FUTURE-GB Trial (Functional and Ultrasound-guided Resection of Glioblastoma) A 2-Stage Trial. A Learning Phase Evaluation of Participating Centres, Followed by a Randomised, Controlled Multicentre Phase III Trial.
Phase: NA
Conditions: Glioma Glioblastoma Multiforme
Sponsor: University of Oxford

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 1 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Study Title:  FUTURE-GB – Functional and Ultrasound guided Resection of Glioblastoma.  
A two Stage trial. 
Stage 1 – Non-randomised learning evaluation of participating centres (an IDEAL study), followed by 
Stage 2 – A multi-centre randomised trial with 2 mechanistic sub-studies. 
 
Internal Reference Number / Short title: FUTURE-GB 
Ethics Ref: 20/LO/0840 
IRAS Project ID: 264482 
Date and Version No: 19Jan2022, V6.0 
ISRCTN: 38834571 
 
Chief Investigator:  
Professor Puneet Plaha, Associate Professor, Nuffield Department of 
Surgical Sciences, University of Oxford 
 
Lead Investigators:  
Ms Sophie Camp, Imperial College Healthcare NHS Trust 
Professor Dipankar Nandi, Imperial College Healthcare NHS Trust 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 2 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Investigators:  
Professor Jonathan Cook, Associate Professor, Oxford Clinical Trials 
Research Unit, University of Oxford 
Professor Adrian Lim, Imperial College Healthcare NHS Trust 
Professor Martin Taphoorn, Haaglanden Medical Center, University of 
Leiden, Netherlands 
Professor Linda Dirven, Haaglanden Medical Center, University of 
Leiden, Netherlands. 
Professor Peter McCulloch, Nuffield Department of Surgical Sciences, 
University of Oxford 
Professor Natalie Voets, Associate Professor, Nuffield Department of 
Clinical Neurosciences, University of Oxford 
Dr Matthew Grech-Sollars, Imperial College Healthcare NHS Trust  
Dr Helen Bulbeck, Brainstrust 
Professor Michael Jenkinson, University of Liverpool & The Walton 
Centre 
Dr Matt Williams, Imperial College Healthcare NHS Trust 
Professor Colin Watts, University Hospitals Birmingham Foundation 
NHS Trust 
Sponsor:  
University of Oxford 
Joint Research Office, 1st Floor, Boundary Brook House, Churchill Drive, 
Headington, OX3 7GB  
Funder: 
Efficacy and Mechanism Evaluation (EME) Programme, an MRC and 
NIHR partnership 
 
 
Conflicts of Interest: None of the investigators have any conflicts of interest. 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics 
Committee, unless authorised to do so. 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 3 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
Contents 
1. 
KEY CONTACTS ................................................................................................................................... 8 
2. 
LAY SUMMARY................................................................................................................................... 9 
2.1. 
Aims and Background ........................................................................................................................ 9 
2.2. 
Design .............................................................................................................................................. 10 
2.3. 
Public and Patient Involvement ...................................................................................................... 10 
2.4. 
Dissemination: ................................................................................................................................. 10 
3. 
SYNOPSIS ......................................................................................................................................... 10 
4. 
ABBREVIATIONS ............................................................................................................................... 16 
5. 
BACKGROUND AND RATIONALE ...................................................................................................... 17 
5.1. 
Health problem to be addressed ..................................................................................................... 17 
5.2. 
Health Related Quality of Life (HRQoL) ........................................................................................... 18 
5.3. 
Knowledge Gap ................................................................................................................................ 18 
5.4. 
Current surgical standard of care .................................................................................................... 19 
5.5. 
Combined iUS* and DTI may improve outcome ............................................................................. 19 
5.6. 
Pilot data shows that combining techniques is the way forward ................................................... 20 
5.7. 
The need for the FUTURE-GB trial ................................................................................................... 20 
6. 
OBJECTIVES AND OUTCOME MEASURES ......................................................................................... 21 
6.1. 
PRIMARY OUTCOME MEASURES ..................................................................................................... 21 
6.1.1. 
Stage 1 ......................................................................................................................................... 21 
6.1.2. 
Stage 2 ......................................................................................................................................... 21 
6.2. 
Secondary Outcome Measures – Stage 2 only ................................................................................ 22 
7. 
STUDY DESIGN ................................................................................................................................. 25 
7.1. 
Stage 1: non-randomised multicentre learning and evaluation stage (IDEAL Stage IIB study) ...... 25 
7.2. 
Stage 2: prospective, Stage III, multicentre randomised controlled trial with internal pilot .......... 26 
8. 
PARTICIPANT IDENTIFICATION ........................................................................................................ 26 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 4 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
8.1. 
Study Participants ............................................................................................................................ 26 
8.2. 
Inclusion Criteria .............................................................................................................................. 26 
8.3. 
Exclusion Criteria ............................................................................................................................. 27 
9. 
PROXY INCLUSION (Stage 2 only) .................................................................................................... 27 
9.1. 
Inclusion Criteria .............................................................................................................................. 27 
10. 
PROTOCOL PROCEDURES ................................................................................................................ 28 
10.1. Stage 1: non-randomised multicentre learning and evaluation Stage (IDEAL Stage IIB study) ...... 28 
10.1.1. 
Pre-Stage 1 Stage Webinar or Symposium .................................................................................. 28 
10.1.2. 
IDEAL IIB Study (Quality assurance, mentoring and trial centres learning). ............................... 28 
10.1.3. 
Pre-RCT Data workflow review. ................................................................................................... 29 
10.2. Recruitment ..................................................................................................................................... 29 
10.2.1. 
Participants .................................................................................................................................. 29 
10.2.2. 
Sites ............................................................................................................................................. 30 
10.3. Screening and Eligibility Assessment ............................................................................................... 30 
10.4. Informed Consent - Participant ....................................................................................................... 30 
10.4.1. 
Informed Consent – Proxy (Stage 2 only) .................................................................................... 31 
10.5. Randomisation ................................................................................................................................. 31 
10.6. Blinding and code-breaking ............................................................................................................. 32 
10.7. Description of study intervention(s), comparators and study procedures (clinical)....................... 32 
10.7.1. 
Description of study intervention(s)............................................................................................ 32 
10.7.2. 
Description of comparator(s) ...................................................................................................... 33 
10.7.3. 
Description of study procedure(s) – Stage 1 ............................................................................... 33 
10.7.4. 
Description of study procedure(s) – Stage 2 ............................................................................... 33 
10.8. Imaging Schedule for both Stage 1 and 2 ........................................................................................ 36 
10.9. Sample Handling .............................................................................................................................. 36 
10.10. Early Discontinuation/Withdrawal of Participants .......................................................................... 37 
10.10.1. Stage 1 ......................................................................................................................................... 37 
10.10.2. Stage 2 ......................................................................................................................................... 37 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 5 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
10.11. Definition of End of Study ............................................................................................................... 38 
11. 
SAFETY REPORTING ......................................................................................................................... 38 
11.1. Definitions ....................................................................................................................................... 38 
11.1.1. 
Adverse Event (AE) ...................................................................................................................... 38 
11.1.2. 
Serious Adverse Event (SAE) ........................................................................................................ 38 
11.2. Reporting Procedures ...................................................................................................................... 38 
11.2.1. 
Events exempt from being reported as SAEs .............................................................................. 39 
11.3. Death during the study .................................................................................................................... 39 
11.4. Elective admissions and supportive care ........................................................................................ 40 
11. 
STATISTICS AND ANALYSIS ............................................................................................................... 40 
11.1. Statistical Analysis Plan (SAP) .......................................................................................................... 40 
11.2. Description of the Statistical Methods ............................................................................................ 40 
11.3. Sample Size Determination for IDEAL IIB Study (Stage 1) ............................................................... 41 
11.4. Sample Size Determination for the RCT (Stage 2) ........................................................................... 41 
11.5. Recruitment Predictions for the RCT (Stage 2)................................................................................ 41 
11.6. Analysis populations ........................................................................................................................ 42 
11.7. Decision points................................................................................................................................ 42 
11.7.1. 
Stage 1 (IDEAL IIB study).............................................................................................................. 42 
11.7.2. 
Stage 2 (RCT) ................................................................................................................................ 42 
11.8. Stopping rules ................................................................................................................................. 43 
11.8.1. 
Stage 1 (IDEAL study) ................................................................................................................... 43 
11.8.2. 
Stage 2 (RCT) ................................................................................................................................ 43 
11.9. The Level of Statistical Significance ................................................................................................. 43 
11.10. Procedure for Accounting for Missing, Unused, and Spurious Data. .............................................. 43 
11.11. Procedures for Reporting any Deviation(s) from the Original Statistical Plan ................................ 43 
11.12. Health Economics Analysis .............................................................................................................. 44 
12. 
DATA MANAGEMENT ...................................................................................................................... 44 
12.1. Source Data ..................................................................................................................................... 44 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 6 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
12.2. Access to Data ................................................................................................................................. 44 
12.3. Data Recording and Record Keeping ............................................................................................... 45 
13. 
QUALITY ASSURANCE PROCEDURES ............................................................................................... 45 
13.1. Risk assessment ............................................................................................................................... 45 
13.2. Study monitoring ............................................................................................................................. 45 
13.3. Study Committees ........................................................................................................................... 45 
13.3.1. 
Data & Safety Monitoring Committee (DSMC) ........................................................................... 45 
13.3.2. 
Trial Steering Committee (TSC) ................................................................................................... 45 
13.3.3. 
Core Trial Management Group (TMG) for all Stages ................................................................... 46 
14. 
PROTOCOL DEVIATIONS .................................................................................................................. 46 
15. 
SERIOUS BREACHES ......................................................................................................................... 46 
16. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 47 
16.1. Declaration of Helsinki .................................................................................................................... 47 
16.2. Guidelines for Good Clinical Practice .............................................................................................. 47 
16.3. Approvals ......................................................................................................................................... 47 
16.4. Other Ethical Considerations ........................................................................................................... 47 
16.5. Reporting ......................................................................................................................................... 47 
16.6. Participant Confidentiality ............................................................................................................... 47 
16.7. Expenses and Benefits ..................................................................................................................... 48 
17. 
FINANCE AND INSURANCE .............................................................................................................. 48 
17.1. Funding ............................................................................................................................................ 48 
17.2. Insurance ......................................................................................................................................... 48 
17.3. Contractual arrangements .............................................................................................................. 48 
18. 
PUBLICATION POLICY ....................................................................................................................... 48 
19. 
DISSEMINATION POLICY .................................................................................................................. 48 
20. 
DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL 
PROPERTY .................................................................................................................................................... 49 
21. 
ARCHIVING....................................................................................................................................... 49 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 7 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
22. 
REFERENCES .................................................................................................................................... 50 
23. 
APPENDIX A: STUDY FLOW CHART .................................................................................................. 55 
24. 
APPENDIX B: DATA COLLECTION CHART  ........................................................................................ 56 
25. 
APPENDIX C: IMAGING DATA WORKFLOW ..................................................................................... 57 
26. 
APPENDIX D:  AMENDMENT HISTORY ............................................................................................. 61 
 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 8 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
1. KEY CONTACTS 
Chief Investigator 
Professor Puneet Plaha 
Consultant Neurosurgeon 
Associate Professor 
Nuffield Department of Surgical Sciences, University of Oxford 
Level 3, West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU 
Tel: 01865 220041   
 
Lead Investigators 
Miss Sophie Camp 
Consultant Neurosurgeon 
Imperial College HealthCare NHS Trust 
Fulham Palace Road, Hammersmith, London W6 8RF 
Tel: 020 3313 5503  
 
Professor Dipankar Nandi 
Consultant Neurosurgeon 
Imperial College HealthCare NHS Trust 
Fulham Palace Road, Hammersmith, London W6 8RF 
Tel: 020 3313 5503  
 
