their care will not be prejudiced or compromised in any way 
through either taking part or not taking part in the study. 
 
 Recruitment 
Only patients under investigation/treatment for hypoglycaemia at St Bartholomew’s 
hospital will be considered for entry to the study. Patient being treated/investigated 
elsewhere who wish to be considered for the study would need to have their care 
transferred to St Bartholomew’s by their GP/current endocrinologist. 
 
 Inclusion / exclusion criteria 
Inclusion/exclusion criteria is intended to screen out patients who have conditions 
that may affect their blood glucose (Diabetes Mellitus, underlying hepatic pathology) 
or in whom CGM is not recommend (pregnancy, critical illness) or in whom 
hypoglycaemia may be cause be extrinsic factors such as Diabetes medication. 
 

 
 
 
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 Study design 
Aside from the wearing of a CGM device and completion of modified Clarke and Gold 
hypoglycaemia questionnaire (arm 2), all treatment is ‘standard of care’. 
In arm 1 (and, initially, arm 2) Patients and investigators are blinded to the CGM readouts. 
Patients are provided (as is usual) with finger prick glucose meters that they can use to check 
their blood sugar should they develop symptoms that they attribute to hypoglycaemia. The 
patients are therefore not disadvantaged by the ‘blinding’ process. 
 
 Risks, burdens, and benefits 
Patients will be counselled about (the few) risks associated with use of the Dexcom device, 
the main risks are those of infection from insertion of the probe under the skin and the risk 
of retained parts upon removal of the probe – and how to minimise these risks. The device is 
worn and as such may restrict the wearer’s choice of clothing and place some minor 
limitations on physical activity – mainly laying on top of the probe or engaging in close 
contact activities which might disrupt the probe’s positioning. 
 
 Confidentiality 
All patients recruited for the study will already be under the medical care of the 
endocrine team at St Bartholomew’s hospital, the study team is made up of staff from 
this department and they will therefore already have legitimate access to medical 
records and pathology results. 
 
Any published data arising from this study will be anonymised.  
Any data shared with Dexcom will be pseudonymised – each participant will receive 
a study number which will not be related to any of their identifiable details 
(name/DOB/address/NHS or hospital number). 
 
 
 Conflicts of interest. 
Dexcom will provide the study team with free receivers, transmitters, consumables 
and training in their equipment’s use. They have not had any influence on the study 
design, but have reviewed our design internally prior to granting approval for 
provision of the above equipment. 
Dexcom will be allowed to share the data that we obtain, which will be 
pseudonymised. They will also be allowed to view the manuscript of any work 
(containing anonymised data) prior to submission to a peer reviewed journal, so that 
they can make suggestions but will not be the determining factor in the decision to 
submit work arising from this study for publication. This decision will reside with the 
study team and be based on scientific merit of the findings. 
 
No other members of the study team have any relevant conflicts of interest. 
 
 
13.1 
Annual Safety Reporting  
 
The CI will send an Annual Progress Report to the REC and the sponsor using the 
HRA template on the anniversary of the REC favourable opinion. 
 
14. Public Involvement 
 

 
 
 
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No public involvement is planned 
 
15. Data handling and record keeping 
 
15.1 
Data management 
 
All electronic data will be stored on password protected NHS computers at an NHS 
site. Data back-ups will be made on NHS encrypted USB sticks, which will be stored 
alongside any paper based records (glucose diaries) in a locked cabinet within a 
locked room inside a hospital ward, accessed only by NHS staff. 
 
CGM data will be obtained through downloading from the patient’s CGM device onto 
a password protected NHS computer. 
 
15.2 
Source data 
 
Glucose data will be obtained from; 
 
CGM devices during the study 
 
Fingerprick glucose devices and patient glucose diaries 
 
Lab measured venous glucose (and other blood tests) – from computerised 
hospital pathology system 
 
Formal diagnosis after inpatient investigation of diagnosis and supporting lab 
results – patient’s electronic notes and pathology results from computerised 
record. 
Medication record; 
 
Computerised patient record 
 
Paper drug chart 
 
 
15.3 
Confidentiality 
 
Information related to participants will be kept confidential and managed in accordance with 
the Data Protection Act 2019, the General Data Protection Regulation (GDPR), NHS 
Caldecott Principles, the UK Policy Framework for Health and Social Care Research, 
and the conditions of NHS Research Ethics Committee favourable opinion. 
 
Potential participants will be identified by their treating endocrine consultants (or deputy) in 
clinic or on the wards. The patient’s permission to forward them to the study will then 
be sought. Once this permission is obtained then their details (hospital/NHSnumber) 
will be forwarded internally either by verbally or by secure NHS email. 
 
Prior to publication, all data will be anonymised and is likely to be discussed as a whole 
rather than individually. In the event that an individual patient’s results are discussed 
then they will be referred to in an anonymous way e.g. ‘patient 1’, with the numbering 
bearing no relation to their name, hospital/NHS number or date of birth. 
 
