Brain Imaging to Predict Toxicity in Elderly Patients After Radiotherapy
Conditions: Glioblastoma Multiforme, Adult, Radiation Toxicity, Quality of Life
Sponsor: Brighton and Sussex University Hospitals NHS Trust

  
BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
 
3/4/2019 
BRITER protocol 
IRAS ID 216343 
 
 
 
 
 
 
 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
 
This protocol has regard for the HRA guidance and order of content 
 
 
FULL/LONG TITLE OF THE STUDY 
Brain Imaging to predict Toxicity in Elderly patients after Radiotherapy 
 
SHORT STUDY TITLE / ACRONYM 
BRITER study 
 
PROTOCOL VERSION NUMBER AND DATE 
Protocol version 0.8 03/04/2019 
RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
216343 
 
SPONSORS Number: 
Generated by the Sponsor. Enter if applicable 
 
FUNDERS Number: 
Generated by the funder. Enter if applicable 
 
 
 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
 
 
 
SIGNATURE 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): 
...................................................................................................... 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
 
 
LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
HRA PROTOCOL COMPLIANCE DECLARATION  
i 
TITLE PAGE  
ii 
RESEARCH REFERENCE NUMBERS 
 
ii 
SIGNATURE PAGE 
iii 
LIST OF CONTENTS  
iv 
KEY STUDY CONTACTS 
v 
STUDY SUMMARY 
v 
FUNDING 
 
vi 
ROLE OF SPONSOR AND FUNDER 
vi 
ROLES & RESPONSIBILITIES OF STUDY STEERING GROUPS AND INDIVIDUALS   
vi 
STUDY FLOW CHART 
 
vii 
SECTION  
1. BACKGROUND 
 
1 
2. RATIONALE 
 
 
3. THEORETICAL FRAMEWORK 
 
4. RESEARCH QUESTION/AIM(S)  
 
5. STUDY DESIGN/METHODS 
 
6. STUDY SETTING 
 
7. SAMPLE AND RECRUITMENT 
 
8. ETHICAL AND REGULATORY COMPLIANCE 
 
9. DISSEMINATION  POLICY 
 
10. REFERENCES 
 
11. APPENDICES 
 
 
 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
KEY STUDY CONTACTS 
Chief Investigator 
Dr Cressida Lorimer 
Clinical Research Fellow 
Clinical Investigation and Research Unit 
Royal Sussex County Hospital 
Brighton  
BN2 5BE 
Tel: 01273 696955 
E-mail: Cressida.lorimer@bsuh.nhs.uk 
Study Co-ordinator 
Dr Cressida Lorimer 
Clinical Research Fellow 
Clinical Investigation and Research Unit 
Royal Sussex County Hospital 
Brighton  
BN2 5BE 
Tel: 01273 696955 
E-mail: Cressida.lorimer@bsuh.nhs.uk 
Sponsor 
Mr Scott Harfield 
Head of Research and Development 
Brighton and Sussex University Hospitals NHS Trust 
Research and Development Office 
16 Bloomsbury Street 
Brighton  
BN2 1HQ 
Tel: 01273 606055 
E-mail: scott.harfield@bsuh.nhs.uk 
Joint-sponsor(s)/co-sponsor(s)  
N/A 
Funder(s) 
Names and contact details of ALL organisations providing 
funding and/or support in kind for this study 
Key Protocol Contributors 
Dr Juliet Brock 
Consultant Clinical Oncologist 
Sussex Cancer Centre 
Brighton 
BN2 5BE 
Tel: 01272 696955 
E-mail: Juliet.brock@bsuh.nhs.uk 
 
Dr Frank Saran 
Consultant Clinical Oncologist 
The Royal Marsden Hospital 
Downs Road 
Sutton 
SM2 5PT 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
Tel: 0208 6426011 
E-mail: frank.saran@rmh.nhs.uk 
 
Professor Anthony Chalmers 
Professor of Clinical Oncology 
Institute of Cancer Sciences & Beatson West of Scotland 
Cancer Centre 
University of Glasgow 
G12 8QQ 
Tel: 0141 3017092 
E-mail: Anthony.chalmers@glasgow.ac.uk 
 
Dr Samantha Mills 
The Walton Centre 
Lower Lane 
Liverpool  
L9 7LJ 
Tel: 0151 525 3611 
E-mail: samantha.mills@thewaltoncentre.nhs.uk 
 
 
STUDY SUMMARY 
 
Study Title 
Brain Imaging to predict Toxicity in Elderly patients 
after Radiotherapy 
Internal ref. no. (or short title) 
BRITER study 
Study Design 
Observational cohort imaging study 
Study Participants 
Patients newly diagnosed with glioblastoma aged > 65 years 
undergoing radiotherapy treatment 
Planned Size of Sample (if applicable) 100 patients 
Follow up duration (if applicable) 
6 months 
Planned Study Period 
2 years 
Research Question/Aim(s) 
 
Can you use MRI derived imaging parameters to predict the 
degree of side effects in patients receiving cranial 
radiotherapy as treatment for Glioblastoma Multiforme? 
 
