FreeSTyle LibRe and hospitAl Admissions, morTality and qUality of Life in High Risk Type 2 diabeteS Patients
Phase: NA
Conditions: Type 2 Diabetes
Sponsor: University of Leeds

STRATUS study: V1.7. 23.6.21 
Ajjan et al. Protocol V1.7. IRAS number 273948 
 
 
STRATUS study protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Long title: FreeSTyle LibRe and hospitAl admissions, morTality and qUality of life in high risk 
type 2 diabeteS patients 
 
Short title: The STRATUS study 
 
Study Protocol: V1.7 
 
Investigators: R.A Ajjan, S.M Pearson, J Bailey and B Whittam 
 
IRAS number: 273948 
 
Funders reference number: 
 

STRATUS study: V1.7. 23.6.21 
Ajjan et al. Protocol V1.7. IRAS number 273948 
 
Signatory page 
 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to the 
principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other regulatory requirement. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the investigation without the prior written consent 
of the Sponsor 
I also confirm that I will make the findings of the study publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account 
of the study will be given; and that any discrepancies from the study as planned in this protocol will be 
explained. 
 
For and on behalf of the Study Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Chief Investigator: 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): 
......................................................................................................
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

STRATUS study: V1.7. 23.6.21 
Ajjan et al. Protocol V1.7. IRAS number 273948 
 
Study summary 
 
Chief Investigator 
Ramzi Ajjan 
R.Ajjan@leeds.ac.uk 
07796676643 
Study Co-ordinator 
Julie Bailey 
Julie.bailey10@nhs.net 
Sponsor 
University of Leeds 
Funder(s) 
Abbott diabetes care 
Key Protocol Contributors 
Ramzi Ajjan 
Sam Pearson 
Julie Bailey 
 
 
Study Title 
FreeSTyle LibRe and hospitAl admissions, morTality and 
qUality of life in high risk type 2 diabeteS patients 
Internal ref. no. (or short title) 
STRATUS study 
Study Design 
Randomized controlled trial 
Study Participants 
Patients with type 2 diabetes whom have been recently 
treated by ambulance staff for hypoglycaemia 
Planned Size of Sample (if applicable) 
300 
Follow up duration (if applicable) 
6 months active involvement followed by a further 18 
months of remote review of participants electronic medical 
records 
Planned Study Period 
April 2021 – April 2024 
 
Role of study sponsor 
 
The study sponsor, the University of Leeds, is responsible for the oversight of this work and ensuring the 
trial is run safely, in a timely manner and in full accordance with good clinical practice guidelines. 
 
Role of study funder 
 
The study funder, Abbott diabetes care, provided monitary support for this study but had no involvement 
in study design, study set up or the setting of the aims/objectives of the study. They will not be involved in 
data analysis or dissemination of results.  
 

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Ajjan et al. Protocol V1.7. IRAS number 273948 
 
Introduction and preliminary data 
The prevalence of diabetes continues to increase and is reaching epidemic proportions 
(http://www.who.int). Optimizing glycemic control is key to prevent microvascular complications and long-
term macrovascular disease 1-4. HbA1c is currently used as the gold standard for monitoring response to 
treatment but this glycemic marker fails to address hypoglycemia and glycemic variability, both of which 
have a role in determining clinical outcome 5. Moreover, HbA1c shows a U-shaped correlation with 
mortality, indicating that lower glucose levels are not always better 6. Indeed, a number of studies have 
shown that hypoglycemia is associated with increased cardiovascular mortality and we have demonstrated 
that severe hypoglycemia in the community is linked to increased mortality, particularly within the first 3 
months of the event 7-10. Moreover, hypoglycemia has a major economic impact on health resources, 
adding to the spiraling cost of managing diabetes 11. Cardiac arrhythmias have been implicated as an 
important mechanism for the association between hypoglycemia and mortality 12. However, there are 
some longer term effects of hypoglycemia as episodes of low blood glucose increase the inflammatory 
response and enhance the thrombotic environment contributing to the vascular pathology in diabetes, as 
we have shown 13.  
Interestingly, our recent single center pilot study of 322 patients sustaining a severe hypoglycemic episode 
requiring ambulance services call out has shown that a 3 month structured nurse intervention in 150 type 
2 diabetes patients (that includes regular glucose testing) reduces mortality over a follow up period of 
approximately 3 years. Mortality of type 2 diabetes patients in the standard arm of the study (managed as 
per local guidelines) was 45%, whereas in the interventional arm this fell to 28%. A third arm of the study 
(termed the observational arm) agreed to have their electronic data analyzed but did not wish to be 
randomized and the mortality in this group was 50% (figure 1).  
 