All patients involved in the study will be under the care of the endocrine team at St 
Bartholomew’s hospital. The study is being conducted by the same department and 
so as treating physicians, the study team already have legitimate access to patient 

 
 
 
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records. Patient records are held securely on (password and username protected) 
NHS computers and require a passcard and separate password to gain access. 
15.4 
Record Retention and Archiving 
 
At the end of the study, all electronically held data relating to the study will be printed 
and added to any paper documentation (glucose diaries etc) and stored in Barts 
Health NHS trust’s secure repository for 20 years, as per the UK policy framework for 
health and social care research.  
Destruction after this period will be in the standard, approved way. 
16. Laboratories  
16.1 
Central and local laboratories 
 
Patient samples for glucose and other blood parameters will not be collected 
separately for this study – patients will continue to have routine ‘standard of care’ 
blood tests associated with standard work-up of suspected hypoglycaemia. These 
will be processed in the normal way in the laboratories at St Bartholomew’s and the 
Royal London Hospitals 
 
16.2 
Laboratory procedures  
 
Current standard of care lab tests will be performed on inpatients having 24 hours 
fasts. These samples will undergo testing in an NHS lab as usual. No extra blood 
samples will be drawn. 
 
16.3 
Sample storage and transfer 
 
N/A 
17.  Interventions and tools  
 
17.1 
Devices 
 
 
Name - Dexcom G6 Mobile continuous glucose monitoring system 
 
Manufacturer - Dexcom 
 
Indication – continuous glucose monitoring, usually in Diabetes Mellitus 
 
CE mark status – has a  CE mark under Medical Device Directive MDD 
93/42/EEC as amended by 2007/47/EC 
 
Source of device - Dexcom 
 
For arm 1 and the blinded portion of arm 2, the device will be worn/used in the 
standard way and used to monitor for hypoglycaemia. The device will be 
programmed so that the alarm functions which usually signal hypoglycaemia are 
inactivated and the screen which displays the current glucose reading will not show 
this information. 
During the unblinded portion of arm 2, the device will be worn in the standard way 
with hypoglycaemia alarms active and the glucose display showing the current 
glucose. 
 

 
 
 
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 
Name – Contour next ONE blood glucose monitoring system 
 
Manufacturer – Ascensia Diabetes care 
 
Indication – finger prick glucose monitoring, usually in Diabetes Mellitus 
 
CE mark status – has a  CE mark Source of device – either through NHS 
trust or directly from Ascensia 
 
Finger prick glucose testing is standard in inpatient investigation of 
hypoglycaemia and also in home monitoring of blood sugar in patients being 
treated for proven hypoglycaemia. We will additionally use prior to patient’s 
admission for investigation of hypoglycaemia (arm 1) as a correlate for CGM 
data. Patients will be asked to perform a finger prick glucose measurement 
whenever they experience the symptoms that they attribute to 
hypoglycaemia 
17.2 
Techniques and interventions 
 
Interventions – patients will be shown how to apply the CGM device upon enrolling in 
study and the start of the monitoring phase, or will have the CGM device applied for 
them by a medical/nursing professional 
Patients will also be shown how to use the finger prick glucose testing device as part 
of standard care. 
 
17.3 
Tools 
 
Each patient will receive a glucose monitoring diary where they can record the finger 
prick glucose level, time, date and symptoms. 
 
 
17.4 
Medicinal product  
None 
 
 
17.5 
Other biological or chemical products 
 
None 
 
 
18. Safety reporting  
 
 
Adverse Events (AEs) and Adverse Reactions (ARs) will be recorded 
 
Serious Adverse Events (SAEs) and Serious Adverse Reactions (SARs) will 
be reported to the CI as medical assessor for the sponsor and coordinating 
team. 
 
All unexpected SARs (SUSARs) will be reported to the JRMO and REC. 
 
18.1 
Adverse Events (AEs) 
 
An AE is any untoward medical occurrence in a participant to whom an intervention 
has been administered, including occurrences which are not necessarily caused by 

 
 
 
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or related to that intervention. An AE can therefore be any unfavourable or 
unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with study activities. 
 
18.2 Adverse Reaction (ARs)  
 
An AR is any untoward and unintended response in a participant to an intervention.  
All adverse events judged by either the reporting investigator or the sponsor as 
having a reasonable causal relationship to the intervention qualify as adverse 
reactions. The expression ‘reasonable causal relationship’ means in general that 
there is evidence or an argument to suggest a causal relationship. 
 
18.3 
Notification and reporting of Adverse Events and Reactions 
 
If the AE is not defined as serious, the AE will be recorded in the study documents 
and the participant followed up by the research team. The AE will be documented in 
the participants’ source documents, the Case Report Form (CRF), and, where 
appropriate, medical records. 
 