 
 
 
 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
(Names and contact details of ALL organisations 
providing funding and/or support in kind for this 
study) 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
Sussex Cancer Fund 
c/o Julia Lenton 
Royal Sussex County Hospital 
Bristol Gate Entrance 
Eastern Road 
Brighton BN2 5BE 
Funded the total cost of the study - £62,000 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 03.04.2019 IRAS ID: 216343 
 
PROTOCOL CONTRIBUTORS 
The protocol has been written by Dr Cressida Lorimer with contributions and approval from Drs Brock, 
Saran, Mills and Prof Chalmers 
 
KEY WORDS: 
Glioblastoma, Radiotherapy toxicity, Geriatric Oncology 
 
STUDY FLOW CHART 
 
 
 
 
 
 
 
 
Insufficient 
images 
 
 
 
 
 
3-5 weeks after radiotherapy finished 
 
 
 
 
7-9 weeks after radiotherapy finished 
Patient recruitment and need for extra 
images assessed 
Baseline questionnaires and clinical 
details 
Extra MRI scan 
No extra scan 
Radiotherapy treatment 
Repeat questionnaires and 
clinical details 
Repeat questionnaires and 
clinical details 
End of study 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
STUDY PROTOCOL 
Brain Imaging to predict Toxicity in Elderly patients after Radiotherapy 
 
1 
BACKGROUND 
Glioblastoma (GBM) is the commonest primary malignant brain tumour among the adult population 
with approximately 2,000 new cases diagnosed in the UK per year. Incidence peaks in the 7th and 8th 
decades of life and as our global population ages, rates are increasing. Outcomes from this disease 
remain poor with median life expectancy in the range of 12-18 months, dropping to 3-6 months in the 
older populationi.  The reasons for this are multifactorial, including more aggressive tumour biology in 
the older age group, decreased tolerance to treatment related side effects and the potential of under 
treatment by doctors within the older age group. 
Given the poor prognosis in this group, treatment must be balanced against side effects and 
worsening quality of life. In patients aged 65 or over there is a lack of consensus on standard of care. 
Radiotherapy has a survival advantage over best supportive care ii however the optimal dose of 
radiotherapy is yet to be establishediiiivv. A recent Phase III trial randomised elderly GBM patients to 
standard radiotherapy with 60Gy in 30#, hypofractionated radiotherapy of 34Gy in 10# or 
temozolomide (TMZ) chemotherapy alone. For patients older than 65, survival was significantly longer 
with TMZ or hypofractionated radiotherapy than with standard radiotherapyvi. Those with defects in the 
DNA repair protein MGMT did significantly better in the chemotherapy arm than those with intact 
MGMT, a result which was replicated in the NOA-08 trial which randomised elderly GBM patients to 
standard radiotherapy with 60Gy in 30# or TMZ alone. This non-inferiority trial showed TMZ to be a 
suitable monotherapy option, with greater effect seen in those with MGMT promoter methylationvii. 
Recently published evidence has shown a survival benefit from adding concomitant and adjuvant TMZ 
to a hypofractionated radiotherapy regime of 40Gy in 15# in patients aged over 65, again with greater 
effect seen in those with MGMT promoter methylationviii. There is therefore now evidence to support 
the use of concomitant chemoradiotherapy or chemotherapy or radiotherapy as single agents amongst 
elderly GBM patients and an increasing interest in using MGMT promoter methylation status as a 
biomarker. However there remains a paucity of data surrounding the clinical and radiological basis by 
which individual patients are assessed for treatment. 
The majority of GBM patients over 65 who are actively treated by oncologists receive some form of 
radiotherapy to the brain. Short term side effects from radiotherapy include fatigue, headache, 
cognitive defects, nausea, weakness and a need for increased steroid doses. Longer term side effects 
include persistent cognitive defects, long term fatigue and hormonal imbalancesix.  Radiation causes 
an inflammatory response within the brain tissue as well as disrupting the blood brain barrier. It affects 
the vasculature of the brain with endothelial cell damage leading to microvascular dilatation, thickening 
of the vessel wall and increased risk of microbleeds and ischemic strokes in the months to followx. 
There is a risk of inducing tissue necrosis from occlusion of small blood vessels within the brain 
parenchyma, leading to coagulation, focal necrosis and demyelination. Animal models have suggested 
radiation is cytotoxic to developing neuroglial progenitor cells with areas of stem cells such as the 
hippocampus and periventricular zones, particularly vulnerable to damage, leading to longer term 
neurocognitive declinexixii. There is evidence to suggest that radiotherapy can stabilise or improve 
functional ability for some older patients with GBM aswell as providing a survival advantage however 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
clinical experience shows that the degree of side effects experienced and their impact on quality of life 
varies widely within this patient cohort.  
Risk factors for toxicities from radiotherapy include dose, fractionation and age however we have no 
more accurate ways of predicting which patients are more likely to suffer side effects. MRI has been 
shown to accurately pick up microhaemmorhages and other ischemic changes which may correlate 
with a ‘vulnerable’ brain pre-treatmentxiiixiv. These MRI changes have been examined in Alzheimer and 
dementia research with correlations shown between MRI markers and disease severityxv, however 
they have not yet been used within the neuro oncology setting.  
We aim to examine the relationship between MRI markers of a ‘vulnerable’ brain and degree of acute 
side effects and change in quality of life amongst a population of older patients being treated with 
cranial radiotherapy for GBM. 
 