 
 
 
 
 
 
 
 
 
Figure 1: A kaplan Meier curve to show survival across the three study groups of the 
original study.  

STRATUS study: V1.7. 23.6.21 
Ajjan et al. Protocol V1.7. IRAS number 273948 
 
A key component of nurse intervention was encouragement to test glucose regularly followed by 
adjustment of hypoglycemic therapies as appropriate. Given that regular glucose testing can be difficult in 
older people, having a simple device to check glucose may prove to be crucial to improve the adverse 
clinical outcome in this population. These data indicate that the high mortality rate in patients with type 2 
diabetes sustaining a severe hypoglycemic episode is potentially modifiable when appropriate glucose 
testing is undertaken and acted upon. Patients with type 1 diabetes (n=149) did not show a reduction in 
mortality in the intensive compared with the standard arm of the study (mortality was 10 and 9%, 
respectively; p>0.1), although the number of events was relatively small and the study lacked power to 
identify a difference in this group.   
 
In addition to hyperglycemia and hypoglycemia, glycemic variability (GV) has been linked to an increased 
rate of both micro and macrovascular complications as well as higher mortality 14;15. An increase in 
oxidative stress as a mechanism for enhanced vascular pathology has been proposed and this has shown 
an association with GV, in turn explaining the relationship between this glucose measure and adverse 
clinical outcome 16.  
 
Patients with diabetes require self monitoring of blood glucose (SMBG) for safe and effective adjustment 
of glycemic therapy, particularly in insulin treated patients 17;18. Previous work has shown that higher rate 
of glucose testing is associated with improved glycemic control 18;19. However, repeated daily glucose 
checks are painful, inconvenient and can be difficult to maintain long-term. A UK-based analysis reported 
2.1 glucose tests/day in insulin-treated patients 20, emphasizing the low rates of testing and providing one 
explanation for poor glycemic control in this population. Traditional continuous glucose monitoring (CGM) 
devices, and more recently the flash glucose monitor (Freestyle Libre), have made glucose checks easier 
with the ability to obtain a large number of glucose readings/day that is simply not possible with SMBG. A 
key advantage of the Freestyle Libre device is factory calibration, making it more convenient and 
eliminating potential inaccuracy encountered with CGM devices when calibration is not undertaken 
properly or frequently enough. 
A recent study on freestyle Libre use in real-life settings has shown frequent glucose testing 21. The number 
of glucose tests demonstrated an inverse correlation with time spent in hyperglycemia and hypoglycemia, 
emphasizing the importance of regular glucose checks for improving glycemic control. While these data are 
valuable, one of the main weaknesses is the inability to address hard end points, such as hospital 
admissions and quality of life measures, which would help to understand the full effects of this device on 

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Ajjan et al. Protocol V1.7. IRAS number 273948 
patient management in real world settings; this would be particularly important in individuals at higher risk 
of dysglycemia. Therefore, more detailed patient data are required to understand the role of Freestyle 
Libre in altering quality of life and reducing emergency healthcare contacts in UK patients with type 2 
diabetes.  
 
Aims/objectives 
Aim 1. Study the effects of Freestyle Libre on health care contact, hospital admissions and mortality in 
individuals with type 2 diabetes who have suffered an episode of severe hypoglycaemia 
Using UK Hospital Episode Statistics (HES) data and GP records, we will establish the number of contacts with 
health care professionals over a period of 12 months before following starting Freestyle Libre. A comparator 
group receiving standard care will also have their health records analyzed. Moreover, the reason for the 
admission will be clarified and grouped into 4 categories: hyperglycemia (including ketoacidosis and 
hyperosmolar state), hypoglycemia, cardiovascular event and other. Mortality data will be collected in all 
patients with the effects of Freestyle Libre on survival analysed during a minimum anticipated median follow 
up period of 24 months. Cause of death will be analysed and grouped in the following manner: 
Cardiovascular cause, infection, renal disease, malignancy, glycaemic emergency, dementia/old age, other. 
This will allow for comparisons not only in mortality rates between groups but also differences in cause of 
death. In addition, data will be supplied by the Yorkshire ambulance service regarding number of contacts 
with emergency services in the year prior to the index event and the two years following this. This will be 
done by the study team contacting the ambulance service to update them as to whom consented to take 
part in the study and providing information regarding this using secure NHS email addresses.  
 
