Frequency of Nocturnal Hypoglycaemia in Adults With Insulin-treated Diabetes and Adrenal Failure Using Prednisolone or Hydrocortisone: a Pilot Study
Conditions: Diabetes Mellitus, Type 1, Adrenal Insufficiency, Diabetes Mellitus Type 2 - Insulin-Treated
Sponsor: Imperial College Healthcare NHS Trust

 
 
 
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<HYPO-DIAD> 
 
 
 
Frequency of nocturnal hypoglycaemia in adults with insulin-
treated diabetes and adrenal failure using prednisolone or 
hydrocortisone: a pilot study. 
 
 
 
 
9th March2023 
 
 
 
 
MAIN SPONSOR: Imperial College Healthcare NHS Trust 
FUNDERS: Imperial Health Charity  
STUDY COORDINATION CENTRE: Imperial College Healthcare NHS Trust 
 
IRAS Project ID: 319768 
REC reference: 23/WS/0012  
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
 Monika Reddy CI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Study Management Group 
 
Chief Investigator:  Dr Monika Reddy                 
 
Co-investigators: Dr Shaila Khan, Prof Nick Oliver, Dr Monika Reddy, Prof Karim 
Meeran 
 
Statistician: Ian Godsland 
 
Study Management: Dr Monika Reddy 
 
Clinical Queries 
 
Clinical queries should be directed to Dr Monika Reddy who will direct the query to 
the appropriate person 
 
 
Sponsor 
 
Imperial College Healthcare NHS Trust is the main research Sponsor for this study.  
For further information regarding the sponsorship conditions, please contact the 
Head of Regulatory Compliance at: 
 
 
 
Research Governance and Integrity Team 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 1862 
Imperial College - Research Governance and Integrity Team (RGIT) Website 
 
 
 
Funder 
 
Imperial Health Charity 
 
 
 
 
 
 
 
 
 
 

 
 
 
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This protocol describes the HYPO-DIAD study and provides information about procedures for entering 
participants.  Every care was taken in its drafting, but corrections or amendments may be necessary. 
These will be circulated to investigators in the study.  Problems relating to this study should be referred, 
in the first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the UK Policy Frame Work for Health and Social Care 
Research. It will be conducted in compliance with the protocol, the Data Protection Act and other 
regulatory requirements as appropriate.  
 
Table of Contents                                                             Page No 
1. 
INTRODUCTION 
6 
1.1. 
BACKGROUND 
6 
1.2. 
RATIONALE FOR CURRENT STUDY 
7 
2. 
STUDY OBJECTIVES 
8 
3. 
STUDY DESIGN 
8 
3.1. 
STUDY OUTCOME MEASURES 
8 
4. 
PARTICIPANT ENTRY 
8 
4.1. 
PRE-REGISTRATION EVALUATIONS 
Error! Bookmark not defined. 
4.2. 
INCLUSION CRITERIA 
8 
4.3. 
EXCLUSION CRITERIA 
9 
4.4. 
WITHDRAWAL CRITERIA 
9 
5. 
ADVERSE EVENTS 
9 
5.1. 
DEFINITIONS 
Error! Bookmark not defined. 
5.2. 
REPORTING PROCEDURES 
Error! Bookmark not defined. 
6. 
ASSESSMENT AND FOLLOW-UP 
13 
7. 
STATISTICS AND DATA ANALYSIS 
15 
8. 
REGULATORY ISSUES 
16 
8.1. 
ETHICS APPROVAL 
16 
8.2. 
CONSENT 
16 
8.3. 
CONFIDENTIALITY 
16 
8.4. 
INDEMNITY 
17 
8.5. 
SPONSOR 
17 
8.6. 
FUNDING 
17 
8.7. 
AUDITS 
17 
9. 
STUDY MANAGEMENT 
17 
10. 
PUBLICATION POLICY 
17 
11. 
REFERENCES 
18 
 
 
 
 
 
 
GLOSSARY OF ABBREVIATIONS 

 
 
 
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CGM 
Continuous glucose monitoring 
AI 
Adrenal insufficiency 
T1D 
Type 1 diabetes 
ICRF 
Imperial College Research Facility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KEYWORDS 
Type 1 diabetes 
Adrenal Failure 
Hypoglycaemia 
Continuous glucose monitoring 
 
 

 
 
 
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STUDY SUMMARY 
 
TITLE 
 
 
DESIGN 
Frequency of nocturnal hypoglycaemia in patients with insulin-treated 
diabetes and adrenal failure using prednisolone or hydrocortisone: a pilot 
study. 
A prospective observational study 
AIMS (1) To measure the frequency of nocturnal hypoglycaemic episodes in 
people with both AI and Type 1 Diabetes, and in age, sex and steroid 
replacement matched controls without diabetes. 
 