2 
RATIONALE  
The poor prognosis of older GBM patients leads to an emphasis on the need for focusing on quality of 
life when deciding on treatment regimes. We have pathological markers which can help us determine 
sensitivity of the tumour to chemotherapy however we have no such guidance when it comes to 
making decisions about radiotherapy. If we were able to predict the degree of side effects likely to be 
experienced by a patient from radiotherapy treatment then it would enable us to make more 
individually tailored, patient centred treatment plans. 
We aim to see if analysis of pre-radiotherapy MRI scans including T2 gradient echo and susceptibility 
weighted imaging sequences can correlate with acute treatment related toxicity and quality of life 
amongst patients aged 65 or over undergoing partial brain radiotherapy for GBM. As these patients 
have an average life expectancy of 3-6 months within the UK we are focussing on acute rather than 
long term side effects of radiotherapy. 
MRI sequences will be utilised to determine any markers of background subclinical microvascular or 
degenerative disease in the normal brain including microhaemorrhage secondary to hypertension or 
cerebral amyloid angiopathy and atrophy with cortical volume measurement of the contralateral 
hemisphere. Additional susceptibility weighted sequences will be performed to identify the presence of 
microhaemorrhages in the contralateral normal-appearing brain parenchyma. These will be semi-
quantitatively assessed using a modified established microhaemorrhage scoring methodology. 
Absolute measures of the contralateral normal-appearing hemisphere cortical volumes will be 
acquired using FSL freesurfer software and a volumetric T1 weighted acquisition. These techniques 
will give us a number of quantitative scores that can then assessed for correlation with changes in 
quality of life and toxicity scoring systems.  
 
3 
THEORETICAL FRAMEWORK 
Older patient with a GBM have an average prognosis of 3-6 months. Treatment options are universally 
palliative and should be aimed at improving or maintaining quality of life for the reminder of these 
patients’ lives. Treatment decisions therefore need to be based around an informed conversation with 
the patient of the balance between survival benefit and side effect profile. Clinical trials have shown 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
efficacy of single agent radiotherapy or chemotherapy or short courses of concurrent chemoradiation. 
Molecular markers have been developed which can help guide decisions regarding the likely efficacy 
of chemotherapy however no such marker exist for decisions regarding radiotherapy. 
Radiotherapy is an effective palliative treatment for GBMs and has been shown in clinical trials to 
maintain or improve health related quality of life. However outside of a clinical trial population, usual 
clinical practice reveals some patients in whom the side effect profile from cranial radiotherapy is 
intolerable and has a significant detrimental effect on patients’ quality of life for their remaining short 
lifespan. The BRITER study aims to examine whether analysis of pre-treatment MRI scans in this 
cohort could help to predict who is more vulnerable to these side effects and therefore reveal a group 
of patients in whom single agent chemotherapy or best supportive care would be better treatment 
options.  
 
4 
RESEARCH QUESTION/AIM(S) 
 
4.1 
Objectives 
 
The BRITER study is being performed in patients aged 65 or over who have a new diagnosis of GBM. 
It tests the hypothesis that there is a relationship between 5 scores of a ‘vulnerable’ brain seen on pre-
treatment MRI and a clinically significant change in patient quality of life, as defined by a 10 point 
change in the EORTC QLQ questionnaire from baseline to 8 weeks post treatment.  
 