In addition to hospital admission and mortality data, detailed glycaemic results will also be collected 
including glycated hemoglobin (HbA1c) at baseline and 6 months after start of Freestyle Libre use. Time 
spent in hypoglycemia in the first 3 days and full 14 days of sensor 1 use will be compared with sensor 6 and 
12 (3 and 6 months). Data from Freestyle Libre will be acquired using the manufacturers (Abbott) secure 
software where possible to avoid in person clinical contact. If this is not possible then in-person review will 
take place. Similar analysis will be conducted on glucose variability, assessed as coefficient of variation (CoV) 
and standard deviation (SD), in the first 3 days and full 14 days of sensor 1, 6 and 12 use.  
 
Aim 2. Analyze the effects of Freestyle Libre on quality of Life measures in type 2 diabetes patients 
Asking the individual to undertake regular SMBG can be distressing and using flash glucose monitoring may 
help to decrease stress levels and improve quality of life. Indeed two RCTs in type 1 and type 2 diabetes 

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Ajjan et al. Protocol V1.7. IRAS number 273948 
patients have shown that Freestyle Libre has a positive effect on QoL measures22 but it is unclear whether 
the same applies in real life setting and in higher risk individuals. In the current proposal we will evaluate 
patient satisfaction with flash glucose monitoring by asking patients to complete a set of validated 
questionnaires including Diabetes Distress Scale (DSS), Diabetes Quality of Life (DoQL) questionnaire and 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) 22-25. Again, QOL measures will be compared between 
those using Freestyle libre and receiving intensive nurse led intervention and those receiving standard care. 
Comparison will be made between baseline and 6 months in the Libre study arm and we will also analyse 
difference between two study arms at 6 months in study cohort (adjusted for baseline). 
 
Aim 3. Explore the role of Freestyle Libre as a substitute for laboratory HbA1c measurements 
First, we will assess the value of estimated HbA1c (eHbA1c), provided by the device, at predicting laboratory 
HbA1c. We will use the mean value of eHbA1c over 3 months (6 sensors) and compare with laboratory hbA1c 
at 6 months. This will help to understand the clinical value of eHbA1c in the management of patients with 
diabetes. We will then move to understand the value of calculated HbA1c (cHbA1c), a new glycemic marker, 
in reflecting laboratory HbA1c. We have recently shown that cHbA1c accurately reflects laboratory HbA1c 
(manuscript in press). This glycaemic marker has the advantage of taking into account red blood cell 
glycation, generation and elimination thus making it person-specific. In the proposed work, we will have 
multiple laboratory HbA1c measurements and continuous glucose data that will further help to assess the 
accuracy of cHbA1c in predicting laboratory HbA1c. The value of cHbA1c will be calculated and subsequently 
used to assess correlation with laboratory HbA1c. This part of the work will be done in collaboration with 
personnel at Abbott who have the necessary experience in assessing cHbA1c and subsequently undertake 
the relevant analyses. Data provided will have important health economic and clinical implications in case 
cHbA1c shows enough accuracy to replace laboratory HbA1c.  
 
Hypothesis 
We propose to test 3 hypotheses: 
1. Following a severe hypoglycemic episode, Freestyle Libre along with regular diabetes nurse contact 
reduces hospital admissions, health care contact and death (including from a cardiovascular cause) 
in type 2 diabetes patients.  
2. Freestyle Libre improves quality of life type 2 diabetes patients at high risk of hypoglycemia.  
3. Calculated HbA1c (cHbA1c), a glycemic marker derived from Freestyle Libre glucose data, closely 
reflects laboratory HbA1c, making glucose assessment more convenient to patients and offering 
healthcare savings. 
 