(2) To compare frequency of nocturnal hypoglycaemia in those taking 
prednisolone versus those taking hydrocortisone. 
 
(3) To compare the diurnal patterns of frequency of hypoglycaemia in 
those taking prednisolone versus those taking hydrocortisone. 
OUTCOME 
MEASURES 
Primary outcomes: Percentage time spent with glucose below 3.0mmol/L 
Secondary outcomes: Percentage time spent with glucose below 
3.9mmol/L, between 3.9mmol/L and 10mmol/L, and above 10mmol/L. 
Number of episodes of hypoglycaemia and severe hypoglycaemia. 
Outcomes will be retrieved for the nocturnal period (midnight to 6am) and 
separately for the 24-hour period. Gold score, Hyperglycaemia Fear 
Survey-II (HFS-II) score and Hospital Anxiety and Depression (HADS) 
Score. 
 
POPULATION Adults with insulin-treated diabetes and adrenal insufficiency 
ELIGIBILITY Confirmed diagnoses of insulin-treated diabetes and adrenal insufficiency 
for at least one year 
DURATION 30 days 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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REFERENCE DIAGRAM 
 
 
 
 
1. INTRODUCTION  
 
BACKGROUND 
 
Adrenal insufficiency (AI) is a serious condition which, without treatment, may be life-
threatening and is associated with increased mortality (1, 2). AI can be caused by 
primary failure of the adrenal glands (primary AI) or by pituitary disorders. Primary AI 
is an autoimmune condition that leads to destruction of the adrenal cortex and its ability 
to produce cortisol. Lack of cortisol can lead to an adrenal crisis which is an acute 
medical emergency requiring urgent treatment.  
 
People with AI require lifelong steroid replacement, traditionally using hydrocortisone 
or more recently with prednisolone. Hydrocortisone has a short half-life and is given 
three times a day, which mimics the natural daily variation in production of cortisol. 
Prednisolone is an alternative option, and owing to its longer half-life needs only to be 
given once a day, offering benefits for ease of compliance. 
 
 
Primary AI is often associated with other autoimmune endocrinopathies such as Type 
1 diabetes, which requires treatment with insulin. Type 1 diabetes and type 2 diabetes, 
which may also require treatment with insulin, are both strongly associated with  

 
 
 
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cardiovascular risk factors (3) and increased mortality (4). Lifelong management with 
insulin requires multiple daily injections and self-management can be challenging. 
 
Hypoglycaemia (low blood glucose) is a common and serious complication of insulin 
therapy and independently causes a twofold increase in risk for cardiovascular disease 
and mortality in insulin-treated diabetes (5). Hypoglycaemic symptoms may include 
irritability, dizziness or confusion. If left untreated this can lead to loss of 
consciousness, seizure or death. Prompt recognition and appropriate treatment is 
paramount and nocturnal hypoglycaemia is particularly concerning. Recurrent 
episodes may lead to impaired awareness of hypoglycaemia, increased frequency of 
episodes and subsequent risk of severe hypoglycaemia, defined as hypoglycaemia 
requiring the assistance of a third party for active treatment.  
 
Hypoglycaemia also occurs in AI in the absence of insulin-treated diabetes. Cortisol 
has an important role in the counter-regulatory response to hypoglycaemia. Lack of 
cortisol in AI causes reduced hepatic glucose output and increased glucose oxidation 
leading to increased insulin sensitivity. Hypoglycaemia may be present in undiagnosed 
AI in some, and in others may be a signifier of untreated or suboptimal treatment of 
AI. 
 