4.2 
Outcome 
The primary outcome is the proportion of patients with a 10 point change in the EORCT QLQ C30 
quality of life questionnaire (with the BN-20 brain and ELD14 elderly patient subsets of questions 
added) from baseline to 8 weeks. 
The impact of side effects from cranial radiotherapy will also be assessed by the secondary outcomes 
of  
 
MOCA cognitive screening questionnaire 
 
use of corticosteroids 
 
degree of grade 3-5 CTCAE toxicity 
 
overall and progression free survival 
 
5 
STUDY DESIGN and METHODS of DATA COLLECTION AND DATA ANALYIS 
The BRITER study is an observational cohort study. Eligible patients will be identified during the 
multidisciplinary team meeting by the participants’ usual care team.  They will have previously been 
informed of their diagnosis and then will meet a member of the oncology team to discuss treatment 
options. Once it has been decided with them by their usual care team that they are to have 
radiotherapy treatment, they will be given a PIS. After the patient has had sufficient time to read the 
PIS and have any questions answered by a member of the study team they will be asked to complete 
a consent form. They will also undergo the baseline clinical assessments prior to starting any 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
radiotherapy treatment. This will be done during the outpatient appointment with the neuro oncology 
team. 
Baseline clinical assessment of the patients will be conducted in the NHS neuro–oncology outpatient 
clinic setting. These will involve the EORTC-QLQ-C30 quality of life questionnaire with the BN-20 
brain and ELD14 elderly patient subsets of questions added, the MOCA questionnaire (please see 
Appendix for examples of these questionnaires) and a record of the amount of corticosteroid the 
patient is currently taking. The EORTC-QLQ-C30 quality of life questionnaires are designed to be 
completed by the patient (they are allowed to ask for help completing from family/carer) and could 
therefore be taken home by the patient or completed in the waiting room rather than being completed 
within the clinic. There is a risk of the questionnaires not being filled in and posted back if participants 
forget. We have costed for stamped addressed envelopes to be given to the patients in order to post 
the questionnaires back. The study team (who know the participant and would usually speak to them 
on the phone anyway during their treatment pathway) are able to call the participant to remind them to 
post back the questionnaires. The MOCA is administered by a member of the study team. 
The original copies of these questionnaires will be in the CRF, alongside details of the participant’s 
age, gender, comorbidities, treatment plan and social situation which will be recorded by the study 
team. 
In most cases, the participant will have undergone an MRI scan as part of their usual care plan prior to 
attending the neuro-oncology clinic. If this scan has the required imaging sequences needed for the 
BRITER protocol then no further scanning is required. This will be assessed by the neuro oncology 
consultant during the outpatient clinic appointment or a member of the study team prior to the 
appointment. A list of the required sequences will be readily available for the study team during this 
process. If not all of the required sequences were completed then the patient will undergo a further 
MRI scan. This will be done prior to the participant starting radiotherapy treatment but should not delay 
the start of their radiotherapy treatment. Depending on local guidelines, this scan will either take place 
on the same site or may require travel to another site. Travel costs will be covered for the patient and 
carer to attend the extra MRI scan. 
The participant’s treatment plan is not affected by enrolment in the study.  The participant will then 
complete their radiotherapy treatment as planned. When they attend for their routine 4 week post-
treatment follow up to the NHS neuro-oncology clinic they will repeat the EORTC-QLQ-C30 quality of 
life questionnaires and MOCA questionnaire as well as having assessment of their CTCAE 
radiotherapy toxicity score and steroid use. Again the EORTC-QLQ-C30 quality of life questionnaires 
could be sent to the patient in advance to complete prior to the clinic appointment or taken home and 
posted back. If the patient is unable to come to a clinic appointment during the required time frame 
they can be posted a questionnaire and send it back. The questionnaires should be completed within 
3 to 5 weeks after treatment has finished. These will be recorded in the CRFs. Members of the study 
team are permitted to phone the patient to remind them to complete the questionnaires if they are not 
returned or can complete them over the phone with the patient. This would normally be done by the 
CNS or doctor who the patient will already know as part of their usual care team and would be 
accustomed to speaking to on the phone.  
When participants attend for their routine 8 week (plus or minus 1 week) post-treatment follow up to 
the NHS neuro-oncology clinic they will repeat the same questionnaires and toxicity assessment. At 
this point their participation in the study is complete. 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
At the end of the study the results of the questionnaires from the CRFs will be transcribed into a 
database using Microsoft Excel. The CRFs will not contain the patient’s name or recognisable patient 
details and the database will therefore be pseudo anonymised. A score of 24 or less on MOCA will be 
deemed abnormal. A change in baseline of 10 points or more on the EORTC-QLQ-C30 quality of life 
questionnaires will be deemed significant.  
The MRI scans for the participants will be anonymised using the patient study ID and electronically 
transferred to Dr Samantha Mills, neuroradiologist The Walton Centre in Liverpool, for analysis. The 
following MRI sequences are ideally required: 
 
Axial T2 4mm slice thickness  
 
Volumetric T1 pre contrast (1mm or below) 
 
Post contrast volumetric T1 (1mm or below) 
 
DWI/ADC (4 mm slice thickness) 
 
Susceptibility weighted imaging (acquired volumetrically typically in the region of 1.5mm slice 
thickness but will vary with scanner setup) 
 
3D volumetric inversion recovery or MP-RAGE (additional sequence - to allow accurate 
quantification of cortical thickness/volumes using Freesurfer software in addition to scoring 
methods of atrophy, must be acquired at 1mm or below) 
 