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Study design 
 
Participant identification and recruitment 
 
• The Yorkshire ambulance service (YAS) is a large emergency healthcare provided covering the areas in 
which the study will be conducted (Leeds, Bradford, Wakefield). 
• When an ambulance crew attends to a patient whom is suffering from hypoglycaemia they provide 
appropriate treatment and when necessary transport the patient to hospital. An existing pathway is in 
place whereby the information surrounding the events is communicated to the ambulance 
administrative team. 
• The YAS research team will contact patients recently treated for hypoglycaemia and ask if they would 
be willing to be contacted by the local diabetes research team for a study researching hypoglycaemia. If 
the treated patient responds yes, their details will be forwarded to the appropriate diabetes research 
nurse covering the local area. 
• The diabetes research nurse will contact the patient within 7 days of the ambulance call out and, after 
introductions and explaining reasons for call, will outline the nature of the study and what it entails. If 
the patient is happy to receive further information a patient information sheet will be sent to them 
with more information. 
• A follow up phone call will be made and if the patient is willing to participate in the study they will be 
offered to attend the relevant diabetes centre or be visited at their home. 
• At this point, prospective participants will be given adequate time to ask questions about the study and 
any concerns they may have about taking part will be addressed. If they wish to continue in the 
enrolment process, written informed consent will be taken by the diabetes research nurse. 
Inclusion and exclusion criteria 
• Inclusion criteria: A known diagnosis of type 2 diabetes, sustained an episode of severe 
hypoglycaemia requiring ambulance call out, >18 years of age, able to give informed written 
consent. 
• Exclusion criteria: A form of diabetes which is not type 2 or diagnosis is not clear, currently 
pregnant, receiving renal replacement therapy, unable to provide informed written consent.  
Randomisation 
• Following the taking of written informed consent participants will be randomised to one of two 
groups using a computerised telephone randomisation programme. Participants will be randomised 
into: i) A group who's care will be returned to their usual diabetes care provider but will be asked to 
wear a blinded glucose sensor for a period of two weeks at month 6 ii) A group receiving increased 
input from a diabetes research nurse with the addition of using Freestyle Libre 2 for a period of 6 
months. 
 
 
Methods 
Day -14 to day 0. 

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• YAS research team contact patient recently treated for hypoglycaemia and ascertain if they are 
happy for their information to be passed to the hospital research nurses. If yes, information passed 
securely. 
• Diabetes research nurse contacts prospective participant and explains trial. Screening questions 
asked to check eligibility for trial. If eligible and prospective participant is happy, trial information 
sent to patient.  
• Patient contacted via telephone and if happy to proceed appointment made for baseline visit and 
consent to be obtained.  
Day 0 (baseline) 
• Written informed consent taken. 
• Data capture form completed to document detailed past medical history, current medications and 
doses, diabetes complications and basic demographic data (age, height, weight, smoking status). 
• Participant examined for lipohypertrophy. 
• Donation of blood sample for HbA1c, U and E’s, LFT’s and lipid profile. Donation of urine sample for 
urine albumin:creatinine ratio (UACR). 
• Both groups are asked to fill in questionnaires assessing diabetes distress (DQOL and DSS) and 
diabetes treatment satisfaction (DTSQ) as well as hypoglycaemic awareness (GOLD score).  
• Those randomised to the freestyle libre arm have first sensor attached and are shown how to apply 
sensor and how to interpret data. Given dedicated contact details for diabetes research nurse in 
case of any issues and to discuss treatment of diabetes at any point.  
• Those in the standard care arm are returned to their usual diabetes care provider. 
• Letters sent to participants GP making them aware of participant trial enrolment.  
Day 4 
• Phone call to participants in Freestyle libre arm to ascertain if any issues with sensor and answer 
any questions. 
Day 14 
• Contact those in freestyle libre arm. Review glucose data and alter diabetes therapy as indicated.  
Day 28 
• Contact those in freestyle libre arm. Review glucose data and alter diabetes therapy as indicated.  
Month 3 
• Contact those in freestyle libre arm. Review glucose data and alter diabetes therapy as indicated.  
Month 6 
• Review of electronic patient data to ensure the participant is not deceased so as to not cause 
distress to friends/family by attempting to make contact in that eventuality.  
• Both groups will attend an in-person meeting with the diabetes research nurse. Blood tests will be 
taken with consent for the same variables as at baseline (HbA1c, U and E’s, LFT’s, Lipids.) Urine for 
UACR collected.  
• Questionnaires will be repeated. 