RATIONALE FOR CURRENT STUDY 
 
There is a complex relationship between AI and Type 1 diabetes, which results in 
higher mortality in people living with both diagnoses compared to either diagnosis 
alone (6). Adrenal crises and hypoglycaemia are both potentially life-threatening 
medical emergencies which often lead to individuals requiring acute medical 
admission to hospital. Recent data demonstrates that more than half of severe 
hypoglycaemic episodes attended by paramedics result in conveyance to hospital (7). 
As having both conditions is rare, there are few studies on this high risk, vulnerable 
and relatively young group. There may be substantial potential to reduce harm and 
burden, and to reduce healthcare utilisation by minimising exposure to hypoglycaemia. 
 
Previous studies conducted at ICHT reported 66% greater mortality in people with AI 
compared to matched controls (8). Furthermore, in people with primary AI, the 
mortality was three times higher in those with treated with prednisolone compared to 
hydrocortisone (9). These findings were reported from the first population-based 
dataset of adrenal failure in the UK.  However, the studies were retrospective and prior 
to 2014, many participants took higher total daily doses of prednisolone (7.5g) than 
current recommended (3g or 4g).  Research in optimal steroid replacement doses has 
since indicated that 7.5g is excessive, leading to steroid-induced complications such 
as hyperglycaemia, increased blood pressure and increased body weight, all of which 
increase cardiovascular risk factors.  This is likely to have significantly contributed to 
the mortality excess in the past but further research in required to determine factors 

 
 
 
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affecting this group currently. This study would aim to investigate frequency of 
hypoglycaemia as a potential cause for this excess. 
 
Research Question: In people with insulin-treated diabetes and adrenal failure, does 
hypoglycaemia occur more frequently in those treated with prednisolone or 
hydrocortisone? 
 
 
 
 
 
2. STUDY OBJECTIVES 
 
(1) To measure the frequency of nocturnal hypoglycaemic episodes in people with 
both AI and insulin-treated diabetes, and in age, sex and steroid replacement 
matched controls without diabetes. 
 
(2) To compare frequency of nocturnal hypoglycaemia in those taking prednisone 
versus those taking hydrocortisone. 
 
(3) To compare the diurnal patterns of frequency of hypoglycaemia in those taking 
prednisolone versus those taking hydrocortisone. 
 
3. STUDY DESIGN 
 
This is a prospective observational study in 16 adults with both insulin-treated diabetes 
and adrenal insufficiency and 16 age, sex and steroid replacement matched controls 
without diabetes. We will recruit and enrol 32 participants in total. Participants will 
spend 30 days in the study. 
 
STUDY OUTCOME MEASURES 
Primary outcomes: Percentage time spent with glucose below 3.0mmol/L 
 
Secondary outcomes: Percentage time spent with glucose below 3.9mmol/L, 
between 3.9mmol/L and 10mmol/L, and above 10mmol/L. Number of episodes of 
hypoglycaemia and severe hypoglycaemia. Outcomes will be retrieved for the 
nocturnal period (midnight to 6am) and separately for the 24-hour period. Gold score, 
Hyperglycaemia Fear Survey-II (HFS-II) score and Hospital Anxiety and Depression 
(HADS) Score. 
 
4. PARTICIPANT ENTRY 
INCLUSION CRITERIA 
- for test group: 
Confirmed diagnoses of adrenal insufficiency and insulin-treated diabetes for more 
than one year.  
Adults aged above 18 years 
 

 
 
 
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-for matched control group: 
Diabetes mellitus excluded on baseline blood review 
Adults aged above 18 years 
 
 
EXCLUSION CRITERIA 
Measured eGFR ≤ 30 
Acute illness 
Abnormal thyroid function 
Admission to hospital 
Pregnant or planning pregnancy 
Breastfeeding 
Enrolled in other clinical trials, except at the discretion of the chief investigator 
Have active malignancy or under investigation for malignancy 
Severe visual impairment 
Reduced manual dexterity 
Unable to participate due to other factors, as assessed by the Chief Investigators 
 
WITHDRAWAL CRITERIA  
The subject has a serious event related to study 
Investigator initiated discontinuation of study due to participation or equipment 
concerns 
Withdrawal of consent 
<70% complete continuous glucose monitoring (CGM) data within 10 day run in period 
 
Withdrawal will be immediate. Identifiable data already collected with consent will be 
retained and used in the study. No further data would be collected or any other 
research procedures carried out on or in relation to the participant. 
 