Sponsor 
University of Oxford   
Joint Research Office, , Boundary Brook House, Churchill Drive, Headington, OX3 7GB 
Tel: 01865 616480 
ctrg@admin.ox.ac.uk  
Funder(s) 
Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership 
Clinical Trials Unit 
Oxford Clinical Trials Research Unit (OCTRU) 
University of Oxford 
Botnar Research Centre, Windmill Road, Headington, Oxford OX3 7LF 
Tel: 01865 223469 
octrutrialshub@ndorms.ox.ac.uk  
Surgical Intervention Trials Unit (SITU) 
Nuffield Department of Surgical Sciences, University of Oxford 
Botnar Research Centre, Old Road, Headington, Oxford OX3 7LD 
Tel: 01865 223491 
futuregb@nds.ox.ac.uk 
situ@nds.ox.ac.uk  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 9 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Trial Statistician 
Tianshu Liu 
Oxford Clinical Trials Research Unit 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford OX3 7LF 
Tel: 01865 223463 
 octru-stats@ndorms.ox.ac.uk 
Senior Statistician 
Professor Jonathan Cook 
Oxford Clinical Trials Research Unit 
University of Oxford 
Botnar Research Centre 
Windmill Road 
Oxford OX3 7LF 
Tel: 01865 223463 
 octru-stats@ndorms.ox.ac.uk 
Committees 
TRIAL STEERING COMMITTEE 
(TSC) 
Chair:  Mr Philip Weir 
Consultant Neurosurgeon 
Belfast Trust 
DATA SAFETY AND  MONITORING COMMITTEE 
(DSMC) 
Chair:  Mr Ian Sabin 
Consultant Neurosurgeon 
Wellington Hospital, London 
2. LAY SUMMARY 
2.1. Aims and Background 
Glioblastoma (GB) is the most common primary brain tumour and is incurable. It grows very quickly from 
the brain tissue itself, rather than from a cancer elsewhere in the body. It is expected that the number of 
people with a brain tumour will rise by 6% in the UK between 2014 and 20351. However, prognosis 
(outcome) remains extremely poor, with most people surviving just over 12 months, and as a patient’s 
tumour grows patients experience a reduction (decline) in their quality of life.  Therefore, we need to 
ensure quality of life, which remains difficult. The main treatments for GB are surgery, radiotherapy and 
chemotherapy, given in combination.  
For patients where it is thought that surgery will benefit, a surgeon often removes as much tumour as 
possible, whilst limiting the risk of causing damage, such as weakness, speech, or cognitive difficulties. 
However, which technology a surgeon should use during surgery to remove the tumour safely is unclear. 
This can affect how soon the cancer returns, what effects of surgery or symptoms a patient develops, 
and how a patient feels.  
High frequency sound waves that create an image, called Ultrasound (US), is one of the tools a surgeon 
can use during the operation to find the tumour and see how much is removed. Another technology, 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 10 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Diffusion Tensor Imaging (DTI), allows important nerve pathways involved in certain functions, for 
example, speech/language, vision and movement, to be avoided in surgery.  
This trial aims to see if GB surgery with these extra technologies (tools) added to the standard ones, 
increases a patient’s good functioning quality of life, so-called Deterioration Free Survival (DFS).  
2.2. Design  
FUTURE-GB is a two Stage trial.  
Stage 1 a non-randomised cohort study using the IDEAL Stage 2b design format2 . It will evaluate 
standard care surgery with the addition of DTI imaging and the ultrasound imaging during the operation. 
This Stage will ensure standardisation of the use of the technologies across all trial centres by expert 
mentoring, and will evaluate quality of delivery, including monitoring of the learning curve for the group 
as a whole. 
Stage 2 is a randomised controlled trial. This means those who agree to take part will be allocated by 
chance (like the tossing of a coin). The trial plans to enrol 357 newly diagnosed patients to receive either 
brain surgery with standard methods without US and DTI, or surgery with the addition of US and DTI as 
well as standard tools. Patients will not know into which group they have been placed, nor will the 
research team assessing them before and after surgery. They will be recruited from at least 15 NHS 
hospitals that routinely undertake GB surgery and have access to these tools. The trial will result in only 
minor changes to the present care pathway. After agreeing to take part, participants will be asked to 
complete questionnaires about their quality of life, such as their walking, ability to look after their 
personal hygiene, how they feel. They will also have a brief physical and cognitive/functional assessment 
before their surgery. Afterwards, the questionnaires and assessments will be repeated, before leaving 
hospital, and at three monthly intervals until 24 months after agreeing to take part (consenting). These 
will be combined with planned hospital visits. How long a patient lives will also be recorded. 
2.3. Public and Patient Involvement 
The trial focuses on keeping good quality of life for people living with a GB for as long as possible. It has 
been designed with the help of patient support groups at the Brain Tumour Charity and Brainstrust, the 
Patient Relative Advisory Group at the Oxford University Hospitals NHS Foundation Trust and the Brain 
Tumour PPI Group at Imperial College Healthcare NHS Trust.  Dr Helen Bulbeck (Brainstrust’s Director) 
has been part of the trial proposal and is one of the trial’s investigators.  
2.4. Dissemination:  
Trial results will be published and widely shared via a variety of channels. If this trial shows that patients 
benefit, it is expected that the tools will become standard care and help GB patients in all 24 UK NHS 
neurosurgery units, and worldwide.  
3. SYNOPSIS 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 11 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Study Title 
FUTURE-GB – Functional and Ultrasound guided Resection of GlioBlastoma (GB):  
A two-Stage trial.  Stage 1: non-randomised learning Stage evaluation of 
participating centres (an IDEAL study). Stage 2: a multicentre definitive trial with 
2 mechanistic sub-studies. 
Internal ref. no. / short title 
FUTURE-GB 
Study registration 
ISRCTN: 38834571 
Sponsor  
University of Oxford   
Funder  
NIHR EME Programme   
Study Design 
FUTURE-GB is a 2-Stage trial: Stage 1 is a non-randomised multicentre learning 
and evaluation Stage (IDEAL IIB study), and Stage 2 a prospective, multicentre 
definitive randomised controlled trial.  
Study Participants 
Newly diagnosed glioblastoma (GB) patients 
Sample Size 
Up to 75 patients will participate in Stage 1, (up to 5 per centre).  
357 patients will participate in the Stage 2, randomised controlled trial 
Planned Study Period 
Patients participating in the trial will be followed at 3 monthly intervals up to 24 
months after randomisation. 
Planned Recruitment period 
6-9 months Stage 1 and then 27 months for Stage 2.   
Intervention(s) 
Surgery to resect the GB using Diffusion Tensor Imaging (DTI) and intraoperative 
Ultrasound (iUS) (navigated iUS where available) in addition to standard care 
(i.e. neuronavigation based on preoperative MRI and intraoperative use of 5-
aminolevulinic acid (5-ALA)) 
Comparator 
The comparator is standard care as per current NICE guidelines (i.e. 
neuronavigation based on preoperative MRI and intraoperative use of 5-ALA).  
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 12 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Stage 1 
Objectives 
Outcome Measures 
Timepoint(s) 
Primary 
Outcomes  
To demonstrate the feasibility of using 
DTI and iUS* in addition to standard of 
care (neuronavigation based on 
preoperative MRI and intraoperative 
use of 5-ALA) for neurosurgery (at 
selected UK NHS hospitals).  
1. Operation length 
2. Successful use of DTI 
neuronavigation and  
iUS* to achieve 
maximal safe tumour 
resection without major 
neurological deficit 
3. Extent of tumour 
resection assessed on 
postoperative MRI 
scan. 
4. Surgical Complication 
and Serious Adverse 
Events 
Hospital discharge 
and 6 months post-
op. 
 
Stage 2 
Objectives 
Outcome Measures 
Timepoint(s) 
Primary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves 
Deterioration Free Survival (DFS)  
(Where deterioration relates to global 
health status only)  
Composite of global health 
status domain of the QLQ-
C30 questionnaire, 
Progression Free Survival 
(PFS) and Overall Survival 
(OS) with an event defined 
as either deterioration, 
progression or death. 
To be recorded at 
baseline; 6wks 
post-op., 3mths 
post-op., and then 
3mthly up to 24 
months  
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
DFS where deterioration relates to 
physical functioning, social functioning 
from the QLQ-C30, and motor 
dysfunction and communication deficit  
4 composites using the 
respective domain of QLQ-
C30 (physical functioning 
and social functioning) and 
BN20 (motor dysfunction 
and communication deficit) 
combined with PFS and OS. 
To be recorded at 
baseline; 6wks 
post-op., 3mths 
post-op., and then 
3mthly up to 24 
months 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 13 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Stage 2 
Objectives 
Outcome Measures 
Timepoint(s) 
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
time to deterioration 
Defined similar to DFS with 
the exception that 
progression is excluded as 
an event (i.e. only 
deterioration or death are 
considered). There will be 
five time to deterioration 
outcomes, one for each of 
the domains utilised in the 
primary and secondary DFS 
outcomes, used in turn to 
define deterioration. 
To be recorded at  
6wks post-op., 
3mths post-op., 
and then 3mthly 
up to 24 months 
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and IUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
Overall Survival (OS)  
OS (time from 
randomisation to death or 
trial closure) 
To be recorded at 
24 months 
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
Progression Free Survival (PFS) 
PFS (time from 
randomisation to 
radiological tumour 
progression on imaging, as 
agreed in local MDT 
MRI at 6 months 
post-op., and then 
3mthly up to 24 
months or an MRI 
performed outside 
protocol if patient 
is symptomatic 
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
the extent of tumour resection  
Extent of resection as % of 
pre-operative tumour 
volume on postoperative 
contrast enhanced MRI 
Post-operative 
review 
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
the incidence of surgical complications 
Number and type of 
surgical complications 
To be recorded at 
5 days post-op, or 
discharge date 
(whichever is 
soonest); 6wks 
post-op., 3mths 
post-op., and then 
3mthly up to 24 
months 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 14 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Stage 2 
Objectives 
Outcome Measures 
Timepoint(s) 
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
the number of patients eligible for 
adjuvant treatment following surgery  
Number of patients eligible 
for adjuvant treatment 
3mths post-op. 
Secondary 
Outcomes  
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (Neuronavigation 
and intraoperative 5-ALA) improves 
functional outcome postoperatively 
WHO performance status 
mini-MoCA (Montreal 
Version) Barthel Index 
MRC grading of power in all 
4 limbs  
To be recorded at 
baseline, 5 days 
post-op., or 
discharge date 
(whichever is 
soonest); 6wks 
post-op., 3mths 
post-op., and then 
3mthly up to 24 
months. 
(MRC grading to be 
assessed at 
baseline and 5 
days post-op., or 
discharge date 
only) 
Secondary 
Outcomes  
Assess the correlation of proxy to 
participant classification assessment of 
quality of life 
At a minimum, answers to 
questions 29 and 30 of the 
QLQ-C30.  Ideally answers 
will be provided to all of the 
QLQ-C30 and BN20. 
Baseline, 6wks 
post-op., 3mths 
post-op., and then 
3mthly up to 24 
months. Proxy will 
not complete 
questionnaires 
when participant 
stops completing 
them. 
Tertiary 
Mechanistic 
Study Objectives 
– on a sub set of 
participants –  
To assess the sensitivity and specificity 
of the anatomico-spatial location of 
DTI fibre tracts compared with 
intraoperative direct electrical 
stimulation/behavioural change 
without stimulation but related to 
adjacent white fibre tract in patients 
undergoing awake surgery, or motor 
evoked potential changes in patients 
undergoing surgery.  
Sensitivity and specificity 
calculation using pre and 
post-surgery MRI images 
Analysis will be 
undertaken post-
surgery.  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 15 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Stage 2 
Objectives 
Outcome Measures 
Timepoint(s) 
Tertiary 
Mechanistic 
Study Objectives 
– on a sub set of 
participants –  
To assess the sensitivity and specificity 
of iUS* to identify the tumour 
boundary when compared with 5-ALA, 
navigated biopsies will be taken from 
tumour boundary tissue planned for 
resection. 
Intra operative iUS* images 
and post-operative MRI 
scans and Intraoperative 
biopsy samples 
Analysis will be 
undertaken post-
surgery when 
biopsy results are 
available. 
*if NiUS available, it is to be used 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 16 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
4. ABBREVIATIONS  
5-ALA 
5-AminoLevulinic Acid – also known as the Pink Drink 
CI 
Chief Investigator 
CRF 
Case Report Form 
DFS 
Deterioration Free Survival  
DSMC 
Data Safety Monitoring Committee 
DTI 
Diffusion Tensor Imaging 
EORTC 
European Organisation for Research and Treatment of Cancer 
FUTURE-GB 
FUncTional and Ultrasound guided Resection of GlioBlastoma 
GB 
Glioblastoma  
GCP 
Good Clinical Practice 
GP 
General Practitioner 
GTR 
Gross Total Resection  
HRA 
Health Research Authority 
HRQoL 
Health Related Quality of Life 
ICF 
Informed Consent Form 
IDEAL 
Idea, Development, Exploration, Assessment, Long-term study 
ITT 
Intention To Treat 
iUS 
Intraoperative Ultrasound  
MDT 
Multi Disciplinary Team 
MHz 
Megahertz 
mm 
millimetre 
MoCA 
The Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging 
NHS 
National Health Service 
NiUS 
Navigated Intraoperative Ultrasound  
OS 
Overall Survival 
PFS 
Progression Free Survival 
PI 
Principal Investigator 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 17 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
PIL 
Participant/ Patient Information Leaflet 
PP 
Protocol Population 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
RGEA 
Research Governance, Ethics & Assurance,  University of Oxford 
SOP 
Standard Operating Procedure 
QLQ 
Quality of Life Questionnaire 
QLQ-BN20 
Quality of Life Questionnaire Brain 
QLQ-C30 
Quality of Life Questionnaire Cancer 
QoL 
Quality of Life 
TMZ 
Temozolomide 
TSC 
Trial Steering Committee 
US 
Ultrasound 
WHO 
World Health Organisation  
5. BACKGROUND AND RATIONALE 
5.1. Health problem to be addressed 
Glioblastoma (GB) is a cancer with unmet needs.  
GB is the most frequent and aggressive form of brain cancer, with an incidence of 4.64/100,000/year in 
the UK.3 Prognosis remains extremely poor with median survival just over 12 months4 and as the tumour 
grows patients experience a progressive decline in health-related quality of life (HRQoL), and caregivers 
report high levels of distress and carer burden.5  Resistance to treatment leads to poor survival,6 with 
high costs to the patient, relatives, society, and the economy.6-8  
Although primary brain tumours represent only 3% of all cancers, a brain tumour reduces life expectancy 
by an average of 20 years, the highest of any cancer, and accounts for more average years of life lost 
than any other cancer.6-8 GB affects adults in their economic prime, and is a leading cause of death in 
those under 40 years, costing the economy £578M per year.6-8 To date, there has been little progress in 
improving outcome, with many trials failing to show an effect.9 Furthermore, the Department of Health 
and Cancer Research UK have identified research in this field as being under resourced,10 and recently 
allocated additional funding of £45 million.11 The Brain Tumour Charity have also recently invested 
£2.8M into the Tessa Jowell BRAIN-MATRIX (British feasibility study of molecular stratification and 
targeted therapy to optimise the clinical management of patients with glioma by enhancing clinical 
outcomes, reducing avoidable toxicity, improving management of post-operative residual and recurrent 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 18 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
disease and improving survivorship), a trial aimed at radically increasing opportunities for brain tumour 
patients to access non-standard treatments.12 This is timely, as the incidence of brain tumours is 
projected to rise by 6% in the UK between 2014 and 2035.1  
A recent James Lind Alliance Priority Setting Partnership13 revealed two of the top ten priorities in Neuro-
oncology are concerned with the long-term physical and cognitive effects of treatment, and the impact 
of extent of resection on survival. These themes are reflected in the comments from engagement with 
the Neuro-oncology Patient and Public Involvement (PPI) Groups at Imperial College Healthcare NHS 
Trust and Oxford University Hospitals NHS Foundation Trust, the Brainstrust PPI group and the Brain 
Tumour Charity-Research Involvement Network (BTC-RIN).  It is apparent that extending survival without 
functional compromise, and maintaining HRQoL is optimum for patients and relatives, given GB is an 
incurable cancer with extremely short survival.  
5.2. Health Related Quality of Life (HRQoL)  
Health Related Quality of Life (HRQoL) is important for patients as GB is incurable and median survival is 
short.  Of late, the role of Quality of Life (QoL) measurement has become increasingly important in 
oncology trials. HRQoL is a key outcome of interest to patients, and more recently has been used as a 
secondary outcome measure in a number of randomised trials of GB treatment.14 For a patient with GB, 
QoL is particularly significant, given there is substantial potential for a negative impact on HRQoL due to 
surgical resection, as well as deterioration due to disease progression. Therefore, it is critical that 
assessments of QoL are relevant to the patient population and the effect of their condition. The EORTC 
QLQ-C30 has been widely used in oncology trials for over 20 years (currently version 3), to assess the 
quality of life of cancer patients.15,16 More recently, an additional brain cancer specific module (QLQ BN-
20) has been produced which complements the main QLQ-C30, with more brain cancer specific 
symptoms and additional QoL domains to ensure a comprehensive and relevant assessment for these 
patients.17 
In newly diagnosed GB, QoL may be relatively high, close to that of a healthy population, it can however 
deteriorate rapidly. The ultimate aim of treatment, therefore, is to prolong survival in a way that is 
clinically meaningful to the patient, i.e. whilst maintaining their reported HRQoL at as high a level as 
possible. Accordingly, in the FUTURE-GB trial the primary outcome is the patient centric Deterioration 
Free Survival (DFS),18 which takes into account decline in QoL, as well as survival, and disease 
progression.  
5.3. Knowledge Gap 
There is currently a knowledge gap: surgery is the mainstay of treatment for GB but optimum surgical 
technologies remain unclear.  Surgery to resect GB is integral to maximum first line treatment, with a 
greater impact on survival than non-operative treatments (radiotherapy and chemotherapy).19 It 
improves symptom control, reduces dependence on dexamethasone, and increases progression free and 
overall survival.20,21 However, maximising the extent of surgical resection must be balanced against the 
potential risk of causing neurological deficit. It remains unclear which technologies should be employed 
intraoperatively, without increasing physical and/or cognitive dysfunction. A recent Cochrane review 
emphasized the lack of high-quality evidence to support the use of any specific intraoperative imaging 
technology.22 Research regarding which technologies have the greatest efficacy is of poor quality, with 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 19 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
few details concerning the impact of more radical surgical resection on neurological function. 
Furthermore, there are no ongoing or new trials evaluating intraoperative UltraSound (iUS), Diffusion 
Tensor Imaging (DTI), or 5-aminolevulinc acid (5-ALA), that will influence treatment guidelines and policy. 
5.4. Current surgical standard of care  
The current standard of care advises gross total resection (GTR), i.e. removing all enhancing tumour seen 
on the preoperative MRI scan), where appropriate, using neuronavigation, based on a preoperative MRI 
scan, and intraoperative 5-aminolevulinic acid (5-
ALA), which is an oral solution administered prior 
to surgery to facilitate tumour visualisation and 
differentiation from surrounding normal brain 
tissue during surgery.5   However there is wide 
variations of surgical standard of care across the 
UK.  Neuronavigation systems allow the 
craniotomy to be placed accurately, and the 
surgeon to locate the tumour. However, once the 
dura has been open, cerebrospinal fluid (CSF) 
and/or cyst fluid is drained, and, as tumour is 
removed, a phenomenon known as ‘brain shift 
occurs’,23 rendering standard neuronavigation 
inaccurate when identifying the tumour margins. Consequently, a surgeon may halt the resection at 
what is perceived to be tumour margin, inadvertently leaving residual disease. 5-ALA use increases the 
extent of tumour resection and progression free survival (PFS).20,24 However, 5-ALA only identifies 
fluorescing tumour immediately apparent in the surrounding tissue, without consideration of volume, or 
of tumour hidden due to an irregular resection cavity. Furthermore, it does not inform of tissue function.  
A survey of all 24 adult UK neurosurgical centres (Telephone and Email survey conducted in 2018 by 
Oxford), showed wide variation in the use of technologies employed during GB resection. Whilst all 
centres employ standard neuronavigation and 5-ALA, only 75% have access to iUS, 62% to DTI, and 16% 
to an intraoperative MRI scanner. However, most of these technologies are not regularly used for 
tumour resection, with surgeons unclear of the efficacy of each, and what is the optimum combination. 
Indeed, the National Institute for Health and Care Excellence (NICE) guidance5 has suggested that the 
available range of intraoperative technologies are considered, as appropriate, in addition to standard 
techniques, for tumour resection.  
5.5. Combined iUS* and DTI may improve outcome 
The desire to achieve a safe, maximal resection, particularly in eloquent regions, has led to an increase in 
the popularity of intraoperative imaging. This attempts to eliminate the error produced by brain shift, an 
inherent problem in navigation systems based on preoperative imaging,23 to demonstrate residual 
tumour at operation, and to visualise accurately relevant white matter tracts and tumour margins. Two 
technologies which facilitate surgical resection intraoperatively are iUS* and DTI.  
1. iUS accommodates for brain shift if it is linked to neuronavigation systems, allowing the surgeon 
to track tumour resection in real time. iUS permits multiple, real time image acquisitions, and, 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 20 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
potentially, if navigated, at each stage, comparison with the preoperative MRI navigation 
sequence, to evaluate brain shift and residual disease. iUS* minimally augments operative 
time,25 allowing precise visualization of tumour resection. It is user friendly, widely available, and 
a pragmatic and cost-effective alternative to intraoperative MRI, which is prohibitively expensive 
for many UK units. iUS, and more recently navigated iUS, has a long history in brain tumour 
surgery,26 facilitating/extending resection,27-31 and improving survival.32 It has also been 
evaluated with respect to histology.33,34 However, there is a learning curve, and image 
interpretation, especially once resecting, can be challenging.26 iUS* demonstrates residual 
tumour in real time. Indeed, it has been reported that navigated iUS and 5-ALA provide different 
information of tumour extent, and when combined, enhance extent of resection.35 Despite this, 
there are no randomised trials assessing its efficacy. 
2. DTI is a special magnetic resonance imaging (MRI) technique that can identify the location of 
white matter nerve tracts important for speech/language/visual/motor functions. The location of 
white matter fibre pathways is the most frequent reason why surgery is halted early, to avoid 
compromising patient function.36 DTI is the only method available to visualise functionally 
important white matter tracts in the vicinity of a tumour before surgery, and can be fused with 
standard intraoperative navigation systems to enable visualisation of the spatial location of the 
tracts during surgery, allowing removal of tumour in close proximity. DTI’s usefulness in brain 
tumour surgery has recently been reviewed.36 Intraoperative visualisation of DTI is reported to 
contribute to maximising safe resection,37-39 reducing visual field deficits,40 and predicting long-
term language problems after surgery.41  A single centre, DTI randomised control trial showed 
significantly better gross total resection rates, a lower risk of movement loss, and improved life 
expectancy.42  Furthermore, DTI-informed awake surgery reduced the occurrence and severity of 
behavioural problems postoperatively, leading to faster recovery, and shorter hospital stay43 DTI 
requires the collection of additional MRI data, specialist software for analysis, and detailed 
knowledge of white matter anatomy and function. In addition, tract visualisation may be limited 
where there is peritumoural oedema. As a result, there is only limited data available on the 
sensitivity and specificity of DTI in GB surgery, particularly with reference to its value as an 
intraoperative tool and in predicting DFS. 
5.6. Pilot data shows that combining techniques is the way forward 
Whilst the current aim for GB surgery is resection of all the contrast-enhancing tumour, several small, 
single centre studies have reported that extending tumour resection beyond the contrast enhanced 
margin, i.e. suptratotal resection, can increase overall survival without additional disability.44-46 A recent 
pilot study,47 incorporating DTI neuronavigation, 5-ALA guidance, and, where indicated, awake surgery 
has shown that supratotal resection prolongs Progression Free Survival (PFS). Furthermore, preliminary 
data in 80 patients, using DTI neuronavigation, in addition to 5-ALA guided surgery, achieved complete 
tumour resection in 72% of cases (65% using 5-ALA alone), with 3% postoperative disability (5-10% 
reported in the literature).48 In 15% of cases the residual tumour on the postoperative MRI scan was 
“hidden/missed” during surgery and would possibly have been detected using iUS.  
5.7. The need for the FUTURE-GB trial 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 21 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Surgery to maximally remove tumour is the initial and most important step of the patient pathway for 
GB patients, and despite the current standard of care,5 there remains great scope for surgical trials and 
improvement in outcome.47 Together with the implementation of the revised brain tumour 
classification,49 which permits more accurate patient categorisation, further enhancing surgical 
techniques will facilitate additional potential gain for patients.  
Intraoperative tools which provide information of residual disease and function are invaluable. 
Combining intraoperative techniques enhances the extent of resection.35,47 With the use of iUS* to 
identify residual disease in real time, and the functional information provided by DTI, in addition to 
standard care, it is anticipated that these two surgical techniques will prolong GB survival without 
increasing disability, and whilst maintaining a good quality of life. Increased survival without functional 
compromise has obvious benefit for patients and relatives, substantial health gains for society, and 
significant economic implications. Proven intraoperative techniques would be applied as standard care 
across the NHS, in all 24 hospitals performing adult neurosurgery. In addition, such surgical technologies 
have clear global appeal and worldwide impact.  
However, considering that this wide use of technologies inevitably varies amongst surgeons, major 
technical variations and significant deficits in competence or experience with trial procedures can 
compromise Randomised Controlled Trials (RCTs) by increasing “noise”, and introducing performance 
bias in relation to the new method/tool. Therefore, this trial has adopted an initial IDEAL IIB study 
format,50,51 a prospective non-randomised multicentre learning and harmonisation stage in which quality 
control measures and mentoring will be employed prior to the definitive randomised controlled stage of 
the trial.   
6. OBJECTIVES AND OUTCOME MEASURES  
6.1. PRIMARY OUTCOME MEASURES 
6.1.1. Stage 1 
The IDEAL study will determine whether surgeons using the technologies employed in the randomised 
controlled trial demonstrate acceptable expertise in delivering the new approach prior to proceeding 
with the randomisation stage. 
Note: There are no set levels for acceptable expertise – this will be an evolving process.  Factors used to 
evaluate expertise will include operation length, successful use of DTI neuronavigation, and iUS* use to 
achieve maximal, safe tumour resection without major neurological deficit; and extent of tumour 
resection. 
6.1.2. Stage 2 
The primary outcome is Deterioration Free Survival (DFS)18 using only the global health domain to 
indicate whether or not deterioration has occurred. Specifically, DFS is defined as the time to a 10-point 
deterioration from baseline in the global health status domain of the QLQ-C30 version 3 scores (regarded 
as clinically meaningful)53, without subsequent 10-point improvement in scores compared with baseline; 
or progressive disease (radiological tumour progression assessed from scan); or death in the absence of 
previous definitive deterioration.  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 22 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
The other four domains will be used to define corresponding DFS secondary outcomes.  
Note: It is imperative that the primary outcome measure is completed by those participating in the trial, 
therefore in addition to the participant completing the questionnaires as far as possible, a proxy will be 
asked to complete a separate set of questionnaires throughout the length of the trial.  A record will be 
taken of whether participants or proxies or both have completed each of the questionnaires at each data 
point.  
6.2. Secondary Outcome Measures – Stage 2 only 
 