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• For those using the Freestyle Libre system the equipment will be returned.  
• For those in the standard care arm, the blinded freestyle Libre device (Freestyle Libre pro) will 
applied and worn for a period of two weeks (facilities to return the sensor after this time will be 
provided.) 
• This will mark the end of active participant involvement in the trial for both groups. 
• Information will be sent to the participants primary care team alerting them that the participant 
has finished involvement in the trial.  
Month 12 
• All participants electronic records reviewed for unscheduled healthcare contacts, further 
ambulance call outs for hypoglycaemia, hospitalisations and death. If death has occurred, cause of 
death ascertained from death certificate.  
Month 24 
• All participants electronic records reviewed for unscheduled healthcare contacts, further 
ambulance call outs for hypoglycaemia, hospitalisations and death. If death has occurred, cause of 
death ascertained from death certificate.  
• Data will be supplied by the ambulance service research department regarding number of 
emergency call outs in the year prior to enrolment and the two years following this.  
 
A summary of trial design is shown in figure 2a and a summary of participant activities for the Freestyle 
Libre arm is shown in figure 2b. 
 
 
 
 
 
 
 
 
 
Figure 2a: A diagrammatic description of trial design 
Figure 2b: A diagrammatic 
description of participant activities 
for Freestyle Libre arm 

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Primary end point 
 
• Mortality at 2 years 
 
Secondary end points 
 
• All cause and cardiovascular mortality at 1 year and cardiovascular mortality at 2 years 
• Number of unscheduled healthcare contacts between groups 
• QOL measures between groups at 6 months 
• Assess accuracy in calculated HbA1c compare to laboratory values at 6 months 
• Assess HbA1c at 6 months in relation to baseline in both arms 
 
 
Statistical analysis and feasibility 
Results from our previous work 9 and the data presented above indicate that survival following severe 
hypoglycemia in type 2 diabetes patients over a median follow up period of 18 months is less than 80%. 
Assuming a conservative 28% reduction in mortality in the intervention compared with the standard arm 
during a median follow up of 18 months, 261 patients with type 2 diabetes will be required, powered at 
90% with a significance level at p<0.05. Therefore, we will aim to recruit 300 patients with type 2 diabetes 
sustaining a severe hypoglycemic episode into the study.  
 
We are unable to provide power calculations for hospital admissions or HCP contact of type 2 diabetes 
patients and therefore this part of the work will be exploratory.  
 
Numbers of patients will be enough to show differences in quality of life measures given the data provided 
by a previous study in type 2 diabetes patients22. 
 
Our previous work on patients with severe hypoglycemia requiring ambulance services intervention has 
shown that a single centre is able to recruit over 90 patients/year. Therefore, we propose recruit the majority 
of participants from a single site (Leeds teaching hospitals) with separate sites in the local area also recruiting 
to this study. The number of sites may be expanded if recruitment goals are not met although based on our 
previous work this is not deemed likely.  
 
 
 
 
COVID-19 precautions 

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• All efforts have been made for consultations to be remote wherever possible, with only 2 in-person 
healthcare contacts taking place. 
• Participants will visit the diabetes research center at baseline and 6 months but the option will be 
given to attend at the participants home if they wish. The day prior to contact the patient will be 
contacted to ascertain if they or any close contact are suffering with symptoms of COVID-19 with the 
appointment rescheduled in that eventuality. On the day of appointment, screening questions will 
be repeated with a temperature taken on entering the diabetes research center.  
 
Data management and ensuring the safety of patient identifiable data 
 
All data will be recorded and stored in accordance with GCP. Electronic data will be stored on NHS 
computers/laptops which are encrypted and password protected. Information pertaining to participants 
medical records will be kept separately (electronically) from patient identifiable information (a separate 
spreadsheet will be used with a participant study number.) Paper records, namely the data capture form 
used at the baseline visit will be kept in a locked, secure area of the diabetes centre at the host institution.  
 
Adverse event reporting 
 
Adverse events will be reported to the study sponsor as soon as it is evident that such an event has taken 
place. It is not deemed likely, given the nature of the study, that this will occur frequently. Any serious and 
unexpected adverse event deemed related to the intervention will be reported to the NHS REC within 15 
days.  
 
 
 
 
 
 
 
 
 
 
 

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