5. ADVERSE EVENTS  
5.1 
Definitions   
Investigational Medical Device  
Medical device being assessed for safety or performance in a clinical investigation. 
This includes medical devices already on the market that are being evaluated for new 
intended uses, new populations, new materials or design changes. 
 
Adverse Event (AE)  
Any untoward medical occurrence, unintended disease or injury, or any untoward 
clinical signs (including an abnormal laboratory finding) in participants, users or other 
persons concerned with the medical device. These may, or may not be, considered 
related to the investigational device, device related procedure or comparator. If the AE 
is considered to have a reasonable causal relationship with the device, then it is 
considered to be an ADE. 
 

 
 
 
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Adverse Device Effect (ADE) An Adverse Event (AE) related to the use of an 
investigational medical device. This includes any AE resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, implantation or operation of 
the medical device or any malfunction. This also includes any AE that is a result of an 
error in use or intentional misuse of the medical device.  
 
Device Deficiency Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. Device Deficiencies include malfunctions, 
misuse or use errors and inadequate labelling.  
 
Serious Adverse Event (SAE) An Adverse Event that results in: 
• Death. 
• Life threatening illness or injury. 
• Permanent impairment of a body structure or body function. 
• Hospitalisation or prolongation of existing hospitalisation. 
• Medical or surgical intervention to prevent life threatening illness, injury or 
impairment to a body structure or body function. 
• Foetal distress, foetal death or congenital anomaly or birth defect. 
• Is otherwise considered medically significant by the Investigator  
 
This includes potential SAEs which were avoided as result of action or intervention. A 
planned hospitalisation for a pre-existing condition, or a procedure required in the 
protocol, without a serious deterioration in health, is not considered an SAE.  
 
NOTE Device deficiencies that might have led to a serious adverse event where a 
suitable action had not been taken or an intervention had not been made or if 
circumstances had been less fortunate are handled under the serious adverse event 
reporting system.  
 
Such adverse events should be reported as soon as possible.  When reporting these 
events please include the total number of patients treated in the UK at the time of 
reporting. 
 
Medical judgement should be exercised in deciding whether an adverse event is 
serious in other situations. Important adverse events that are not immediately life-
threatening or do not result in death or hospitalisation but may jeopardise the subject 
or may require intervention to prevent one of the other outcomes listed in the definition 
above, should also be considered serious.  
 

 
 
 
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Severity: The term “severe” is often used to describe the intensity (severity) of a 
specific event. This is not the same as “serious”, which is based on patient/event 
outcome or action criteria.  
 
Suspected Serious Device Effect (SADE) An Adverse Device Effect (ADE) that 
results in: 
• Death. 
• Life threatening illness or injury 
• Hospitalisation, or prolongation of existing hospitalisation. 
• Persistent or significant disability or incapacity.  
• Foetal distress, foetal death or congenital anomaly or birth defect. 
• Is otherwise considered medically significant by the Investigator  
 
Any hospitalisation planned prior to enrolment is not a SADE.  
 
Unanticipated Serious Adverse Device Effect (USADE) Serious adverse device 
effect which by its nature, incidence, severity or outcome has not been identified in the 
current version of the risk analysis report.  
 
Responsibilities There are a number of responsibilities when managing adverse 
events. Below is a list of responsibilities for both the Investigator and the Sponsor (the 
Research Governance and Integrity Team (RGIT) will act on behalf of the Sponsor).  
 
The CI has overall responsibility for the conduct of the study. The Principal Investigator 
(PI) has responsibility for the research at a local site where the study involves specified 
procedures requiring site-specific assessment. There should be one PI for each 
research site. In the case of this single-site study, the CI and the PI are the same 
person.  
 