• 
DFS as defined for the primary outcome except that physical functioning, social functioning from 
the QLQ-C30, and motor dysfunction and communication deficit from the QLQ-BN20 are each 
used instead of global health status to determine deterioration.    
Note: The QLQ-C3015,16 and QLQ-BN2017 will be collected for participants throughout the follow-
up period. The 5 HRQoL scale scores from these two questionnaires which are most pertinent to 
patients with GB are global health status, physical functioning, social functioning from the QLQ-
C30, and motor dysfunction and communication deficit from the QLQ-BN20. Both the QLQ-C30 
and the QLQ-BN20 questionnaires will be scored according to the EORTC scoring manual15 
following the strategy employed in the placebo arm of the AVAglio trial.18     
• 
Time to Deterioration – defined similar to DFS with the exception that progressive disease is 
excluded as an event.  
Note: There will be five time to deterioration outcomes, one for each of the scales utilised in the 
primary and secondary outcome DFS, used in turn to define deterioration. 
• 
Overall Survival (OS) – defined as time from randomisation to death or trial closure.  
• 
Progression Free Survival (PFS) – defined as time from randomisation to radiological tumour 
progression (scan date), as identified by local neuro-oncology MDT agreement.  
Note: Each MDT will investigate as per local protocols to differentiate true versus pseudo 
progression. Scan date confirming progression will be used as date of progression.  
• 
Extent of tumour resection on postoperative contrast enhanced MRI – measured as a % of the 
tumour volume when compared to the preoperative MRI scan. 
• 
Surgical complications and serious adverse events – recorded postoperatively and at follow up 
visits. 
• 
Number of patients eligible for adjuvant treatment following surgery (radiotherapy and/or 
chemotherapy). 
• 
Functional outcome postoperatively: World Health Organisation (WHO) performance status,55 
mini-MoCA (Montreal Version),56 Barthel Index57 and MRC power grading in all 4 limbs. 
Mechanistic component outcomes: 
• 
Sensitivity and specificity of the anatomico-spatial location of DTI fibre tracts compared with 
intraoperative direct electrical stimulation/behavioural change without stimulation but 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 23 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
related to adjacent white fibre tract in patients undergoing awake surgery, or motor evoked 
potential changes in patients undergoing surgery. 
• 
Sensitivity and specificity of iUS* to identify the tumour boundary when compared with 5-
ALA, navigated biopsies will be taken from tumour boundary tissue planned for resection. 
 
Objectives 
Outcome Measures 
Timepoint(s) 
Primary Stage 2 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves 
Deterioration Free Survival (DFS) 
(Where deterioration relates to 
global health status only) 
Composite of global health 
status domain of the QLQ-C30 
questionnaire, Progression 
Free Survival (PFS) and Overall 
Survival (OS) with an event 
defined as either 
deterioration, progression or 
death. 
Baseline; 6wks post-op., 
3mths post op., and 
then 3mthly up to 24 
months  
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves DFS 
where deterioration relates to 
physical functioning, social 
functioning from the QLQ-C30, and 
motor dysfunction and 
communication deficit  
4 composites using the 
respective domain of QLQ-C30 
(physical functioning and social 
functioning) and BN20 (motor 
dysfunction and 
communication deficit) 
combined with PFS and OS. 
Baseline; 6wks post-op., 
3mths post op., and 
then 3mthly up to 24 
months 
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves time 
to deterioration 
Defined similar to DFS with the 
exception that progression is 
excluded as an event (i.e. only 
deterioration or death are 
considered). There will be five 
time to deterioration 
outcomes, one for each of the 
domains utilised in the primary 
and secondary DFS outcomes, 
used in turn to define 
deterioration. 
6wks post-op., 3mths 
post op., and then 
3mthly up to 24 months 
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA improves 
Overall Survival (OS)  
OS (time from randomisation 
to death or trial closure) 
24 months 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 24 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
 
Objectives 
Outcome Measures 
Timepoint(s) 
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves 
Progression Free Survival (PFS) 
PFS (time from randomisation 
to radiological tumour 
progression on imaging, as 
agreed in local MDT). 
MRI at 6 months post-
surgery and then 
3mthly up to 24 months 
or an MRI performed 
outside protocol if 
patient is symptomatic. 
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves the 
extent of tumour resection  
Extent of resection as % of pre-
operative tumour volume on 
postoperative contrast 
enhanced MRI 
Post-operative review 
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves the 
incidence of surgical complications 
Number and type of surgical 
complications 
5 days post-op., or 
discharge date 
(whichever is soonest); 
6wks post-op.,3mths 
post op., and then 
3mthly up to 24 months 
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves the 
number of patients eligible for 
adjuvant treatment following surgery  
Number of patients eligible for 
adjuvant treatment 
3mths post-op. 
Secondary 
To assess whether additional 
intraoperative imaging (DTI and iUS*) 
to standard of care (neuronavigation 
based on preoperative MRI scan and 
intraoperative 5-ALA) improves the 
functional outcome postoperatively 
WHO performance status 
mini-MoCA (Montreal Version) 
Barthel Index 
MRC grading of power in all 4 
limbs  
Baseline, 5 days post-
op., or discharge date 
(whichever is soonest); 
6wks post-op.,3mths 
post op.  and then 
3mthly up to 24 months 
(MRC grading at 
baseline and 5 days 
post-op., or discharge 
date (whichever is 
soonest) only) 
Secondary 
Assess the correlation of proxy to 
participant classification assessment 
of quality of life 
At a minimum, answers to 
questions 29 and 30 of the 
QLQ-C30. Ideally answers will 
Baseline, 6wks post op, 
3mths post op.  and 
then 3mthly up to 24 
months.  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 25 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
 
Objectives 
Outcome Measures 
Timepoint(s) 
be provided to all of the QLQ-
C30 and BN20. 
Tertiary – 
Mechanistic 
Study Objectives 
– on a sub-set of 
participants 
Sensitivity and specificity of the 
anatomico-spatial location of DTI 
fibre tracts compared with 
intraoperative direct electrical 
stimulation/behavioural change 
without stimulation but related to 
adjacent white fibre tract in patients 
undergoing awake surgery, or motor 
evoked potential changes in patients 
undergoing surgery. 
Sensitivity and specificity 
calculation using pre and post-
surgery MRI images 
Analysis will be 
undertaken post-
surgery.  
Tertiary – 
Mechanistic 
Study Objectives 
– on a sub-set of 
participants 
Sensitivity and specificity of iUS* to 
identify the tumour boundary when 
compared with 5-ALA and post-
operative MRI scan. Navigated 
biopsies will be taken from tumour 
boundary tissue planned for 
resection. 
Intra operative iUS* images 
and post-operative MRI scans 
and Intraoperative biopsy 
samples 
Analysis will be 
undertaken post-
surgery when biopsy 
results are available. 
 