Axial T2* gradient echo (4mm slice thickness) 
 
The scan thickness and sequences performed may vary slightly between sites however prior to 
opening the sites will confirm they can produce the necessary sequences for Dr Mills to produce 5 
quantitative scores (tumour volume, contralateral hemispheric brain volume, contralateral cerebral 
hemisphere cortical thickness, microhaemorrhage score and white matter hyperintensity score) from 
the images which reflect the degree of potential vulnerability of the brain to the side effects of 
radiotherapy. These will then be analysed in relation to the clinical questionnaires, steroid usage and 
grade 3-5 CTCAE radiotherapy toxicity score using SPSS. Multivariable logistic regression models will 
be fitted to look for significant (P<0.05) relationships between the 10 point change in EORTC QLQ 
quality of life questionnaires and the MRI parameters. Exploratory statistical analysis of the 
relationships between the MRI parameters and the secondary endpoints will be performed although 
the study is not powered to detect statistically significant relationships between these. 
 
The creation of the database and statistical analysis of the results will be performed by the CI with the 
help of a research assistant.   
 
6 
STUDY SETTING 
The study is a multicentre study and will be run within a number of UK NHS neuro oncology outpatient 
Trusts. The imaging analysis will be done remotely at the Walton Centre, Liverpool. The Trusts 
involved all have a neuro-oncology outpatient clinic where the patients will be approached and 
reviewed as part of the study. They also have appropriate MRI scanners attached to the trusts for the 
type of imaging sequences that are required. The local protocols for which MRI sequences are 
performed are slightly different in each trust which is why some patients may require an extra MRI 
scan.  

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
The recruitment process is similar in each site however the location of the MRI scanners differs 
slightly. In sites where the MRI scanner is not on the same trust as the outpatient clinic, the costs of 
taxi journeys to the scanner and back will be covered. 
7 
SAMPLE AND RECRUITMENT 
7.1  
Eligibility Criteria 
7.1.1 Inclusion criteria  
 
Patients aged > 65 years with a new diagnosis of GBM. Diagnosis made via histological 
confirmation following biopsy or debulking surgery or radiologically during an MDM meeting 
confirmmed by a consultant neuro radiologist. This lower age limit is due to previous clinical trials 
which have established gold standard treatment regimes for patients under the age of 65. Patients 
aged 65 or over have less clinical trial data available to them and treatment decisions are more 
nuanced with a greater emphasis on quality of life given the poorer prognosis of older patients.  
 
Patients undergoing radiotherapy treatment to the brain for treatment of their GBM 
 
Patients able to undergo an MRI scan 
 
Patients undergoing treatment at one of the study centres 
 
Patient have capacity to participate in the study 
 
Patients with physical impairments that prevent them filling in their questionnaires involved in the 
study may still participate if they are able to communicate their answers though a third party 
 
7.1.2 Exclusion criteria  
 
Patients not fit for radiotherapy treatment or having single agent chemotherapy with no 
radiotherapy 
 
Patients lacking capacity 
 
Patients who do not have sufficient grasp of the English language to be able to complete the 
questionnaires  
 
Patients unable to communicate their responses to the questionnaires  
 
Patients who are concurrently enrolled in a Clinical Trial of an Investigational Medicinal Product 
(CTIMP)  
 
7.2  
Sampling 
 
7.2.1  Size of sample 
Sample size calculations have been performed assuming a clinically significant end point of a 10 point 
change (SD=22.1 taken from the EORTC website reference guide) in EORTC QLQ questionnaire 
score between baseline and 8 weeks. Estimated sample size for one-sample comparison of 
proportion to hypothesized value assuming a 2 sided alpha of 0.05 and power of 0.9 gives a sample of 

 
 
 
 
 
 
   
 
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73. However, allowing for 20% attrition in questionnaire completion, this results in a sample size of 91. 
With 73 patients at 8 weeks, we will have 90% power for 5% significance to detect 5% of patients 
achieving a 10 point change in QoL. However, this small a proportion will only allow us to fit one 
variable in the model. It has therefore been recommended by the statistical team to aim for a 
recruitment target of 100 patients in order to fit the 5 MRI variables to the model. 
Patients who are enrolled within CTIMP studies will not be eligible to be recruited into the study as 
they would introduce too many unknown variables for adequate statistical analysis with a cohort of this 
size. 
Previous work done by this study group has shown this is a feasible recruitment target over 2 years.  
The study team will review recruitment at 9 months and if it has not reached 25% then they will 
explore ways to increase recruitment, including opening at other sites. 
 
7.2.2  Sampling technique 
The sample aims to cover all eligible patients presenting over a 24 month period across a number of 
NHS Trusts. Retrospective work the study team has carried out has shown that it is feasible to achieve 
the required sample size during this time period however is recruitment is poor then there is scope to 
expand to other sites or to extend the duration of the study period. The different trusts are located across 
the UK and should produce an unselected cohort in terms of gender, educational achievement and 
socioeconomic background.  
 