Investigator’s Responsibilities  
1. CI to report all SAEs within agreed timelines to Sponsor  
2. CI to report SAEs within agreed timelines to Sponsor, REC and relevant NHS 
Trust Research and Development Office (R&D) 
3. Provide the Sponsor with details of all AEs identified in the protocol as critical 
to the evaluation of safety within the agreed timeframes specified in the 
protocol. 
4. Review SAE reports from Investigators and perform an evaluation with respect 
to seriousness, causality and expectedness. 
5. Supply the Sponsor, REC and relevant NHS Trust R&D with any supplementary 
information they request.  
 

 
 
 
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Sponsor’s Responsibilities  
1. In collaboration with the Device Manufacturer, perform ongoing safety 
evaluation of the trial device and report any findings that may affect the health 
of subjects to the Device Manufacturer. 
2. Promptly notify all Investigators and REC(s) of any findings that may affect the 
health of subjects. 
3. Keep detailed written reports of all AEs reported by PIs and performing an 
evaluation with respect to seriousness, causality and expectedness. 
4. Report all relevant safety information and SAEs to the relevant REC within the 
relevant timelines 
5. Submit the annual report to Sponsor and REC.  
 
Note that for Imperial AHSC sponsored studies the above sponsor 
responsibilities are delegated to the CI. 
 
PROCEDURES  
 
Study Planning  The device’s User Guide written by the device manufacturer lists 
known side effects and adverse reactions contained within the manufacturer’s product 
information. Rare/very rare events may or may not be included depending on 
individual study requirements.  
 
During the Trial Each AE will be evaluated for seriousness, causality, and 
expectedness. The responsibility for this evaluation and reporting to the sponsor rests 
with the CI.  
 
Causality Adverse reactions will be assessed for causality. The definitions below will 
be used.  
 
 

 
 
 
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Assessment of Expectedness  
Expected: The reaction is consistent with the effects of the device listed in the 
manufacturer’s User Guide 
Unexpected: the reaction is not consistent with the effects of the device listed in the 
manufacturer’s User Guide .  
 
Reporting  
Once the CI has evaluated the AE in terms of seriousness, causality and 
expectedness, the following guidelines will be followed.  
 
AEs/ADEs AEs that will be reported and are not considered serious will be included 
in the patient notes and on the relevant case report forms (CRFs). The completed form 
will be filed along with the other CRFs for the study.  
 
SAEs/SADEs If the AE is assessed as serious, the CI must be informed immediately 
and within 24 hours.  The CI will record the event with assessment of seriousness, 
(along with causality, expectedness and severity) on a trial SAE form. The CI will 
ensure that follow-up information is provided when available. Where supporting 
documents are sent with this form, these will be pseudonymised. Where the 
information available is incomplete at that time, as much information as can be 
ascertained will be sent to ensure timely reporting, with additional information provided 
as soon as it is known. Additional information received for an event (follow-up or 
corrections to the original event data) will to be detailed on a new SAE form. The CI 
must ensure that SAEs are reported to RGIT within 24 hours via email to 
RGIT@imperial.ac.uk.  
 
USADEs Reports of USADEs shoulde be submitted to the REC within 15 days of the 
CI becoming aware of the event.   
 
 
Follow-up of adverse events All adverse events will be followed-up until resolution 
or death of the participant.  
 
6. ASSESSMENT AND FOLLOW-UP  
 
6.1  
Recruitment  
Recruitment will be undertaken in endocrinology and diabetes clinics at Imperial 
College Healthcare NHS Trust. Participant information sheets will be given to potential 
subjects and, following any questions, informed consent will be taken. We will identify 
potential participants from medical records and post/email them a copy of the Patient 
Information Sheet (PIS) prior to approaching them in clinic. 

 
 
 
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Participants will be given as much time as they require (and at least 24 hours) to decide 
whether or not to take part – this can vary on a per participant basis. 
 