7. STUDY DESIGN 
7.1. Stage 1: non-randomised multicentre learning and evaluation stage (IDEAL Stage IIB 
study) 
This is a non-randomised multicentre learning and harmonisation stage in which quality control 
measures and mentoring will be employed to improve and evaluate standards of practice (IDEAL Stage 
IIB Study).50,51 The IDEAL Stage IIB study will determine whether surgeons using the technologies 
employed in the randomised controlled trial demonstrate acceptable expertise in delivering the new 
approach prior to proceeding with the randomisation stage. 
 Stage 1 is divided into 3 components: 
1. Pre-trial Webinar (see section 9.1.1) 
2. IDEAL Stage IIB (Quality assurance, Mentoring and Trial centres evaluation) (see section 9.1.2) 
3. End of Stage 1, Pre-Stage 2 RCT, each participating centre will have a data workflow review 
(Appendices C-E) with the Lead Investigators to review  the cases completed in Stage 1.  
The IDEAL Stage IIB study will comprise the following: 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 26 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
• 
Mentoring for local site surgeons. 
• 
Quality assurance of operative procedure.  
Mentoring by the CI and Lead Investigators will be provided through visits to participating centres and 
frequent participant meetings, together with a helpline for individual advice sessions from the CI and 
Lead Investigators and co-applicants, as appropriate. Neurosurgeons will contribute data to ensure 
standardisation of the protocol and acceptable expertise in delivering the new approach. This will be 
evaluated using the following metrics: operation length; successful use of DTI neuronavigation and iUS* 
to achieve maximal safe tumour resection without major neurological deficit; and extent of tumour 
resection assessed on postoperative MRI scan.  The number of cases required for this may vary, but 
is expected to be small (up to 5 cases) as most surgeons are already familiar with the component 
techniques and are not anticipated to require substantial assessment. Ensuring all participating surgeons 
are ready to take part will minimize performance bias in Stage 2 and ensure standardisation of 
intraoperative technique. 
7.2. Stage 2: prospective, Stage III, multicentre randomised controlled trial with internal 
pilot 
This is a parallel group two arm, multicentre, randomised controlled trial.  See Appendix A for a 
Flowchart depicting the flow through the trial.  
Population: 357 participants with GB suitable for maximal, safe resective surgery (attempted gross total 
resection of all enhancing tumour), as agreed at the local Neuro-oncology Multi-Disciplinary Team 
meeting. 
Intervention: standard care surgery (neuronavigation based on preoperative imaging and intraoperative 
use of 5-ALA) with the addition of DTI neuronavigation and iUS*. 
Control: standard care surgery (neuronavigation based on preoperative imaging and intraoperative use 
of 5-ALA) 
Outcome: Deterioration Free Survival 
Setting: UK NHS Trusts undertaking GB surgery 
8.  PARTICIPANT IDENTIFICATION 
 
8.1. Study Participants 
Patients aged 18-70 year with a primary GB tumour which is deemed maximally resectable (attempted 
gross total resection of all enhancing tumour) by the local Neuro-oncology Multi-Disciplinary Team 
(MDT) meeting, will be potentially suitable for inclusion in the trial.  
8.2. Inclusion Criteria 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 27 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
• 
Age 18-70 years 
• 
Neuro-oncology Multi-Disciplinary Team (MDT) decision that the imaging shows a primary GB 
tumour which is maximally resectable (attempted gross total resection of all enhancing tumour) 
• 
Patient is suitable for concomitant adjuvant radiotherapy and Temozolomide (TMZ) 
chemotherapy or adjuvant TMZ at the time of MDT decision 
• 
Able to receive 5-ALA 
• 
Willing and able to give informed consent  
• 
Able to complete trial questionnaires, this may be with support where English is not their first 
language (where compatible with the validation of questionnaires). (Stage 2 only)  
• 
Able to provide a proxy who is willing to complete questionnaires as requested (Stage 2 only). 
8.3. Exclusion Criteria 
The participant may not enter the trial if ANY of the following apply: 
• 
Midline/basal ganglia/cerebellum/brainstem GB   
• 
Multifocal GB  
• 
Recurrent GB  
• 
Suspected secondary GB 
• 
Contraindication to MRI  
 
9. PROXY INCLUSION (Stage 2 only) 
It is widely recognised in quality of life research that an individual may measure their quality of life 
differently from how another person would do, even if that person is close to the individual (e.g. carer, 
partner etc.). We have therefore set the study up so that we can collect both the participants own 
assessments (as they are able to provide them), and also the proxy/participant’s assessment. By doing so 
we will be able to explore potential difference in assessment between the two particularly with regards 
to deterioration of quality of life. This require both assessments to be collected whenever possible.  
 
The proxy/participant assessment is also important as it will be collected for the small subset of 
individuals who are not able to complete the quality of life questionnaires but do not lose capacity, have 
disease progression or die until sometime later. Thus, providing a measure of the quality of life which in 
the absence of the patients is the next best measure. 
 
It is vitally important in terms of the study's validity to be able to collect data on quality of life, death and 
time to progression to the point of death to the end of the follow-up, hence the need to include a Proxy 
in this study and has start and end questionnaire data.  
Proxies will receive questionnaires as per the schedule in 10.7.4.  The quality of life questionnaires will be 
the same as those given to the participant except in the third rather than first person.  
(Note where a participant dies, loses capacity or withdraws from the study – this will also automatically 
cease the proxy’s involvement in the study). 
9.1. Inclusion Criteria 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 28 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
• 
Age 18-75 years 
• 
Nominated by an individual who has consented to participate in Stage 2 
• 
Willing and able to give informed consent  
• 
Able to understand written English to enable completion of trial questionnaires 
10. PROTOCOL PROCEDURES  
10.1. Stage 1: non-randomised multicentre learning and evaluation Stage (IDEAL Stage IIB 
study) 
Patients will be recruited at each centre following the same procedures as detailed in Sections 10.2 to 
10.6 (see below for variation in consent information).  They will undergo the same pre-operative 
assessment as patients in Stage 2.  All Stage 1 patients will undergo standard care surgery and in addition 
iUS* and DTI, which will be used in the experimental arm of the Stage 2 trial.  Awake surgery will be used 
at the discretion of the operating surgeon.  Postoperative assessment by MRI scan and assessment of 
any complications will be performed the same as in Stage 2, including evaluation of DTI and iUS images 
versus post-operative MRI assessment.   
Stage 1 is divided into the following three components:  
10.1.1. Pre-Stage 1 Stage Webinar or Symposium 
At the start of Stage 1, a Webinar or Symposium will be held at which expert providers and practitioners 
will demonstrate and discuss the use of DTI and iUS* expected in the study.  In the case of DTI, 
neurosurgeons will be updated on the latest MRI/DTI sequences, intraoperative DTI neuronavigation 
software (BrainLAB Elements or Medtronic Stealth), and the clinical application with case examples and 
white fibre tract surgical anatomy refreshed. Variations in clinical MRI hardware mean it will not be 
possible to fully eliminate variance in diffusion data collected across all study sites. However, every effort 
will be made to standardise the sequence acquisition parameters; each site will be asked to acquire a 
routine diffusion acquisition with, preferably, 30  evenly-distributed diffusion directions at a b-value of 
1000 s/mm2, an isotropic resolution of 2x2x2mm and no slice gap. 
Guidance will be provided on minimum necessary diffusion processing and analysis using the BrainLAB 
Elements and Medtronic Stealth software in use at each site to maximise standardisation in tractography 
and image fusion to the neuronavigation system.  With respect to iUS*, all recruiting centres already 
deploy iUS as appropriate, with the use of a range of ultrasound machines.  The centres also all have 
access to probes within the range of 5-10MHz.  As probe selection is dependent on the location of the 
lesion and the overlying craniotomy, it is not possible to stipulate use of the same equipment uniformly. 
However, this is actually a strength of the study, as should the use of iUS be shown to be beneficial, it 
allows far more generalisability of the results, and hence global appeal.  
The symposium or webinar will permit surgeons to refresh their ultrasonography skills, case study 
examples from the lead centres, and the opportunity to consult with the ultrasound expert and the Lead 
Investigators using iUS* routinely for tumour resection. 
10.1.2. IDEAL IIB Study (Quality assurance, mentoring and trial centres learning).   

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 29 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Mentoring will take place at participating centres through visits as necessary from the expert trial faculty, 
and arrangements made for e-mail and telephone support where participating surgical teams are less 
familiar with aspects of the protocol. 
Participants will be recruited at each centre following the same procedures as detailed in Sections 10.2 
to 10.6. The number of cases required for this may vary, but is expected to be small (up to 5 cases) for 
most surgeons, as the participating centres are already familiar with the component techniques. 
10.1.3. Pre-RCT Data workflow review.  
For each participating centre, following the planned completion of Stage 1, the Lead Investigators, and 
the centre Principal Investigator/s, will meet via a Webinar hosted by the Surgical Interventional Trials 
Unit (SITU). This will review progress and initial data from Stage 1, with particular focus on the 
experimental interventions, namely DTI neuronavigation and iUS*. Surgeons will have the opportunity to 
discuss the quality standards for the interventions. The discussion of early results and experiences will 
permit group learning, which may be used to update/refine the protocol for the Stage 2 part of the trial.  
In addition, any concerns raised by experience during Stage 1 about (a) participant inclusion criteria (b) 
acceptable variations in intra-operative practice will be discussed in the light of the early results, and 
modifications made to this protocol if necessary.    
10.2. Recruitment 
10.2.1. Participants  
Recruitment into the trial will be undertaken in two phases in conjunction with the separate stages of 
the trial. There will be a separate Patient Information Sheet and Consent Form for patients entering 
Stage 1 (IDEAL IIb) and Stage 2 (RCT).   
Note: The stages are sequential at participating sites and the stages cannot be recruited to in parallel.  
 
Posters advertising the trial will be displayed in electronic and paper formats as allowed in participating 
sites.  All potentially eligible participants will have the trial mentioned at the same time the options 
regarding their surgery are discussed in dedicated neuro-oncology clinics.  Depending upon the site, the 
resources available, and most importantly how the participant is dealing with their diagnosis, the 
recruitment process and approach may vary across and within sites.  Potential participants may straight 
away be provided with the trial participant information sheet and asked to consider the trial, and that a 
member of the local research team will contact them.  It may be the case that individuals are asked if it 
would be acceptable for their name to be passed to the research team who will make contact at a later 
timepoint, or potential participants may be given the participant information sheet and asked to call the 
number on it if they wish to find out more about the trial. 
Note: When a potential participant is approached for verbal consent for their details to be passed onto 
the local research team – if this consent is given this should be recorded in their clinical notes.  
 
The local and co-ordinating team’s details will be on the participant information sheet so that individuals 
and their families can make contact to have any questions/queries answered. In addition, brain tumour 
charities will be contacted to promote and display information regarding FUTURE-GB. Furthermore, both 
OCTRU and SITU have twitter feeds which will be utilised to promote the trial, and acknowledge when 
milestones are met (i.e. sites open to recruitment, first recruitment at a site, 10% of recruitment, 100 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 30 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
patients recruited etc.) Also, it is anticipated that patient bodies who have their own social media feeds 
may post about the trial.   
10.2.2. Sites 
Sites that would like to participate in the trial will be required to complete a site feasibility questionnaire, 
deliver GB surgery, and have access to the technology being utilised in the trial. Site feasibility will be 
assessed on an individual unit basis, however research experienced and research naïve sites will be 
included.  Those sites assessed as being suitable will recruit participants initially into Stage 1 and then 
proceed to recruit participants to Stage 2.  
10.3. Screening and Eligibility Assessment 
Following screening and consent, participants will be entered into the Stage that is currently open at 
their site.  
Note: Screening should only be undertaken by those listed on the trial screening log, where individual site 
Principal Investigators’ have delegated this trial responsibility.  Eligibility checks will involve checking that 
participants meet all inclusion criteria and none of the exclusion criteria.   
 
There will be no waivers regarding eligibility, i.e. each participant must satisfy all the approved inclusion 
criteria of the protocol.  Changes to the approved inclusion and exclusion may only be made by a 
substantial amendment to the protocol. 
10.4. Informed Consent - Participant 
The participant must personally sign and date the latest approved version of the Consent form before 
any trial specific procedures will be performed.  Due to different timelines used at sites, the exact timing 
and location of the consent may vary – however as a minimum, consent must be given before a 
participant undergoes the routine pre-operative imaging as the participants needs to have been 
randomised by this Stage to ensure that all imaging required is undertaken. Patient Information Sheets 
will differ slightly between Stage 1 and Stage 2: In Stage 1 the purpose of the Stage within the overall 
Trial will be explained and it will be made clear that randomised allocation of treatment will not occur – 
all entrants will receive the experimental treatment protocol, but reduced follow-up. 
Written and verbal versions of the Participant Information Sheet and electronic and verbal versions of 
the Informed Consent will be presented to the participants detailing: the exact nature of the trial; what it 
will involve for the participant; the implications and constraints of the protocol; the known side effects 
and any risks involved in taking part. It will be clearly stated that the participant is free to withdraw from 
the trial at any time for any reason without prejudice to future care, without affecting their legal rights, 
and with no obligation to give the reason for withdrawal. 
The potential participants will be allowed as much time as desired to consider the information and will 
also be given the opportunity to question the Investigator/ a member of the research team, their GP or 
other independent parties to decide whether they will participate in the trial. However, neither the trial, 
nor time to think about participating in the trial, should cause a delay to any surgery to be undertaken. 
Electronic Informed Consent will then be obtained by means of a completed eConsent form, emailed to 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 31 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
the participant via the trial’s instance of REDCap, or by electronic completion in clinic. Whichever of 
these is used, it will include a participant dated electronic signature and dated name of the person who 
presented and obtained the Consent. The person who obtains the consent must be suitably qualified and 
experienced and have been authorised to take consent by the site’s Principal Investigator. A copy of the 
signed Consent Form will be emailed securely as a PDF to the participant (or a printed version provided if 
requested), a copy placed in the medical notes, and the original will be retained securely on REDCap.  
At the same time as taking consent in Stage 2 only, the participant will be asked to provide the name of a 
proxy, such as a friend/relative/spouse who they would nominate to also answer questions about their 
perception of the patient’s quality of life.   This individual will be given a separate Information Leaflet and 
asked to complete a separate proxy eConsent form, in the same way as the participant consent process.  
To be eligible for the RCT, the participant must have a proxy who agrees to consent to also participate in 
FUTURE-GB, by questionnaire completion. 
Note: If at some point a patient wishes to change their proxy, or the proxy needs to change, for example 
their contact reduces with the patient, the patient or proxy can suggest another proxy to be approached 
for consent and questionnaire completion. 
 