7.3 
 Recruitment 
 
7.3.1 Sample identification 
Eligible participants will be identified from weekly multidisciplinary team meetings (MDTs). These are 
attended by the usual clinical neuro oncology care team for the patient who will also make up the 
study team, thus no one outside of the usual care team will have access to patient identifiable data. 
The patient lists for the MDTs will be examined and patients meeting the eligibility criteria for the study 
will be identified.  
No public recruitment (i.e. posters/leaflets/website) will be performed. It is UK practice that all newly 
diagnosed GBM patients must be discussed at a relevant MDT meeting. Participants will be attending 
for their usual NHS neuro oncology clinic appointment when they are recruited. The follow up 
assessment will also be done during their routine NHS follow up appointments. The only potential 
extra appointment would be if the patient requires an additional MRI scan. In these cases the travels 
costs for the participant and carer will be covered within reason.  
 
7.3.2 Consent 
Eligible participants will be approached at or soon after their initial neuro oncology outpatient clinic 
appointment after it has been confirmed that they are eligible for the study (i.e they are to undergo 
radiotherapy treatment for treatment of their GBM). Treatment decisions are made prior to enrolment 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
within the study and are not affected by the study. Capacity assessments will be undertaken during 
this clinic appointment by a member of the clinical or study team who has the appropriate training prior 
to enrolment within the study. Capacity will be reassessed at each subsequent follow up (4 week and 
8 week post treatment appointments). If participants lose capacity the participant would be withdrawn 
from the study. Identifiable data or tissue already collected with consent would be retained and used in 
the study. No further data or tissue would be collected or any other research procedures carried out on 
or in relation to the participant. This is outlined in the patient information sheet. 
Eligible participants will be given a patient information sheet and adequate time to read and discuss 
any queries with a member of the study team during their outpatient consultation. If they agree to 
participate in the study then they will complete a written consent form. This consent form will include 
permissions for the study team to access their clinical records and pathological samples as well as 
performing the extra MRI sequences. The consent form will be received by a member of the study 
team (usually the oncology consultant or nurse specialist) during the outpatient consultation.  
 
8 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
8.1 
Assessment and management of risk 
Risk of significant harm to the participant is unlikely within this study. Participants who require a further 
MRI scan may require the administration of gadolinium contrast. This is generally safe and well 
tolerated however the risk profile of this will be discussed with the patient prior to administration and 
local policies will be followed if the patient has a reaction to the contrast agent. MRI scans are in 
general well tolerated and do not involve ionising radiation therefore do not carry with them any 
increased malignancy risk.  
Participants will be attending clinic for their routine follow up visits when they complete the 
assessments and therefore will not need any extra visits to hospital. During their clinic visit they may 
need to spend slightly more time than they would usually do in order to complete the questionnaires. 
In order to minimise this we have allowed for carers/family/a member of the study team to assist with 
the self-reported questionnaires or for the patient to take the questionnaire home with them to 
complete and post back to the study team. 
The participant’s GP will be informed of their involvement within the study. If there are concerns from 
the answers to the questionnaires that the participants may be at risk of harm to themselves or to 
others then this will be discussed with the participant's GP or other teams. The participants will be 
aware of this. In the unlikely event that any psychological distress is caused to the participants by 
completing the questionnaires, we would address this within the clinic visit and if necessary refer to 
their GP or local psychiatric services for further support.  
 
8.2  
 Research Ethics Committee (REC) and other Regulatory review & reports 
Before the start of the study, a favourable opinion will be sought from a REC for the study protocol, 
informed consent forms and other relevant documents  

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
Substantial amendments that require review by NHS REC will not be implemented until that review is 
in place and other mechanisms are in place to implement at site.  All correspondence with the REC 
will be retained. The Chief investigator will produce the annual reports as required and will notify the 
REC of the end of the study. An annual progress report (APR) will be submitted to the REC within 30 
days of the anniversary date on which the favourable opinion was given, and annually until the study is 
declared ended. If the study is ended prematurely, the Chief Investigator will notify the REC, including 
the reasons for the premature termination. Within one year after the end of the study, the Chief 
Investigator will submit a final report with the results, including any publications/abstracts, to the REC. 
Regulatory Review & Compliance  
Before any site can enrol patients into the study, the Chief Investigator/Principal Investigator or 
designee will ensure that appropriate approvals from participating organisations are in place. Specific 
arrangements on how to gain approval from participating organisations are in place and comply with 
the relevant guidance.  
For any amendment to the study, the Chief Investigator or designee, in agreement with the sponsor 
will submit information to the appropriate body in order for them to issue approval for the amendment. 
The Chief Investigator or designee will work with sites (R&D departments at NHS sites as well as the 
study delivery team) so they can put the necessary arrangements in place to implement the 
amendment to confirm their support for the study as amended. 
Amendments  
If the sponsor wishes to make a substantial amendment to the REC application or the supporting 
documents, the sponsor must submit a valid notice of amendment to the REC for consideration. The REC 
will provide a response regarding the amendment within 35 days of receipt of the notice. It is the 
sponsor’s responsibility to decide whether an amendment is substantial or non-substantial for the 
purposes of submission to the REC. 
 