6.2  
Enrolment and study conduct 
 
6.2.1 Visit 1: Baseline Screening 
(Day 0, to last approximately 2 hours) 
 
Participants will attend an initial screening visit at the NIHR Imperial College Research 
Facility (ICRF). Following informed consent, the research team will collect full medical 
and medication history and conduct routine anthropometry (height and weight). The 
research team will also carry out a physical examination including a general chest 
examination and abdominal examination (auscultation of lungs, heart and abdomen 
and palpation of the chest wall and abdomen). Participants will be asked to provide a 
urine sample (urine albumin:creatinine ratio) and a venous blood sample will be taken 
(full blood count, HbA1c, urea, creatinine and electrolytes, thyroid function, c-peptide 
and glucose). We will measure baseline steroid replacement with serum prednisolone 
levels or hydrocortisone day curves (see appendix 2). Blood samples will be sent to 
the accredited Imperial College Healthcare NHS Trust laboratory for analysis. Urine 
pregnancy tests will be done in females of childbearing age. Urine and blood samples 
will not be stored. Participants will complete the Gold questionnaire to assess for 
hypoglycaemia awareness, the Hyperglycaemic Fear Survey-II and Hospital Anxiety 
and Depression Survey. All questionnaires used are validated. 
 
Participants will be provided with a continuous glucose monitoring (CGM) device. The 
system continuously measures glucose levels in interstitial fluid through a small sensor 
which is inserted under the skin. For the control group, the device will be blinded to 
the participant.  In participants who have insulin-treated diabetes, the data can be read 
on a display device (receiver) or a compatible smart app. Each participant will have a 
sensor fitted in clinic. They will be given education for use of the device according to 
the manufacturer's guidelines. They will have access to the Dexcom G6 User Guide, 
which is available online. Participants will be shown how to insert the sensors 
themselves and provided with adequate sensors and transmitters for the duration of 
the trial. If the participants’ sensor fails or falls out the research team will provide a 
new sensor. Participants will be instructed to test their glucose as per standard care, 
and to manage as their usual care if symptoms of hypo- or hyperglycaemia occur. 
Refresher education regarding general diabetes management and management of 
hypoglycaemia specifically will be offered. 
 
Participants will be supported to change their glucose sensor every 10 days at home. 
Those with unblinded devices will be given education and support to manage the alerts 

 
 
 
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and alarms provided by the system. At this visit the glucose threshold low alert will be 
set to 4.4 mmol/L and the high threshold alert will be set to 12mmol/L. These can be 
personalised by participants throughout the study to manage alert burden. Participants 
will have access to a helpline for any queries or concerns regarding their device. 
 
6.2 
Visit 2: Final Study Visit 
(Day 30, to last approximately 1 hour) 
 
Participants will attend the ICRF 30 days after their baseline screening for data 
collection. Participants will be invited to review and discuss the data collected with a 
clinician. This review may be conducted over the telephone as per the participant’s 
preference. 
 
All study equipment will be returned, and participants will return to standard care.  
 
6.3 
End of Study 
End of study will be defined as Last Subject Last Visit (LSLV) 
 
6.3.1 Incidental findings 
 
Incidental findings identified from laboratory investigations during the study will be 
reviewed by the investigators and will then be communicated by the study team to the 
participant and to the participant’s GP. 
Incidental findings identified from laboratory investigations during the study will be 
reviewed by the investigators and will then be communicated by the study team to 
the participant and to the participant’s GP with a clear management plan. 
Examples of potential incidental findings include: 
1. A new diagnosis of pre-diabetes or diabetes in the control group 
2. Hypothyroidism (underachieve thyroid) or hyperthyroidism (overactive thyroid) 
3. Anaemia  
 
7. STATISTICS AND DATA ANALYSIS 
 
This is a pilot study and therefore we are not proposing a fully-powered study (4). The 
data gathered from the proposed work will serve as robust pilot data to support a larger 
randomised study.   
 

 
 
 
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The primary outcome is the percent time spent with glucose below 3.0mmol/L. This is 
in accordance with international consensus for hypoglycaemia. Glucose data will be 
extracted from the 30 days of unblinded/blinded CGM and used for analysis.  
 
A two-tailed unpaired t-test will be performed to compare the primary and secondary 
glucose outcomes between groups. A p-value of <0.05 will be considered statistically 
significant. 
 
All study data including personal and pseudoanonymised data and all appropriate 
documentation will be stored for a minimum of 5 years after the completion of the 
study, including the follow-up period.   
 