FUTURE-GB is a paperless trial, but if necessary, paper Consent can be used in clinic for both Participant 
and Proxy consent. 
10.4.1. Informed Consent – Proxy (Stage 2 only)  
The proxy must personally sign and date the latest approved version of the Consent form.  Due to 
different timelines used at sites, the exact timing and location of the consent may vary – however as a 
minimum, consent must have been given before the individual they are the proxy to is randomised to 
the trial. 
Written and verbal versions of the Proxy Participant Information and electronic and verbal versions of 
the Informed Consent will be presented to the potential proxy participants detailing: the exact nature of 
the trial; what it will involve for themselves; and any risks involved in taking part. It will be clearly stated 
that the participant is free to withdraw from the trial at any time for any reason without prejudice to 
future care, without affecting their legal rights, and with no obligation to give the reason for withdrawal.  
It is anticipated that these will initially be given to the participant to decide who they will ask to be their 
potential proxy.  It is also anticipated that the potential proxy may well be the person attending the 
standard clinic appointments with the participant.   
Note: There is no specific requirements on who can act as a proxy for a participant – this includes 
relationship to the participant, time known to the participant, and time spent with the participant each 
week. 
10.5. Randomisation 
Randomisation of patients will only occur in Stage 2 of the trial. Every centre and each participating 
surgeon will offer surgery under both arms of the trial.  
Randomisation will be via the web-based service provided by the Oxford Clinical Trials Research Unit 
(OCTRU), using the method of minimisation. The minimisation factors will be trial site, age (≤ 55 yrs or > 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 32 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
55 yrs), expected surgery status (under general anaesthesia or awake), and eloquence of tumour location 
(non-eloquent or eloquent).  
Participants will be randomised after having given written consent, however they will remain blinded as 
to which arm of the trial they have been allocated.  The local clinical team at site will receive an email 
from the randomisation system detailing the arm of the trial to which a participant has been 
randomised.   Randomisation has to occur before the pre-operative imaging takes place so that the 
assigned trial pre-operative imaging can be undertaken. 
Participants will be randomised 1:1 to either: 
• 
Standard care surgery (neuronavigation based on preoperative imaging and intraoperative use of 
5-ALA) (Control arm) 
• 
Standard care surgery (neuronavigation based on preoperative imaging and intraoperative use of 
5-ALA) AND of DTI neuronavigation and iUS* (Intervention arm) 
The participant’s identifiable information will be recorded on the randomisation form, and will be 
uploaded to an encrypted, separate database at the University of Oxford. 
10.6. Blinding and code-breaking 
Stage 1 is not blinded; the participants will be receiving all of the technologies during their surgery.  
In Stage 2, the participant will be blinded to the allocation (intervention or control arm), and the treating 
clinician will be aware, as he/she needs to perform the surgery with the intraoperative technologies as 
allocated. In addition to the participant, the radiologist (reviewing the postoperative MRI) will be blinded 
to the trial arm. Given this, only on the operation CRF will data of the allocation be included.  
There is no code breaking procedure required, as the intervention is a single time point application for 
the duration of the participants’ surgery. If there are any complications/issues that arise post-
operatively, the arm to which the patient has been allocated will not affect any subsequent actions 
undertaken by the participant’s clinical care team.  
10.7. Description of study intervention(s), comparators and study procedures (clinical) 
The intervention comprises standard care surgery (neuronavigation based on preoperative imaging and 
intraoperative use of 5-ALA) with DTI neuronavigation and iUS*. The comparator is the control, which is 
standard care surgery (neuronavigation based on preoperative imaging and intraoperative use of 5-ALA). 
Surgery will be undertaken, using the technology allocated. 
10.7.1. Description of study intervention(s)  
The planned experimental intervention is: GB tumour resection using standard care surgery (i.e. 
neuronavigation based on preoperative imaging and intraoperative use of 5-ALA), with the addition of 
DTI neuronavigation and iUS*. All patients entering Stage 1 will receive this intervention.    
Note: Support for imaging and image transfer workflows will be available to sites.  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 33 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
10.7.2. Description of comparator(s)  
The control intervention is: GB tumour resection using standard care surgery (i.e. neuronavigation based 
on preoperative imaging and intraoperative use of 5-ALA). 
10.7.3. Description of study procedure(s) – Stage 1 
All patients will undergo a routine preoperative neuronavigation scan. All patients will have a DTI scan 
(additional 5 minutes).  
Additionally, baseline data will be collected including sex, hand dominance, date of primary diagnosis, 
tumour location and details of any co-morbidities. In theatre, details of the procedure and technology 
use will be collected alongside any images captured. Post-operative data will be collected on any 
complications, new symptoms, or other significant findings. In addition to MGMT methylation status, 
EGFR amplification and TERT promoter mutations60  will be collected from the tumour biopsies and 
recorded post-operatively, where available.  
There will be minimal deviation from the standard care pathway for GB patients undergoing resective 
surgery.  Awake surgery and/or that using intraoperative electrophysiological monitoring is permitted as 
clinically indicated.  Surgery will be performed by a dedicated neuro-oncology surgeon. There is no 
alteration to the standard radiotherapy and chemotherapy dosing regimen or treatment schedule for 
participants. Postoperative assessments will be undertaken pre-discharge (5 days post-operatively, or at 
discharge).  
Within 72 hours of surgery, patients will undergo an MRI with contrast, permitting a volumetric 
evaluation of residual contrast enhancing tumour, which will be recorded. Further follow up MRI scans 
will be undertaken at 6 months postoperatively, as per standard care pathway. A notes check will be 
conducted at 6 months postoperative. 
Time point from Operation Data 
Data Collection Method 
At discharge 
Surgical complications and 
serious adverse events 
NIHR research nurse / local clinical team at 
routine appointment on trial CRFs   
6months 
Surgical complications and 
serious adverse events 
NIHR research nurse / local clinical team at 
routine appointment on trial CRFs     
 
10.7.4. Description of study procedure(s) – Stage 2 
All participants will undergo a routine preoperative neuronavigation scan. Those participants 
randomised to the experimental arm, will have a DTI scan (additional 5 minutes).  
All participants will have preoperative assessments that will comprise: HRQoL (EORTC QLQ-C3015,16 and 
BN2017) and functional performance status (WHO performance status,55 mini-MoCA (Montreal 
Version),56 Barthel Index,57 MRC power grading of limbs).  
Proxies will be asked to provide their relationship to the participant, the time on average they spend 
with the participant. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 34 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Baseline, intra-operative and post-operative data will be collected in the same way as in Stage 1, with the 
addition of other measures, as detailed in the table below. 
Within 72 hours of surgery, patients will undergo an MRI with contrast, permitting a volumetric 
evaluation of residual contrast enhancing tumour, which will be recorded. Further follow up MRI scans 
will be undertaken at 6 months postoperatively, and 3 monthly thereafter as per standard care pathway. 
The patient, radiologist (reviewing the postoperative MRIs), will be blinded to study arm.  
Surgery will be undertaken, using the technology allocated.  Awake surgery and/or that using 
intraoperative electrophysiological monitoring is permitted in either group, as clinically indicated. 
Surgery will be performed by a dedicated neuro-oncology surgeon, who has participated in Stage 1 of the 
trial.  There will be minimal deviation from the standard care pathway for GB patients undergoing 
resective surgery, and no alteration to the standard radiotherapy and chemotherapy dosing regimen or 
treatment schedule for participants.  Data will be collected on the operation performed and histology 
reported locally at site.  Postoperative assessments will be undertaken pre-discharge (5 days post-
operatively, or at discharge), and at six weeks post randomisation, with 3 monthly assessments 
subsequently. Survival will be tracked for 24 months.  
Once the patient has been randomised, the chance of intra operative crossover is very small, and would 
only arise if there was an unexpected surgical complication, whereby the surgeon during the operation 
considered he/she required the use of ultrasound.  If this occurred, this would be a protocol deviation, 
and should be reported to the trial team.  
Note: DTI cannot be performed during surgery, and therefore this does not apply.  
The Strummer et al. surgical trial,24 which evaluated a similar change in surgery-related practice, did not 
report any crossover due to surgeon equipoise, and only in 2 of 322 patients was there a technology 
issue.  
The schedule of trial assessments and methods for data collection are described in the table below after 
consent has been given.  As per standard practice, those undertaking any trial assessments/data 
collection – should establish that the participant still has capacity to continue to decide to participate in 
the trial: 
Time point from 
Randomisation 
Data 
Data Collection Method 
Baseline 
CRF data including sex, hand dominance, date 
of primary diagnosis, tumour location and 
details of any co-morbidities.  
 
HRQoL (EORTC QLQ-C30 and BN20) 
 
 
Functional performance status (WHO 
performance status, mini-MoCA (Montreal 
Version), Barthel Index, MRC power grading 
of limbs†)  
NIHR research nurse / local clinical team on trial CRFs 
 
 
 
Participant and proxy will complete electronic 
questionnaires online. 
 
NIHR research nurse / local clinical team on trial CRFs  
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 35 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Time point from 
Randomisation 
Data 
Data Collection Method 
Theatre  
(~ 7-14 days) 
Details of the procedure, and technology used 
during surgery 
NIHR research nurse / local clinical team on trial CRFs 
5 days post-op., 
or at discharge, 
Details of any complications, new symptoms, 
or other significant findings. Also, pathology 
data including MGMT methylation status. 
EGFR amplification and TERT promoter 
mutations, (where available) will be collected 
from the tumour biopsies60 where available. 
 
Functional performance status (WHO 
performance status, mini-MoCA (Montreal 
Version), Barthel Index, MRC power grading 
of limbs†) 
 
Surgical complications and serious adverse 
events 
NIHR research nurse / local clinical team on trial CRFs  
 
 
 
 
 
 
NIHR research nurse / local clinical team on trial CRFs 
(these may be collected remotely via 
telephone/videocall where this is more feasible) 
 
 
NIHR research nurse / local clinical team on trial CRFs  
6 weeks, 3 
monthly and 3 
monthly 
thereafter until 
24 months 
Details of any complications, new symptoms, 
or other significant findings. Also details of 
any radio/chemotherapy or other treatment 
received 
 
HRQoL (EORTC QLQ-C30 and BN20) * 
 
 
Functional performance status (WHO 
performance status, mini-MoCA (Montreal 
Version), Barthel Index, MRC power grading 
of limbs†) 
 
Surgical complications and serious adverse 
events 
NIHR research nurse / local clinical team on trial CRFs  
 
 
 
 
Participant* and proxy will self-complete electronic 
questionnaires online.  
 
NIHR research nurse / local clinical team on trial CRFs  
(these may be collected remotely via 
telephone/videocall where this is more feasible) 
 
 
NIHR research nurse / local clinical team on trial CRFs  
24 months  
Mortality data‡ 
NIHR research nurse / local clinical team on trial CRFs  
* NOTE: Due to the natural progression of this disease, a participant may not be able to complete the questionnaires at 
all or in their entirety.  It is hoped that the full questionnaire pack is completed, however for the primary outcome, only 
2 of the questions in the questionnaires are required to be answered as the primary outcome is based on just one of the 
DFS domains that is part of the questionnaire.  Proxies will be contacted for completion of the questionnaires for each 
time point applicable to the participants for whom they are a proxy. 
† MRC power grading only performed while participant is an inpatient. 
‡Progression of disease and occurrence of death are the universal outcome measures by which cancer treatments are 
assessed to enable the study to report overall survival rates for the study.  These have to be collected to fulfil the widely 
held standards for cancer-based research in this area.  
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 36 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
The specific questions that need to be answered for the primary outcome are:  
Please circle the number between 1 and 7 that best applies to you 
29. How would you rate your overall health during the past week? 
1 2 3 4 5 6 7  
 
Very poor to excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 2 3 4 5 6 7  
  
Very poor to excellent 
 
10.8. Imaging Schedule for both Stage 1 and 2 
Time point 
Imaging 
Part of Standard Care? 
Preoperative 
Neuronavigation MRI scan (T1 with contrast) 
 
Aim: to facilitate surgery 
Yes, however, if part of Stage 1 or 
randomised to experimental arm, this will 
include a DTI scan (which may add up to 5 
minutes to the MRI scan) 
Postoperatively 
(within 48-72 
hours of surgery) 
Diagnostic MRI (T1 +/- contrast) 
 
Aim: to determine extent of resection as a % of 
preoperative contrast enhancing tumour volume 
Yes  
6 months 
Diagnostic MRI (T1 +/- contrast) 
 
Aim: to assess response following concomitant 
radiotherapy and chemotherapy 
Yes 
Subsequent 3 
monthly follow 
up scans  
Diagnostic MRI (T1 +/- contrast) 
 