18.4 
Serious Adverse Events (SAEs) or reactions 
 
A serious adverse event (SAE) is defined as an untoward occurrence that: 
 
Results in death, 
 
Is life-threatening, 
 
Requires hospitalisation or prolongation of existing hospitalisation, 
 
Results in persistent or significant disability or incapacity, 
 
Consists of a congenital anomaly or birth defect, or 
 
Is otherwise considered medically significant by the investigator. 
 
SARs will be reported to the REC where in the opinion of the Chief Investigator the 
event was serious and: 
 
Related (it may have resulted from administration of any of the research 
interventions), and 
 
Unexpected (the type of event is not listed in the protocol or other Reference 
Safety Information as an expected occurrence). 
 
18.5 
Notification and reporting of Serious Adverse Events  
 
Serious Adverse Events (SAEs) that are considered to be ‘related’ and ‘unexpected’ 
will be reported to the sponsor within 24 hours of learning of the event, and to the 
REC within 15 days in line with the required timeframe.  
 
The treatment code for the participant will be broken when reporting an ‘unexpected 
and related’ SAE. The unblinding of individual participants by the PI / CI in the course 
of a clinical study will only be performed if necessary for the safety of the study 
participant.  
 
18.6 
Urgent Safety Measures 
 

 
 
 
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The CI will take urgent safety measures if necessary to ensure the safety and 
protection of the clinical study participant from immediate hazards to their health and 
safety. The measures will be taken immediately. The approval of the REC prior to 
implementing urgent safety measures is not required. However the CI will inform the 
sponsor and Research Ethics Committee (via telephone) of this event immediately.  
 
The CI will inform the REC in writing within 3 days, in the form of a substantial 
amendment. The sponsor (Joint Research Management Office (JRMO)) will be sent 
a copy of the correspondence with regards to this matter.  
 
18.7 
Annual Safety Reporting 
 
The CI will send the Annual Progress Report to the REC using the HRA template (the 
anniversary date is the date on the REC “favourable opinion” letter) and to the 
sponsor.  
 
18.8 
Overview of the Safety Reporting responsibilities 
 
The CI is the medical assessor on behalf on the sponsor and will review all events 
reported. The CI will ensure that safety monitoring and reporting is conducted in 
accordance with the sponsor’s requirements.  
 
19. Monitoring and auditing 
 
The sponsor or delegate retains the right to audit any study, study site, or central 
facility. Any part of the study may be audited by the funders, where applicable. 
 
20. Trial committees 
 
The chief investigator will convene a monthly trial committee meeting, consisting of at 
least the chief investigator and one other investigator from the single site study 
 
21. Finance and funding 
 
Dexcom will be providing free sensors, receivers and transmitters for this study. 
 
 
22. Indemnity 
 
NHS indemnity scheme will apply. It provides cover for the design, management, and 
conduct of the study. 
 
23. Dissemination of research findings 
 
We intend to publish the results of this work in a peer reviewed journal. Should 
publishing constraints allow and a suitable occasion arise we will put forward an 
abstract of this work to the British endocrine society for consideration for an oral 
presentation at their annual conference, similarly we will seek opportunities to 
disseminate our work internally within Barts Health NHS Trust and QMUL. Research 
findings are likely to form the basis of any departmental review on the investigation, 
diagnosis and management of hypoglycaemia. 

 
 
 
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All study participants will be offered the chance to receive a lay summary of any 
published work. 
24. References 
1. Kwon EB, Jeong HR, Shim YS, Lee HS, Hwang JS. Multiple Endocrine Neoplasia 
Type 1 Presenting as Hypoglycemia due to Insulinoma. J Korean Med Sci. 
2016;31(6):1003-6.  
2. Unger J. Uncovering undetected hypoglycemic events. Diabetes Metab Syndr 
Obes. 2012;5:57-74.  
3. Thirumalai A, Levander XA, Mookherjee S, White AA. Insulinoma presenting with 
cardiac arrest and cardiomyopathy. BMJ case reports. 2013;2013.  
4. Kumar P, Chauhan A, Dixit J, Jyotsana, Gupta H. Insulinoma Causing Prolonged 
Hypoglycaemic Coma. J Clin Diagn Res. 2016;10(8):OD01-2.  
5. Iscovich AL. Sudden cardiac death due to hypoglycemia. Am J Emerg Med. 
1983;1(1):28-9.  
6. Adolfsson P, Rentoul D, Klinkenbijl B, Parkin CG. Hypoglycaemia Remains the 
Key Obstacle to Optimal Glycaemic Control - Continuous Glucose Monitoring is the 
Solution. Eur Endocrinol. 2018;14(2):50-6. 
7. Wadwa RP, Laffel LM, ShahVN,Garg SK. Accuracy of a factory-calibrated, real-
time continuous glucose monitoring system during 10 days of use in youth and adults 
with Diabetes. Diabetes Technol Ther. 2018. Jun 1; 20(6): 395-402.