8.3  
Peer review 
8.4  
Patient & Public Involvement 
The study protocol and patient information sheet have been reviewed by the JAFFA panel - a patient 
and public involvement (PPI) lay research panel based at Brighton and Sussex University Hospitals 
Trust. Their feedback was instrumental in restructuring the protocol and PIS to make the design of the 
study clearer to understand and confirm the importance of using quality of life as the primary outcome. 
A lay summary of the study was circulated to The Brains Trust PPI panel during the design of the 
study who again aided in the structure of the study and gave their full support. It was also sent to The 
Brain Tumour Charity Research Involvement Network, a group of brain tumour patients and their 
carers. They sent detailed feedback and felt the study was well explained and clear to understand and 
some points they raised surrounding the sequence of consenting and enrolling in the study led to an a 
adaptation of the study protocol. They did not feel undergoing and extra MRI scan would be onerous 
the participants. They unanimously agreed that the objectives of the study were worth pursuing and 
that it was a valid study question.  
 

 
 
 
 
 
 
   
 
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8.5 
Protocol compliance  
Accidental protocol deviations can happen at any time. They must be adequately documented on the 
relevant forms and reported to the Chief Investigator and Sponsor immediately.  
Deviations from the protocol which are found to frequently recur are not acceptable, will require 
immediate action and could potentially be classified as a serious breach. 
 
 
8.6 
Data protection and patient confidentiality  
All investigators and study site staff will comply with the requirements of the Data Protection Act 1998 
with regards to the collection, storage, processing and disclosure of personal information and will 
uphold the Act’s core principles.  
No patient identifiable data will be accessed by anyone outside of their usual direct care team. The 
study members are all part of the usual direct care team. Patient identifiable data will be accessed by 
the study team in order to identify eligible participants from the MDM list and if necessary access their 
postal addresses in order to send them the initial PIS and consent form. All paperwork from the study 
will be recorded using the participant study ID numbers. Data will be pseudo anonymised locally and 
survival data will be collected on participants at the end of the study period. The study database 
created at the end of the study period once survival data has been collected will be fully anonymised. 
No patient identifiable data will be recorded on the study database. Data protection and confidentiality 
will be respected at all times. Data will be handled as per data management above.  
Prior to MRI scans being transferred electronically via the national IEP system, the scans will be 
allocated the participants study ID by the local study team. No patient identifiable data will therefore be 
transferred electronically. 
The database will be kept on password protected NHS computers within a locked office. The paper 
copies of the CRFs will be kept within secure NHS offices by the members of the local study team. 
Any transfer of data will be done via secure NHS.net e-mail systems or an encrypted USB however no 
patient identifiable details will be transferred off site. 
The data will be stored for 5 years after the end of the study date. 
 
8.7 
Indemnity 
The study will be covered by the usual NHS indemnity policies 
 
8.8 
Access to the final study dataset 
All members of the study team will have access to the completed anonymised database if necessary.  

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
8.9  Study & safety assessments 
As the study does not employ an Investigational Medicinal Product, Adverse Events (AE) or Serious 
Adverse Events (SAE) will be recorded and reported as per Sponsor’s guidelines (Brighton & Sussex 
University Hospitals NHS Trust) and Health Research Authority (HRA) (see Figure 2 below).  
A serious adverse event (SAE) is defined as an untoward occurrence that:  
(a) results in death;  
(b) is life-threatening;  
(c) requires hospitalisation or prolongation of existing hospitalisation;  
(d) results in persistent or significant disability or incapacity;  
(e) consists of a congenital anomaly or birth defect; or  
(f) is otherwise considered medically significant by the investigator 
An SAE occurring to a research participant will be reported to the main REC where in the opinion of 
the Chief Investigator the event was:  
 
Related – that is, it resulted from administration of any of the research procedures, and   
 
Unexpected – that is, the type of event is not listed in the protocol as an expected occurrence. 
 