Aim: to assess response following adjuvant 
chemotherapy and detect early tumour recurrence 
Yes 
10.9. Sample Handling  
All participants in both Stage 1 and Stage 2 of the trial will have biopsy samples taken from their tumour 
as standard of care (tumour surface, tumour core and margin). This includes, as appropriate, 
samples from tumour margin tissue planned for resection, where no fluorescence is seen, but the iUS* 
image shows signal change suggestive of possible tumour/abnormal tissue (those patients in Stage 1 
and in the experimental arm of Stage 2). These biopsies will be sent to the pathology lab as per standard 
protocols/guidelines at each participating centre. No special precautions are required when handling 
these tissue samples.  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 37 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
10.10. Early Discontinuation/Withdrawal of Participants  
10.10.1. Stage 1 
Principal investigators may withdraw participants for the following reasons: 
1. If, following consent but prior to surgery, a participant decides to refuse surgery. 
2. If, following consent but prior to surgery, a clinician decides that resective surgery is no longer 
considered in the participant’s best interests. 
If participants are withdrawn from their interventions for these reasons, they will continue to be 
followed up in line with the protocol. 
Participants may also withdraw from the trial intervention and some or all of the follow-up at any time, 
without this affecting their clinical care. Where appropriate, remote follow-up and reasons for 
withdrawal will be collected where possible.  As there is no set sample size for this part of the study, 
participants that withdraw will not be replaced.  
All data and samples collected for the purposes of the study will be retained by the trial team.   
10.10.2. Stage 2 
Principal investigators may withdraw participants from their randomised intervention for the following 
reasons: 
1.  If, following consent but prior to surgery, a participant decides to refuse surgery. 
2. If, following consent but prior to surgery, a clinician decides that resective surgery is no longer 
considered in the participant’s best interests. 
3. During surgery if, for an unforeseen reason, the surgeon decides it is in the best interest of the 
participant that the use of NiUS or iUS will facilitate surgery above that which is otherwise possible.  
If participants are withdrawn from their interventions for these reasons, they will continue to be 
followed up in line with the protocol. 
Participants may also withdraw from their randomisation intervention and or some or all of the follow-
up at any time, without this affecting their clinical care. Where appropriate, remote follow-up, and 
proxy-completed data collection will be encouraged. Reasons for withdrawal will be collected where 
possible. The type of withdrawal and reason will be recorded in the CRF.   All data and samples collected 
for the purposes of the study will be retained by the trial team.   
Participants who withdraw will not be replaced, as a loss to follow-up allowance has been included to 
allow for sufficient numbers to be analysed.  Replacements will however be recruited if requested after a 
DSMC review.  
If a participant withdraws from the study or loses capacity, this will cease also all contact with their proxy 
and no further contact will be made. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 38 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
10.11. Definition of End of Study 
The end of study is the point at which all the study data have been entered, any queries resolved, and a 
hard data lock has taken place of stage 2. 
11. SAFETY REPORTING  
The trial will be run in accordance with OCTRU’s Standard Operating Procedures (SOPs) and operational 
policies, which all adhere to applicable UK regulatory requirements. An independent Data and Safety 
Monitoring Committee (DSMC) and Trial Steering Committee (TSC) will be appointed. The DSMC will 
monitor data arising from the trial, review confidential interim reports of accumulating data, and 
recommend whether there are any ethical or safety reasons why the trial should not continue. The TSC 
will monitor the trial’s progress and will provide independent advice. Both committees will comprise 
independent clinicians, statisticians, health service researchers and patient representatives. The project 
will also be monitored by the Sponsor (University of Oxford), and progress reports will be submitted to 
the Funder. Given the nature of the primary outcome and the interest in key secondary outcomes 
(namely, OS and PFS), no formal interim analyses are planned. 
11.1. Definitions 
11.1.1. Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical trial participant. 
Note: An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporarily associated with the trial procedures, 
whether or not considered related to the procedures.  
11.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
results in persistent or significant disability/incapacity 
Other ‘important medical events’ may also be considered a serious adverse event when, based upon 
appropriate medical judgment, the event may jeopardise the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
Note: The term "life-threatening" in the definition of "serious" refers to an event in which the participant 
was at risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
11.2. Reporting Procedures  
It is important to consider the natural history of a high-grade brain tumour affecting each participant 
enrolled, the expected sequelae of the illness, and the relevance of these complications to the trial 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 39 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
treatment. All eligible participants have a poor prognosis, and due to the complexity of their condition 
are at increased risk of experiencing multiple adverse events. Consequently, only Serious Adverse Events 
(SAE) will be recorded in this trial.  This is limited to serious adverse events, which might reasonably 
occur as a consequence of the trial treatment (i.e. not events that are part of the natural history of the 
primary disease process or expected complications of a brain tumour). 
SAEs, as defined above, experienced by a participant from their enrolment until their completion of the 
trial must be reported in the participant’s medical notes, on the trial CRF, and reported to the CTU using 
the SAE Reporting Form, within 24 hours of observing or learning of the SAE(s). All sections of the SAE 
Reporting Form must be completed. 
A SAE occurring to a participant will be reported to the REC that gave a favourable opinion of the study 
where in the opinion of the Chief Investigator the event was ‘related’ (resulted from administration of 
any of the research procedures) and ‘unexpected’ in relation to those procedures. Reports of related and 
unexpected SAEs should be submitted within 15 working days of the Chief Investigator becoming aware 
of the event, using the HRA report of serious adverse event form 
11.2.1. Events exempt from being reported as SAEs 
The following hospitalisations are not considered a SAE:  
o a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
o admissions as per protocol for a planned medical/surgical procedure 
o admissions for planned chemotherapy and/or radiotherapy and any related sequelae 
o routine health assessment requiring admission for baseline/trending of health status (e.g. 
routine colonoscopy) 
o medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study 
o admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason) 
o admission for administration of anticancer therapy in the absence of any other SAEs (applies to 
oncology protocols) 
o disease progression where not considered to be related to study intervention 
o non-surgical sequelae which can result from any operative procedure or a diagnosis of 
malignancy (for example, but not limited to: pneumonia, urinary tract infection, pulmonary 
embolism, deep vein thrombosis) 
o unplanned admissions resulting from pre-existing co-morbidities recorded at baseline 
11.3. Death during the study 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 40 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Death due to disease under study is to be recorded on the Death CRF form providing the death is not 
unexpected or if a causal relationship suspected. The investigator must clearly state whether the death 
was expected or unexpected and whether a causal relationship to the study intervention or other protocol 
treatment intervention is suspected.  
11.4. Elective admissions and supportive care 
Elective admissions to hospital for patient convenience or for planned procedures or investigations or 
treatment as specified in this protocol and standard supportive care are not SAEs, and do not require SAE 
reporting.   
11. STATISTICS AND ANALYSIS 
11.1. Statistical Analysis Plan (SAP) 
The statistical aspects of the study are summarised here, with details fully described in a statistical 
analysis plan (SAP).  The SAP will be agreed to by the TSC, with input from the DSMC, prior to unblinding 
of trial results to the team.  The SAP will be finalised prior to the final analysis taking place, and prior to 
unblinding of trial results to the team.  
11.2. Description of the Statistical Methods  
The analysis of the primary outcome will be a time-to-event analysis using a mixed effect Cox 
proportional hazard regression model. Minimisation factors (age, anticipated patient operative state and 
tumour location), and MethylGuanine-DNA MethylTransferase (MGMT) status will be adjusted for as 
fixed effects. Centre will be included as a random effect.  
The assumption of proportional hazard for the Cox model will be examined. If the proportional hazard 
assumption is not met, parametric survival analysis, such as the accelerated failure time method will be 
considered. A sensitivity analysis will look at the impact of adjusting for surgeon instead of centre. 
Secondary analysis will explore the influence of progression as an event by assessing DFS minus 
progression. An unadjusted comparison using a log-rank test will also be carried out. Kaplan-Meier 
curves will also be generated. Secondary Time-to-event outcomes (e.g. Overall Survival) will be analysed 
in a similar manner.  
 
Quality of life amongst survivors will be quantified without a formal statistical comparison between 
treatment groups.  
There are multiple factors that may influence how a patient rates his/her HRQoL, which may be related 
to factors other than the intervention. However, by using a randomized trial design, it is assumed that 
patients in both treatment arms are comparable on all aspects, both measured (e.g. age, performance 
status) and unmeasured (e.g. mood, coping strategy, personality). This means that the impact of the 
psychological state on the evaluation of HRQoL is treated as similar for the two trial arms. Thus, the 
study will be able to measure whether the experimental intervention has an impact on HRQoL when 
compared to patients receiving standard treatment. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 41 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
11.3. Sample Size Determination for IDEAL IIB Study (Stage 1) 
There is no formal sample size for the IDEAL study.  Participants will be recruited at each centre, the 
number of cases required from each centre will vary depending upon caseload numbers and the number 
of neurosurgeons, but is expected to be small for most sites (up to 5), as the participating centres are 
already familiar with the component techniques. 
11.4. Sample Size Determination for the RCT (Stage 2)  
The sample size is based on the primary outcome of DFS based upon the global health status domain in 
the QLQ-C30 questionnaire, version 3,18,53,54 as previously defined, and achieving a statistical power of 
90% for the primary analysis (see below) with 2-sided significance level of 5%.  
Assuming a Hazard Ratio (HR) of 0.7, median DFS survival time of 5 months in the control arm, 24 
months follow-up on all participants and allowing for 5% loss to follow-up occurring by month 3, this 
yields an overall target of 357 participants (178/179 per arm; 335 events overall) (Stata  “artsurv” 
www.stata.com). The global health status DFS outcome had median survival times of 6 months in the 
standard treatment arm (surgical resection with standard radiotherapy and chemotherapy) group in a 
recent trial.18  Additionally, the observed HR was 0.64, 95% CI (0.56, 0.74) for the DFS measures in this 
trial suggesting that a HR of 0.7 as assumed above is a plausible magnitude of effect to be observed for 
this population.58  It would also be one which would be considered important to clinicians and patients 
given the definition of a DFS event (death, progression or a patient anchor determined clinically 
meaningful deterioration of 10 points).  
For key secondary outcomes (i.e. the other four DFS outcomes, PFS and OS) there is over 80% power for 
this size of study, assuming a median overall survival time of 6-9, 7 and 15 months respectively in the 
control arm,5 a HR of 0.70 for both, and other inputs as per above.  
11.5. Recruitment Predictions for the RCT (Stage 2) 
Approximately 15 NHS Trusts have already agreed participation in the study. These centres collectively 
review approximately 1600-1866 GB patients per year (2531 cases diagnosed in 2015 with projected 6% 
annual rise).59 Assuming 40% of patients are deemed suitable for maximal resective surgery, and 
allowing trial exclusion criteria, this creates a potential annual pool of 600-700 patients. Brain tumour 
research recruitment rates are often over 50%, higher than the typical 33%. Therefore, conservatively, it 
is anticipated that 250-300 patients/year could enrol. 15 centres have up to 25 dedicated neuro-
oncology surgeons and it is predicted that each site may recruit on average 1 participant per month.  A 
total of 357 patients will be recruited across UK participating sites. The trial documentation and 
procedures will be developed together with patient representative input, and OCTRU involvement, to 
ensure optimum recruitment rates. 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 42 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
 
11.6. Analysis populations 
The principal analysis will be performed once data collection is completed and on the intention to treat 
(ITT) population, whereby participants will be analysed according to their randomisation allocation, 
irrespective of compliance with the protocol. If appropriate, additional analysis population, such as a per 
protocol population (PP), will be defined in the statistical analysis plan. A PP population may exclude 
participants who deviate from specific aspects of the protocol. 
11.7. Decision points  
11.7.1. Stage 1 (IDEAL IIB study) 
The trial team will evaluate patient CRF and imaging data continuously on a case by case basis from each 
site and provide regular feedback and assessment, any additional training/guidance is provided as 
needed.  
After a site has done an adequate number of cases and has objectively met the primary outcomes and 
workflow requirements, the completed data set will be revaluated by the trial team including the CI and 
Lead Investigators.   
A meeting with the trial team (including the CI and Lead Investigators) and site is then held to allow 
feedback from the site and discussion of lessons learned. This meeting is formally documented and if all 
the criteria are met, the site can then progress to Stage 2 (see Appendices C-E). 
11.7.2. Stage 2 (RCT) 
Built into the trial is an internal pilot of recruitment to the RCT (Stage 2).  There will be a formal stop/go 
review after 12 months of recruitment to the RCT to review the number of randomisations over the pilot 
period. If the target of at least 80 randomisations has been met, the trial will continue to recruit for a 
further 15 months. Data from the 80 patients will be included in the final analysis. All Stage 2 patients 
will be followed up to 24 months after randomisation.  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 43 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
The following stop-go criteria are proposed for the Trial Steering Committee (TSC) after 12 months of 
recruitment: 
 
actual recruitment after 12 months of recruitment 
target = 80 
>80 participants 
65 - 80 participants 
<65 participants 
recruitment rate 
(per centre per month) 0.6 
0.45 
0.37 
stop-go criteria 
recruitment feasible 
 