 
8. REGULATORY ISSUES  
 
ETHICS APPROVAL  
The Study Coordination Centre has obtained approval from the xxx Research Ethics 
Committee (REC) and Health Research Authority (HRA). The study must also receive 
confirmation of capacity and capability from each participating NHS Trust before 
accepting participants into the study or any research activity is carried out. The study 
will be conducted in accordance with the recommendations for physicians involved in 
research on human subjects adopted by the 18th World Medical Assembly, Helsinki 
1964 and later revisions. 
 
CONSENT   
Consent to enter the study must be sought from each participant only after a full 
explanation has been given, an information leaflet offered and time allowed for 
consideration.  Signed participant consent should be obtained.  The right of the 
participant to refuse to participate without giving reasons must be respected.  After the 
participant has entered the study the clinician remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the 
participant’s best interest, but the reasons for doing so should be recorded.  In these 
cases the participants remain within the study for the purposes of follow-up and data 
analysis.  All participants are free to withdraw at any time from the protocol treatment 
without giving reasons and without prejudicing further treatment. 
 
CONFIDENTIALITY  
Pseudonymised data is data that can be linked back to a person (e.g. coded data).  It 
is considered both personal and identifiable data. Anonymised data is data that has 
no code and cannot be linked back to a person (e.g. aggregated data for publication, 
data without a code that cannot be linked back to a person) 
 

 
 
 
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The Chief Investigator will preserve the confidentiality of participants taking part in the 
study and is registered under the Data Protection Act. 
 
 
 
Data will be pseudonymised  
Dexcom is a separate data controller and is able to access pseudoanonymised CGM 
data from Dexcom device users. They have a separate privacy notice and subject 
rights which can be accessed online here: https://www.dexcom.com/en-
GB/linked/documentservice/PrivacyPolicy.  
 
INDEMNITY 
Imperial College Healthcare NHS Trust holds standard NHS Hospital Indemnity and 
insurance cover with NHS Resolution for NHS Trusts in England, which apply to this 
study  
 
SPONSOR  
Imperial College Healthcare NHS Trust will act as the main Sponsor for this study.  
Delegated responsibilities will be assigned to the NHS trusts taking part in this study.   
 
FUNDING  
The Imperial Health Charity are funding this study.   
 
AUDITS   
The study may be subject to audit by Imperial College Healthcare NHS Trust under 
their remit as sponsor and other regulatory bodies to ensure adherence to GCP and 
the UK Policy Frame Work for Health and Social Care Research.  
 
 
9. STUDY MANAGEMENT  
 
The day-to-day management of the study will be co-ordinated through Dr Shaila Khan.   
 
 
10. PUBLICATION POLICY  
 
The study will be registered on the clinicaltrials.gov system and results will be 
disseminated by peer reviewed scientific journals, internal report, conference 
presentation and publication on websites. No identifiable personal data will be 
published. All anthropometry and personal clinical data will be expressed as mean/ 
median and spread of the population in the study. Details of any publications that arise 
from the study will be disseminated to participants on request.   
 

 
 