Who 
When 
How 
To whom 
SAE 
Chief Investigator (CI) or 
sponsor 
Within 7-14 days of 
the CI becoming 
aware of the event 
(in line with the  
Sponsor’s 
Collaboration 
Agreement 
SAE report form for 
non-CTIMPs 
available from HTA 
website 
Main REC for the 
trial 
Urgent safety 
measures 
Chief Investigator (CI) or 
sponsor  
Or exceptionally by local 
principal investigator 
(PI) 
(i) Immediately 
(ii) Within 3 days 
(i) By telephone 
(ii) Notice in writing 
setting out the 
reasons for 
urgent safety 
measures and 
the plan for 
further action 
Main REC for trial 
REC co-ordinator 
will acknowledge 
within 30days 
If notified by PI, 
relevant local REC 
should also be 
informed 
 
9 
DISSEMINIATION POLICY 
9.1  
Dissemination policy 
Findings will be submitted for presentation at national and international conferences and publication in 
peer reviewed journals. Brains Trust will also disseminate the anonymised study findings through their 
patient support groups and social media. We will share the results of this study with individual 
participants if they express a desire for them. No patient identifiable data will be published. The final 

 
 
 
 
 
 
   
 
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BRITER Protocol V0.8 04.04.18 
 
study data will be owned by the CI. As is current accepted practice, it will be unacceptable for 
collaborators to independently publish data of individuals that they have recruited for the study 
 
9.2  
Authorship eligibility guidelines and any intended use of professional writers 
The final study report will be written up by the CI and main protocol contributors. The authorship of the 
study will include the study teams who will be asked for input to the final study manuscript.  
 
10.  
APPENDICIES 
 
11.1 
Appendix 1- Questionnaires to be used  
 
11. 
REFERENCES 
 
                                               
i Brodbelt A, Greenberg D, Winters T, Williams M, Vernon S, Collins VP. Glioblastoma in England: 
2007-2011. Eur J Cancer. 2015;51(4):533-42. 
 
ii Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, et al. Radiotherapy 
for glioblastoma in the elderly. New England Journal of Medicine. 2007;356(15):1527-35. 
 
iii Roa W, Kepka L, Kumar N, Sinaika V, Matiello J, Lomidze D, et al. International Atomic Energy 
Agency Randomized Phase III Study of Radiation Therapy in Elderly and/or Frail Patients With Newly 
Diagnosed Glioblastoma Multiforme. J Clin Oncol. 2015. 
 
iv Roa W, Brasher PMA, Bauman G, Anthes M, Bruera E, Chan A, et al. Abbreviated course of 
radiation therapy in older patients with glioblastoma multiforme: A prospective randomized clinical trial. 
Journal of Clinical Oncology. 2004;22(9):1583-8. 
 
v  McAleese JJ, Stenning SP, Ashley S, Traish D, Hines F, Sardell S, et al. Hypofractionated 
radiotherapy for poor prognosis malignant glioma: matched pair survival analysis with MRC controls. 
Radiother Oncol. 2003;67(2):177-82 
 
vi Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, et al. Temozolomide versus 
standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years  
with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncology. 2012;13(9):916-26 
 
vii Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide  
chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 
randomised, phase 3 trial. Lancet Oncology. 2012;13(7):707-15. 
 
viii Perry JR, Laperriere N, O'Callaghan CJ, Brandes AA, Menten J, Phillips C et al. Short-Course 
Radiation plus Temozolomide in Elderly Patients with Glioblastoma. N Engl J Med. 2017 Mar 
16;376(11):1027-1037 
 

 
 
 
 
 
 
   
 
13 
BRITER Protocol V0.8 04.04.18 
 
                                                                                                                                                                 
ix Powell C, Guerrero D, Sardell S, Cumins S, Wharram B, Traish D, et al. Somnolence syndrome in 
patients receiving radical radiotherapy for primary brain tumours: a prospective study. Radiother 
Oncol. 2011;100(1):131-6 
 
x Burger PC, Mahley MS, Jr., Dudka L, Vogel FS. The morphologic effects of radiation administered 
therapeutically for intracranial gliomas: a postmortem study of 25 cases. Cancer. 1979;44(4):1256-72 
 
xi Monje M, Dietrich J. Cognitive side effects of cancer therapy demonstrate a functional role for adult 
neurogenesis. Behav Brain Res. 2012;227(2):376-9. 
 
xii Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, et al. Radiation-induced 
impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp 
Neurol. 2004;188(2):316-30. 
 
xiii Lupo JM, Chuang CF, Chang SM, Barani IJ, Jimenez B, Hess CP, et al. 7-Tesla susceptibility-
weighted imaging to assess the effects of radiotherapy on normal-appearing brain in patients with 
glioma. Int J Radiat Oncol Biol Phys. 2012;82(3):e493-500. 
 
xiv Naylor G, Murray A, Chalmers A. P03ASSOCIATION OF SHELTENS SCALE AND SURVIVAL IN 
GLIOBLASTOMA PATIENTS. Neuro Oncol. 2014;16(Suppl 6):vi1. 
xv Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E et al. Medial temporal 
lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular 
cognitive impairment: a prospective study with pathological verification of diagnosis. Brain. 2009 
Jan;132(Pt 1):195-203.