 
proceed with study 
review recruitment strategies 
report to TSC 
 
continue but modify and monitor 
closely 
recruitment not feasible 
 
 
decision not to proceed 
The TSC and the funder would make the final decision to terminate the trial.  
11.8. Stopping rules  
11.8.1. Stage 1 (IDEAL study) 
There are no formal stopping rules for this Stage of the study.   
11.8.2. Stage 2 (RCT) 
Given the nature of the primary, and key secondary, outcomes and the planned study length, no formal 
interim analyses with stopping guidelines are planned.  An independent Data Safety and Monitoring 
Committee (DSMC) will review the accumulating data at regular intervals and may recommend pausing 
or stopping the trial in the event of safety concerns.  
11.9. The Level of Statistical Significance 
All principal analyses will be performed at the 2-sided 5% significance level. 
11.10. Procedure for Accounting for Missing, Unused, and Spurious Data. 
The procedure for handling spurious or missing data will be described in the Statistical Analysis Plan, and 
the Data Monitoring Plan. The trial will attempt to collect data as completely as possible. 
The main analysis will include participants for whom endpoint data are available, with other participants 
being censored after their last available relevant outcome measure. Sensitivity analyses will examine the 
effects of alternative assumptions about the missing data. 
11.11. Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
Any deviation(s) from the original statistical plan will be described and justified in the final report, should 
these occur. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 44 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
11.12. Health Economics Analysis  
There are no health economic analyses to be undertaken as part of the trial.  
12. DATA MANAGEMENT 
A data management and sharing plan will be produced for the trial in accordance with OCTRU Standard 
Operating Procedures (SOPs), this will include reference to confidentiality, access and security 
arrangements. 
All data will be processed following the SOPs, which have been written in line with all applicable 
regulatory requirements. All trial-specific documents, except for the signed consent form and follow-up 
contact details, will refer to the participant with a unique study participant number/code and not by 
name. All patient data will be stored securely in accordance with OCTRU SOPs All trial data will be stored 
securely in offices only accessible by swipe card by the central coordinating team staff in Oxford, and 
authorised personnel.  
Data will be collected from participants and proxies via questionnaires and case report forms that will be 
returned to the central trial office in Oxford, via post using a pre-addressed freepost envelope, or NHS 
email as appropriate, or directly into an online secure database – the study’s dedicated instance of 
REDCap. In addition, participant images will be stored within the cloud database Quentry (BrainLab AG). 
As a third-party processor BrainLab will not receive any data that could identify participants.  
Participant data will be stored and transported in accordance to SOPs. Upon completion of the trial, fully 
de-identified research data may be shared with other organisations at the behest of the funder.  
12.1. Source Data 
Source documents are where data are first recorded, and from which participants’ CRF data are 
obtained. These include, but are not limited to, hospital records (from which medical history and 
previous and concurrent medication may be summarised into the CRF), clinical and office charts, 
laboratory and pharmacy records, scans, diaries, microfiches, radiographs, and correspondence. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no 
other written or electronic record of data).  All documents will be stored safely in confidential conditions. 
On all study-specific documents, other than the signed consent and follow-up contact details, the 
participant and proxy will be referred to by the study participant/proxy number/code, not by name. 
12.2. Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
Where data is submitted directly to the trial office, contemporaneous access by local research teams to 
the online database will enable the local research teams at sites to download copies of their participants’ 
data.  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 45 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
12.3. Data Recording and Record Keeping 
The data will be stored and used in compliance with the relevant, current data protection laws (Data 
Protection Act 2018; General Data Protection Regulation (GDPR) 2018). The trial data (including data for 
SAEs) will be entered onto a validated REDCap study database developed and maintained by OCTRU and 
which can only be accessed by authorised users via the application. The application resides on a 
webserver hosted and managed by Oxford University’s IT Services division.  The server is on the 
university’s backbone network and is backed up nightly to a secure off-site location.  
After closure of the trial and data analyses, the data will be made publicly available at the time of 
publication. The Trial Master File will be archived for five years from the end of the study. 
13.  QUALITY ASSURANCE PROCEDURES 
The study may be monitored, or audited in accordance with the current approved protocol, GCP, 
relevant regulations and CTU standard operating procedures. This research will be coordinated by the 
Surgical Interventional Trials Unit (SITU), which falls under the Oxford Clinical Trials Research Unit 
(OCTRU) and SITU personnel work according to OCTRU SOPs. The OCTRU SOPs and related quality 
assurance and control procedures will be used by SITU to ensure that the study procedures are assessed 
and carried out as defined in this protocol.  
13.1. Risk assessment  
A risk assessment and monitoring plan will be prepared before the study opens and will be reviewed as 
necessary over the course of the study to reflect significant changes to the protocol or outcomes of 
monitoring activities.  
13.2. Study monitoring  
Monitoring will be performed following a central monitoring and audit plan. Data will be evaluated for 
compliance with the protocol and accuracy in relation to source documents.  
13.3. Study Committees  
13.3.1. Data & Safety Monitoring Committee (DSMC)  
The DSMC will meet regularly throughout the trial at time-points agreed by the Chair of the Committee 
and the CI.  At a minimum this will be on an annual basis. The DSMC will review the safety data 
generated, including all adverse events, and make recommendations as to whether the protocol should 
be amended to protect patient safety. Recommendations of the DSMC will be discussed between the CI, 
TSC, and the Sponsor. 
13.3.2. Trial Steering Committee (TSC)  
The role of the Trial Steering Committee (TSC) is to provide the overall supervision of the trial. The TSC 
will monitor trial progress and conduct, and will advise on scientific credibility. The TSC will consider and 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 46 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
act, as appropriate, upon the recommendations of the Data and Safety Monitoring Committee (DSMC) 
and ultimately carries the responsibility for deciding whether the trial needs to be stopped on grounds of 
safety or efficacy.  
13.3.3. Core Trial Management Group (TMG) for all Stages 
The Trial Management Group (TMG) consists of those individuals responsible for the operational 
management of the trial such as the chief investigators, the clinical trial manager and representatives 
from OCTRU. 
The TMG will meet every month throughout the lifetime of the Stage 2 study and will:  
• 
Supervise the conduct and progress of the study, and adherence to the study protocol  
• 
Assess the safety as compiled by SITU and assessed by the DSMC, and efficacy of the 
interventions during the study 
• 
Evaluate the quality of the study data  
• 
Review relevant information from other sources (e.g. related studies)  
• 
Escalate any issues for concern to SITU, specifically where the issue could compromise patient 
safety or the integrity of the study or quality of the study data  
14. PROTOCOL DEVIATIONS  
A study related deviation is a departure from the ethically approved study protocol or other study 
document or process (e.g. consent process or administration of study intervention) or from the 
principles of Good Clinical Practice (GCP) or any applicable regulatory requirements. Any deviations from 
the protocol will be documented in a protocol deviation form and filed in the trial master file. 
15. SERIOUS BREACHES 
A “serious breach” is a breach of the protocol or of the conditions or principles of Good Clinical Practice 
which is likely to affect to a significant degree – 
(a) the safety or physical or mental integrity of the trial subjects; or 
(b) the scientific value of the research. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In 
collaboration with the Chief Investigator, the serious breach will be reviewed by the Sponsor and, if 
appropriate, the Sponsor will report it to the approving REC committee and the relevant NHS host 
organisation within seven calendar days.  
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 47 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
16. ETHICAL AND REGULATORY CONSIDERATIONS 
16.1. Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki.  
16.2. Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with the principles of Good 
Clinical Practice. 
16.3. Approvals 
Following Sponsor approval, the protocol, consent form, participant information sheet and any proposed 
advertising material will be submitted to an appropriate Research Ethics Committee (REC), and HRA and 
host institutions for written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
16.4. Other Ethical Considerations 
In the unlikely event of identifying any additional structural abnormalities on imaging, the scan will be 
checked by a clinical specialist. If the specialist feels that the abnormality is medically important, they will 
discuss the implications with the participant, and arrange for further investigations as necessary. 
Participants will not be informed unless the doctor considers the finding has clear implications for their 
current or future health.  
16.5. Reporting 
The Chief Investigator will submit once a year throughout the study, or on request, an Annual Progress 
report to the REC Committee, HRA (where required) host organisation, Sponsor and funder (where 
required). In addition, an End of Study notification and final report will be submitted to the same parties. 
16.6. Participant Confidentiality 
The study will comply with the UK General Data Protection Regulation (GDPR) and Data Protection Act 
2018, which require data to be de-identified as soon as it is practical to do so. Participant identifiable 
information stored on ICFs in the electronic database(s) will have strict access controls permitting access 
only to authorised users. The processing of the personal data of participants will be minimised by making 
use of a unique participant study number only on all study documents and in the rest of the electronic 
database(s).  All documents will be stored securely and only accessible by study staff and authorised 
personnel. The study staff will safeguard the privacy of participants’ personal data. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 48 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
16.7. Expenses and Benefits 
There is no budget to pay for any expenses incurred as a result of the study. However, study visits at the 
hospital have been scheduled to coincide with routine clinical appointments.   
17. FINANCE AND INSURANCE 
17.1. Funding 
This trial is funded by NIHR Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR 
partnership.  The views expressed in this publication are those of the author(s) and not necessarily those 
of the MRC, NIHR or the Department of Health and Social Care. 
The trial is supported by Industry partners BrainLab Pvt Ltd and Medtronic Plc. The Industry partners will 
provide software/hardware/personnel support during the trial. Contract agreements have been put in 
place between BrainLab, Medtronic and the University of Oxford as Sponsor of the trial. The views 
expressed in this publication by the author(s) are independent and not necessarily those of the 
collaborating industry partners. 
  
17.2. Insurance 
The University has a specialist insurance policy in place which would operate in the event of any 
participant suffering harm as a result of their involvement in the research (Newline Underwriting 
Management Ltd, at Lloyd’s of London).  NHS indemnity operates in respect of the clinical treatment that 
is provided. 
17.3. Contractual arrangements  
Appropriate contractual arrangements will be put in place with all third parties.  
18. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authors will acknowledge that the study was funded by 
the Efficacy and Mechanisms Evaluation Programme (EME), an NIHR and MRC Partnership. Authorship 
will be determined in accordance with the ICMJE guidelines and other contributors will be 
acknowledged. 
19. DISSEMINATION POLICY 
The trial has been prospectively registered, prior to ethics approval, on the International Standard 
Randomised Controlled Trial Number register. The trial protocol will be published in an open-access 
peer-reviewed journal in accordance with the Standard Protocol Items: Recommendations for 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 49 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
Interventional Trials statement (SPIRIT, www.spirit-statement.org/). The trial results will be published in 
an open-access journal, in accordance with the NIHR’s policy on open-access research. The study will be 
reported following the Consolidated Standards of Reporting Trials guideline (CONSORT, www.consort-
statement.org), in particular the extensions for non-pharmacological interventions, patient-reported 
outcomes and pilot and feasibility studies. The Template for Intervention Description and Replication 
(TIDieR) statement will be used for reporting the intervention,57 ensuring that replication is possible.  
20. DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL 
PROPERTY  
 
Ownership of IP generated by employees of the University vests in the University.  The protection and 
exploitation of any new IP is managed by the University’s technology transfer office, Oxford University 
Innovations.   
21. ARCHIVING 
During the clinical trial and after trial closure the Investigator will maintain adequate and accurate 
records to enable the conduct of the clinical trial and the quality of the research data to be evaluated 
and verified. All essential documents will be stored in such a way that ensures that they are readily 
available, upon request for the minimum period required by national legislation or for longer if needed. 
The medical files of trial subjects will be retained in accordance with applicable national legislation and 
the host institution policy.  
Retention and storage of laboratory records for clinical trial samples will also follow these guidelines.  
 
It is the University of Oxford’s policy to store data for a minimum of 3 years from publication. 
Investigators may not archive or destroy study essential documents or samples without written 
instruction from the trial office. 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 50 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
22. REFERENCES 
1) Smittenaar CR, Petersen KA, Stewart K, Moitt N. Cancer incidence and mortality projections in 
the UK until 2035. Br J Cancer. 2016;115(9):1147-55. 
 