 
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11. REFERENCES  
1. Bensing S, Brandt L, Tabaroj F, et al. Increased death risk and altered cancer 
incidence pattern in patients with isolated or combined autoimmune primary 
adrenocortical insufficiency. Clin Endocrinol (Oxf). Nov 2008;69(5):697-704. 
doi:10.1111/j.1365-2265.2008.03340.x 
2. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature 
mortality in patients with Addison's disease: a population-based study. J Clin 
Endocrinol Metab. Dec 2006;91(12):4849-53. doi:10.1210/jc.2006-0076 
3. Chantzichristos D, Persson A, Eliasson B, et al. Mortality in patients with 
diabetes mellitus and Addison's disease: a nationwide, matched, observational 
cohort study. Eur J Endocrinol. Jan 2017;176(1):31-39. doi:10.1530/EJE-16-0657 
4. Julious SA. Sample size of 12 per group rule of thumb for a pilot 
study. Pharmaceutical Statistics. 2005;4(4):287-291. 
doi:https://doi.org/10.1002/pst.185 
5. Lu CL, Shen HN, Hu SC, Wang JD, Li CY. A Population-Based Study of All-
Cause Mortality and Cardiovascular Disease in Association With Prior History of 
Hypoglycemia Among Patients With Type 1 Diabetes. Diabetes Care. Sep 
2016;39(9):1571-8. doi:10.2337/dc15-2418 
6. Ngaosuwan K, Johnston DG, Godsland IF, et al. Cardiovascular Disease in 
Patients With Primary and Secondary Adrenal Insufficiency and the Role of 
Comorbidities. J Clin Endocrinol Metab. 04 23 2021;106(5):1284-1293. 
doi:10.1210/clinem/dgab063 
7. Ngaosuwan K, Johnston DG, Godsland IF, et al. Increased Mortality Risk in 
Patients With Primary and Secondary Adrenal Insufficiency. J Clin Endocrinol 
Metab. 06 16 2021;106(7):e2759-e2768. doi:10.1210/clinem/dgab096 
8. Ngaosuwan K, Johnston DG, Godsland IF, et al. Mortality Risk in Patients With 
Adrenal Insufficiency Using Prednisolone or Hydrocortisone: A Retrospective 
Cohort Study. J Clin Endocrinol Metab. 07 13 2021;106(8):2242-2251. 
doi:10.1210/clinem/dgab347 
9. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Diabetes mellitus, 
fasting glucose, and risk of cause-specific death. N Engl J Med. Mar 03 
2011;364(9):829-841. doi:10.1056/NEJMoa1008862 
10. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose 
concentration, and risk of vascular disease: a collaborative meta-analysis of 102 
prospective studies. Lancet. Jun 26 2010;375(9733):2215-22. doi:10.1016/S0140-
6736(10)60484-9 

 
 
 
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11. Uduku C, Pendolino V, Godsland I, Oliver N, Reddy M, Fothergill RT. Cross-
sectional analysis of emergency hypoglycaemia and outcome predictors among 
people with diabetes in an urban population. Diabet Med. Nov 2021;38(11):e14654. 
doi:10.1111/dme.14654 
 
 
 
 
Appendix 1. Summary of activities at and between visits 
 
  
VISIT 1 
Day 0  
  
Day 10  
  
Day 20  
VISIT  2 
Day 30  
Medical history  
x  
  
  
  
Medication history  
x  
  
  
  
Physical examination  
x  
  
  
  
Pregnancy test 
(urine)  
x  
  
  
  
Full Blood Count  
x  
  
  
  
Renal Function  
x  
  
  
  
HbA1c  
x  
  
  
  
TFT  
x  
  
  
  
C peptide  
x  
  
  
  
Glucose  
x  
  
  
  
Cortisol day curve/ 
Prednisolone level 
x  
  
  
  
Gold score  
x  
  
  
  
QoL questionnaires  
x  
  
  
  
CGM education  
x  
  
  
  
CGM 
insertion (supervised 
by research team) 
x  
 
 
  
CGM insertion 
(independently by 
participant 
 
 x 
x  
 
CGM download  
x  
 x 
Data review  
  
  
  
  x  
 
 
 
Appendix 2. Protocols for baseline steroid measurement  
 
Prednisolone Level 
Preparation  
• Stop all oestrogen therapy 6 weeks prior to test.  
• No need to fast.  
• Take normal morning prednisolone and patient should note down actual time 
taken. 
 
Method 

 
 
 
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A sample is taken 8h following the administration of prednisolone. If the dose was 
taken at 7am at home, the final sample should be taken at 3pm. 
 
Hydrocortisone Day Curve 
Preparation  
• Stop all oestrogen therapy 6 weeks prior to test.  
• No need to fast.  
• Take normal morning hydrocortisone and patient should note down actual time 
taken.  
• Equipment required: 18-20g cannula.  Red or yellow top Vacutainers. Syringes.  
 
Method 
Take blood at the following times:  
1. Blood sample on arrival, noting time of sample and time and dose of 
hydrocortisone.  
2. Pre lunchtime (2nd) dose  
3. 1 hour post lunchtime (2nd) dose  
4. pre evening (3rd) dose  
5. post evening (3rd) dose or at 6pm.  
 
Source: Endocrinology Handbook. Imperial Centre for Endocrinology. Imperial 
College Healthcare NHS Trust. Latest edition February 2018.  Bible2018.pdf 
(imperialendo.co.uk)