2) Hirst A, Philippou Y, Blazeby J, Campbell B Campbell M, Feinberg J, et al. No Surgical Innovation 
Without Evaluation: Evolution and Further Development of the IDEAL Framework and 
Recommendations. Ann Surg. 2019;269(2):211-220. 
3) Brodbelt A, Greenberg D, Winters T, Williams M, Vernon S, Collins VP, et al. Glioblastoma in 
England: 2007-2011. Eur J Cancer. 2015;51:533-42. 
4) Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus 
concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96. 
5) NICE Guideline [NG99] : Brain tumours (primary) and brain metastases in adults. July, 2018. 
6) Cancer Research UK "Beating Cancer Sooner" - Our Research Strategy. 2014, CRUK. 
7) Burnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP. Years of life lost (YLL) from cancer is an 
important measure of population burden and should be considered when allocating research 
funds. Br J Cancer. 2005;92(2):241-45. 
8) Creighton H, Beach B, Bamford SM. Rethinking Cancer The big 'c':quantifying the social and 
economic impact. September, 2015. 
9) Cihoric N, Tsikkinis A, Minniti G, Lagerwaard FJ, Herrlinger U, Mathier E, et  al. Current status and 
perspective of interventional clinical trials for glioblastoma - analysis of clinical trials.gov. 
Radiation Oncology. 2017;12(1):1. 
10) House of Commons Petitions Committee Funding for research into brain tumours: Government 
Responses to the Petitions Committee's First Report of Session 2015-2016. First Special Report of 
Session 2016-2017. 
11) Report of the Task and Finish Working Group on Brain Tumour Research. Department of Health 
and Social Care, 2018. 
12) Tessa Jowell Brain-MATRIX: British feasibility study of molecular stratification and targeted 
therapy to optimise the clinical management of patients with glioma by enhancing clinical 
outcomes, reducing avoidable toxicity, improving management of post-operative residual and 
recurrent disease and improving survivorship. The Brain Tumour Charity.  
13) James Lind  Alliance Neuro-oncology Top 10 Priorities.  
14) Dirven L, Koekkoek JAF, Reijneveld JC, Taphoorn MJB. Health-related quality of life in brain 
tumour patients:as an endpoint in clinical trials and its value in clinical care. Expert Review of 
Quality of Life in Cancer Care. 2016;1(1):37-44. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 51 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
15) Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf of the EORTC 
Quality of Life Group. EORTC QLQ-C30 Scoring Manual (3rd edition). Brussels: EORTC, 2001. 
16) Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ. et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use 
in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76.  
17) Taphoorn MJ, Claassens L, Aaronson NK, Coens C, Mauer M, Osoba D, et al. An international 
validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-
related quality of life and symptoms in brain cancer patients. Eur J Cancer. 2010;46(6):1033-40. 
18) Taphoorn MJB, Henriksson R, Bottomley A, Cloughesy T, Wick W, Mason WP, et al. Health-
related quality of life in a randomized phase III Study of bevacizumab, temozolomide, and 
radiotherapy in newly diagnosed glioblastoma. J Clin Oncol. 2015;33(19):2166-75.  
19) Li YM, Suki D, Hess K, Sawaya R. The influence of maximum safe resection of glioblastoma on 
survival in 1229 patients: Can we do better than gross-total resection? J Neurosurg. 
2016;124(4):977-88.  
20) Stummer W, Reulen HJ, Meinel T, Pichlmeier U, Schumacher W, Tonn JC, et al. Extent of 
resection and survival in glioblastoma multiforme: identification of and adjustment for bias. 
Neurosurgery. 2008;62(3):564-76;discussion 564-76. 
21) Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, et al. Association of the 
extent of resection with survival in glioblastoma: A systematic review and meta-analysis. JAMA 
Oncol. 2016;2(11):1460-69. 
22) Jenkinson MD, Barone DG, Bryant A, Vale L, Bulbeck H, Lawrie TA, et al. Intraoperative imaging 
technology to maximise extent of resection for glioma. Cochrane Systematic Review, 2018.   
23) Hajioff D, Dorward NL, Wadley JP, Crockard HA, Palmer JD, et al. Post-imaging brain distortion: 
magnitude, correlates, and impacts on neuronavigation. J Neurosurgery. 1998;88:656-62. 
24) Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Sanella F, Reulen HJ, et al. Fluorescence-
guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised 
controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401. 
25) Sastry R, Bi WL, Pieper S, Frisken S, Kapur T, Wells W 3rd, et al. Applications of ultrasound in the 
resection of brain tumours. J Neuroimaging. 2017;27(1):5-15. 
26) Bal J, Camp SJ, Nandi D. The use of ultrasound in intracranial tumour surgery. Acta Neurochir 
(Wien). 2016;158(6):1179-85.   
27) Unsgaard G, Gronningsaeter A, Ommedal S, Nagelhus Hernes TA. Brain operations guided by 
real-time two-dimensional ultrasound: new possibilities as a result of improved image quality. 
Neurosurgery. 2002; 51(2): 402-11. 
28) Unsgaard G, Ommedal S, Muller T, Gronningsaeter A, Nagelhus Hernes TA. Neuronavigation by 
intraoperative three dimensional ultrasound: initial experience during brain tumour resection. 
Neurosurgery. 2002;50(4):804-12. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 52 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
29) Unsgaard G, Rygh OM, Selbekk T, Muller TB, Kolstad F, Lindseth F, et al. Intra-operative 3D 
ultrasound in neurosurgery. Acta Neurochir (Wien). 2006;148(3):235-53. 
30) Mahboob S, McPhillips R, Qiu Z, Jiang Y, Meggs C, Schiavone G, et al. Intraoperative ultrasound-
guided resection of gliomas: A meta-analysis and review of the literature. World Neurosurg. 
2016;92:255-63.  
31) Serra C, Stauffer A, Actor B, Burkhardt JK, Ulrich NH, Bernays RL, et al. Intraoperative high 
frequency ultrasound in intracerebral high-grade tumours. Ultraschall Med. 2012;33(7):306-12.   
32) Saether CA, Torsteinsen M, Torp SH, Sundstrom S, Unsgard G, Solheim O. Did survival improve 
after the implementation of intraoperative neuronavigation and 3D ultrasound in glioblastoma 
surgery? A retrospective analysis of 192 primary operations. J Neurol Surg A Cen Eur Neurosurg. 
2012;73(2):73-8. 
33) Woydt M, Krone A, Becker G, Schmidt K, Roggendorf W, Roosen K. Correlation of intra-operative 
ultrasound with histopathologic findings after tumour resection in supratentorial gliomas. A 
method to improve gross total resection. Acta Neurochir (Wien). 1996;138(12):1391-8. 
34) Camp SJ, Apostolopoulos V, Raptopoulos V, Mehta A, O’Neill K, Awad M, et al. Objective image 
analysis of real-time three-dimensional intraoperative ultrasound for intrinsic brain tumour 
surgery. J Ther Ultrasound. 2017;16:5:2. 
35) Moiyadi A, Shetty P. Navigable intraoperative ultrasound and fluorescence-guided resections are 
complementary in resection control of malignant gliomas: One size does not fit all. J Neurol Surg 
A Cent Eur Neurosurg. 2014;75(06):434-41.  
36) Voets NL, Bartsch A, Plaha P. Brain white matter fiber tracts: a review of functional neuro-
oncological relevance. J Neurol Neurosurg Psychiatry. 2017;88:1017-25. 
37) Herbert G, Maheu M, Costi E, Lafargue G, Duffau H. Mapping neuroplastic potential in brain-
damaged patients. Brain. 2016;139(Pt 3):829-44.  
38) Vassal F, Schneider F, Sontheimer A, Lemaire JJ, Nuti C. Intraoperative visualisation of language 
fascicles by diffusion tensor imaging-based tractography in glioma surgery. Acta Neurochir 
(Wien). 2013;155(3):437-48. 
39) Bello L, Riva M, Fava E, Ferpozzi V, Castellano A, Raneri F, et al. Tailoring neurophysiological 
strategies with clinical context enhances resection and safety and expands indications in gliomas 
involving motor pathways. Neuro Oncol. 2014;16(8):1110-28. 
40) Winston GP, Daga P, White MJ, Micallef C, Miserocchi A, Manicini L, et al. Preventing visual field 
deficits from neurosurgery. Neurology. 2014;83(7):604-11. 
41) Caversazi E, Hervey-Jumper SL, Jordan KM, Lobach IV, Li J, Panara V, et al. Identifying 
preoperative language tracts and predicting postoperative functional recovery using HARDI q-
ball fiber tractography in patients with gliomas. J Neurosurg. 2016;125(1):33-45. 
42) Wu JS, Zhou LF, Tang WJ, Mao Y, Hu J, Song YY, et al. Clinical evaluation and follow-up outcome 
of diffusion tensor imaging-based functional neuronavigation: a prospective, controlled study in 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 53 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
patients with gliomas involving pyramidal tracts. Neurosurgery 2007;61(5):935-48; discussion 
948-9. 
43) Ma R, Livermore LJ, Plaha P. Fast track recovery program after endoscopic and awake 
intraparenchymal brain tumor surgery. World Neurosurg. 2016;93:246-52. 
44) Chaichana KL, Cabrera-Aldana EE, Jusue-Torres I, Wijesekera O, Olivi A, Rahman M, et al. When 
gross total resection of a glioblastoma is possible, how much resection should be achieved? 
World Neurosurg. 2014;82(1-2):e257-65.  
45) Esquenazi Y, Friedman E, Liu Z, Zhu JJ, Hsu S, Tandon N. The survival advantage of “supratotal” 
resection of glioblastoma using selective cortical mapping and the subpial technique. 
Neurosurgery. 2017;81(2):275-88. 
46) Li YM, Suki D, Hess K, Sawaya R. The influence of maximum safe resection of glioblastoma on 
survival in 1229 patients: Can we do better than gross-total resection? J Neurosurg. 
2016;124(4):977-88.  
47) Plaha P. et al. Functionally Guided Supramaximal resection of IDH Wild Type High grade glioma. 
Abstract and Oral presentation. British Neuro Oncology Society Annual Meeting, Winchester, UK  
4-6th July 2018. 
48) Lau D, Hervey-Jumper SL, Chang S, Molinaro AM, McDermott MW, Phillips JJ, et al. A prospective 
phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative 
fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas. 
J Neurosurg. 2016;124(5):1300-9.  
49) Louis DN, Perry A, reifenberger G, Von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 
2016 World Health Organization Classification of Tumours of the Central Nervous System: a 
summary. Acta Neuropathol. 2016;131(6):803-20.  
50) McCulloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, et al. No surgical 
innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374(9695):1105-12. 
51) McCulloch P, Cook JA, Altman DG, Heneghan C, Diener MK, IDEAL Group. IDEAL framework for 
surgical innovation 1: the idea and development stages. BMJ. 2013; 346:f3012. 
52) Biau DJ, Williams SM, Schlup MM, Nizard RS, Prorcher R. Quantitative and individualised 
assessment of the learning curve using LC-CUSUM. B J Surg. 2008; 95(7):925-9. 
53) Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significant of changes in health-
related quality-of-life scores. J Clin Oncol. 1998;16(1):139-44. 
54) Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, et al. Influence of 
treatment with tumour-treating fields on health-related quality of life of patients with newly 
diagnosed glioblastoma:a secondary analysis of a randomized clinical trial. JAMA Oncol. 
2018;4(4):495-504. 
55) West HJ, Jin JO. Performance status in patients with cancer. JAMA Oncol. 2015;1(7)998. 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 54 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
56) MoCA Montreal - Cognitive Assessment. (2019). MoCA Montreal - Cognitive Assessment. [online] 
Viewed 18 October 2021.<https://www.mocatest.org/faq/>. 
57) Mahoney F, Barthel D. Functional evaluation: the Barthel Index. Md State Med J. 1965;14:61–5.  
58) Cook JA, Julious SA, Sones W, Hampson LV, Hewitt C, Berlin JA, et al.  DELTA2 guidance on 
choosing the target difference and undertaking and reporting the sample size calculation for a 
randomised controlled trial. BMJ. 2018;363:k3570. 
59) Philip A, Henshaw DL, Lamburn G, O’Carroll MJ. Brain tumours:rise in glioblastoma multiforme 
incidence in England 1995-2015 suggests an adverse environmental or lifestyle factor. Journal of 
Environmental and Public Health 2018;article ID 7910754, 10 pages. 
60) David N Louis, Arie Perry, Pieter Wesseling, Daniel J Brat, Ian A Cree, Dominique Figarella-
Branger, Cynthia Hawkins, H K Ng, Stefan M Pfister, Guido Reifenberger, Riccardo Soffietti, 
Andreas von Deimling, David W Ellison, The 2021 WHO Classification of Tumors of the Central 
Nervous System: a summary, Neuro-Oncology, Volume 23, Issue 8, August 2021, Pages 1231–
1251 
 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 55 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
23. APPENDIX A: STUDY FLOW CHART 
 
 
 
1-7 days post surgery 
Complications and adverse 
events, Functional 
performance status. 
Follow up at 6 months 
MRI (standard of care), 
HR-QoL, Complications 
and adverse events, 
Functional performance 
status. 
Follow up at 72 hours 
MRI (standard care) 
Follow up at 9, 12,15, 
18,21,24 months 
MRI (standard of care), 
HR-QoL, Complications 
and adverse events, 
Functional performance 
status. Mortality status 
1-7 days post surgery 
Complications and adverse 
events, Functional 
performance status. 
Follow up at 72 hours 
MRI (standard care) 
Abbreviations: 5-ALA – Aminolevulinic acid; DTI – Diffusion tensor imaging; iUS – 
Intraoperative ultrasound; MRI – magnetic resonance imaging; QoL – quality of life. 
OUTCOMES: (Tracked for 24 months) 
Primary- Deterioration Free Survival ӿ ‡ 
Secondary: 
 Overall survival ӿ 
 Time to Deterioration ӿ ‡ 
 Progression free survival †  
 Extent of tumour resection on 
postoperative contrast enhanced MRI † 
 Surgical complications and Adverse 
Events ӿ* 
 Number of patients eligible for Adjuvant 
therapy following surgery (Radiotherapy 
and Chemotherapy) ӿ* 
 Functional outcome post surgery 
(WHO) performance status, Cognitive 
ability (MoCA), Physical ability (Barthel 
Index and MRC power grading in all 4 
limbs) ӿ* 
 Mechanistic study outcomes 
 HR-Quality of Life Questionnaires: 
EORTC QLQ-C30 and BN20 ‡ 
* Notes review, † Radiology report, ‡ Patient 
(carer) reported, ӿ Trial Office tracked; MRC 
grading assessed during inpatient stay only 
Stage 1 
Non-randomised multicentre learning curve and evaluation phase (IDEAL Phase IIB study) 
Stage 2 
Prospective, Phase III, multicentre randomised controlled trial with internal pilot 
Randomised (n=357) 
Adults (18-70 yrs) scheduled to undergo maximal safe resection surgery for a primary high-grade brain 
tumour (Glioblastoma)  
Two Mechanistic Sub Studies: 
1) Sensitivity and specificity of the 
anatomico-spatial location of DTI fibre 
tracts compared with intraoperative 
findings in patients undergoing awake 
surgery.  
2) Sensitivity and specificity of iUS to 
identify the tumour boundary when 
compared with 5-ALA, navigated 
biopsies will be taken from tissue 
planned for resection. 
Follow up at 6 months 
MRI (standard of care), 
HR-QoL, Complications 
and adverse events, 
Functional performance 
status. 
Follow up at 9, 12,15, 
18,21,24 months 
MRI (standard of care), 
HR-QoL, Complications 
and adverse events, 
Functional performance 
status. Mortality status 
Control Group (n=178) 
Surgery using standard 
neuronavigation and 5-ALA 
Treatment Group 
(n=179) 
Surgery using Standard 
neuronavigation and 5-ALA 
with the addition of Intraop 
DTI and iUS 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 56 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
24. APPENDIX B: DATA COLLECTION CHART 
  

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 57 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
25. APPENDIX C: IMAGING DATA WORKFLOW 
FUTURE-GB Perioperative imaging and workflow – Brainlab sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BRAINLAB LAPTOP  
PLAN CASE WITH 
ELEMENTS 
AND DTI 
THEATRE 
EXPORTING TO QUENTRY 
 
• PRE OP MRI PLAN 
• INTRA OP DTI & US DATA 
• POST OP MRI SCAN 
TAKING INTRAOP 
POINTS FOR DTI 
CONFIRMATION 
US NAVIGATION 
TRANSFER USB / PACS 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 58 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
 
Brainlab sites – imaging needed 
 
Pre-op: Volume post contrast T1 MRI with 5 DTI tracts constructed (corticospinal, optic radiation, ILF, IFOF, Arcuate/SLF) 
and converted to “objects” 
 
Intra-op:  
• Ultrasound video – pre resection (in 2 planes), post resection (in 2 planes)  
Each video plane 15-20 seconds please. In total 4 video clips. 
• Ultrasound picture – where tumour resection cavity wall biopsy taken. 
• “Acquired” DTI data points on navigation system for:  
o only awake cases or cases with neurophysiology  
o where tumour resection cavity wall biopsy taken 
 
Post-op: T1 pre and post contrast MRI 
 
 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 59 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
FUTURE-GB Perioperative imaging workflow – Medtronic sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDTRONIC STEALTHVIZ  
PLAN CASE WITH 
STEALTHVIZ 
AND DTI 
THEATRE 
EXPORTING TO QUENTRY 
 
• PRE OP MRI PLAN 
• INTRA OP DTI & US DATA 
• POST OP MRI SCAN 
TAKING INTRAOP 
POINTS FOR DTI 
CONFIRMATION 
US IMAGES/VIDEOS 
US NAVIGATION 
TRANSFER USB / PACS 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 60 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
 
 
Medtronic sites – imaging needed 
 
Pre-op: Volume post contrast T1 MRI with 5 DTI tracts constructed (corticospinal, optic radiation, ILF, IFOF, Arcuate/SLF) – 
this is the Hybrid Navigation Exam 
 
Intra-op:  
• Ultrasound video – pre resection (in 2 planes), post resection (in 2 planes) 
Each video plane 15-20 seconds please. In total 4 video clips. 
• Ultrasound picture – where tumour resection cavity wall biopsy taken. 
• DTI screenshots on navigation system for:  
o only awake cases or cases with neurophysiology  
o where tumour resection cavity wall biopsy taken 
 
Post-op: T1 pre and post contrast MRI 
 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 61 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
26. APPENDIX D:  STAGE 1 SITE DATA COLLECTION FOR PROGRESSION 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 62 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 63 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
27. APPENDIX E: STAGE 2 PROGRESSION APPROVAL AGREEMENT 
 
 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 64 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
28. APPENDIX F: AMENDMENT HISTORY 
Amendment No. 
Protocol 
Version No. 
Date issued Author(s) of 
changes 
Details of Changes made 
N/A 
V2.0 
07Aug2020 
 
V2.0 was first accepted version of the protocol by REC 
AMD_01_NSA001 
V3.0 
13Oct2020 
Amy Jones 
Addition of wording for eConsenting during the COVID-19 pandemic 
AMD_02_NSA002 
V4.0 
14Oct2020 
Amy Jones 
• Removal of 6 week and 3 month follow up from Stage 1 to streamline data collection. 
• Correction of minor typographical errors and grammar for clarity 
AMD_03_SA001 
V5.0 
28Apr2021 
Amy Jones 
• Incorporation of eConsent into main body of protocol.  
• Clarification of statistical reporting timelines. 
• Redefinition of tertiary mechanistic objective measure for clarity. 
• Clarification of language regarding iUS/NiUS usage. 
• Lowering of inclusion age criterion to 70, and addition of 5-ALA as an inclusion criterion.  
• Removal of Surgical Trainee Network members of the TMG. 
• Appending of data collection chart, and imaging data workflows for Brainlab and Medtronic 
sites.  
• Removal of MRC power grading Functional Assessment from the follow up time points to 
facilitate remote data collection from site.  
• Correction of minor typographical and grammar errors. 
• Correction of amendment naming to comply with all local processes 
AMD_09_SA002 
V6.0 
16Feb2022 
Amy Taylor 
• Re-wording of the English comprehension inclusion criteria, to allow support for the 
participant, where needed 
• Removal of HRQoL data collection at post-op/discharge 
• Clarification of language in Stage 1 primary outcome from “complete resection” to “maximal 
safe resection” 
• Clarification of process for sites to move from Stage 1 to Stage 2 

Date and version No: FUTUREGB_Protocol_V6.0_19Jan2022.docx  
Clinical Research Protocol Template version 14.0 
 
 
 
 
 
Page 65 of 65 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2018 
CONFIDENTIAL 
 
 
 
• Addition of events exempt from SAE reporting, where those events result from pre-existing 
comorbidities prior to trial enrolment, and events that can occur as a result of undergoing 
any surgical procedures. 
• Correction of minor typographical and grammar errors. 
• Addition of imaging information into appendix C 
• Addition of Appendices D and E to demonstrate the data collection and approval process of 
progressing a site from Stage 1 to Stage 2 
• Update of name of university sponsor office from CTRG to RGEA