TSPO PET as a Measure of Post-stroke Brain Inflammation: a Natural History Cohort
Phase: NA
Conditions: Stroke, Ischemic, Inflammatory Response, Stroke, Acute
Sponsor: Imperial College London

Protocol GBR-TYS-16-11060  
Version 3.1 
TSPO PET as a measure of post-stroke brain inflammation 
CONFIDENTIAL 
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Sponsor-Investigator. 
Page 1 
 
 
Sponsor: Imperial College London 
Investigator: Roland Veltkamp 
 
Professor of Neurology 
Chair of Stroke Medicine 
Imperial College London 
Charing Cross Campus 
3 East 6 
Fulham Palace Road 
London, W6 8 RF 
UK 
Tel: 44-20-33130133 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
TRACKING NUMBER: 
 
GBR-TYS-16-11060 
 
 
PHASE OF DEVELOPMENT: 
NA 
 
 
 
 
 
PROTOCOL TITLE: TSPO PET as a measure of post-stroke brain inflammation: a 
natural history cohort 
 
 
EUDRA CT NO: 
NA 
 
 
DATE: 
30/06/2017 
Version 3.1 
 
 
 
 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
TSPO PET as a measure of post-stroke brain inflammation 
CONFIDENTIAL 
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Sponsor-Investigator. 
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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................4 
2. 
LIST OF ABBREVIATIONS.......................................................................................5 
3. 
SYNOPSIS ...................................................................................................................6 
4. 
SCHEDULE OF EVENTS ...........................................................................................9 
5. 
INTRODUCTION ......................................................................................................11 
5.1. 
Background .................................................................................................................11 
5.2. 
Rationale .....................................................................................................................11 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................14 
6.1. 
Objectives and Endpoints ...........................................................................................14 
7. 
STUDY DESIGN .......................................................................................................15 
7.1. 
Study Overview ..........................................................................................................15 
7.2. 
Overall Study Duration and Follow-Up .....................................................................15 
7.3. 
Early Termination of Study ........................................................................................15 
8. 
STUDY POPULATION .............................................................................................16 
8.1. 
Inclusion Criteria ........................................................................................................16 
8.2. 
Exclusion Criteria: ......................................................................................................16 
9. 
STUDY PROCEDURES ............................................................................................18 
9.1. 
Screening, Enrollment and Registration of Subjects ..................................................18 
9.2. 
Follow-up ....................................................................................................................18 
10. 
DATA COLLECTION ...............................................................................................19 
10.1. 
Imaging Assessments ..................................................................................................19 
10.2. 
Clinical Assessments ..................................................................................................21 
11. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................23 
11.1. 
Definitions ..................................................................................................................23 
11.1.1. 
Adverse Event (AE) ....................................................................................................23 
11.1.2. 
Serious Adverse Event ................................................................................................23 
11.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................23 
11.2. 
Safety Classifications ..................................................................................................24 
11.2.1. 
Investigator Assessment of Events .............................................................................24 
11.2.2. 
Severity of Events .......................................................................................................24 
11.3. 
Monitoring and Recording Events ..............................................................................24 

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TSPO PET as a measure of post-stroke brain inflammation 
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11.3.1. 
Adverse Events ...........................................................................................................24 
11.3.2. 
Serious Adverse Events ..............................................................................................24 
11.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................25 
11.3.4. 
Deaths .........................................................................................................................25 
11.4. 
Procedures for Handling Special Situations ...............................................................25 
11.4.1. 
Reporting Pregnancy ..................................................................................................25 
11.4.2. 
Medical Emergency ....................................................................................................25 
11.5. 
Sponsor-Investigator Responsibilities ........................................................................25 
12. 
STATISTICAL CONSIDERATIONS .......................................................................27 
12.1. 
Sample Size Justification ............................................................................................27 
12.2. 
Analysis Population ....................................................................................................27 
12.3. 
Methods of Analysis ...................................................................................................27 
12.4. 
Endpoints Analysis .....................................................................................................27 
13. 
ETHICAL REQUIREMENTS ...................................................................................28 
13.1. 
Ethics Committee ........................................................................................................28 
13.2. 
Subject Information and Consent ...............................................................................28 
13.3. 
Subject Data Protection ..............................................................................................29 
13.4. 
Compensation for Injury .............................................................................................29 
13.5. 
Conflict of Interest ......................................................................................................29 
13.6. 
Registration of Study and Disclosure of Study Results ..............................................29 
14. 
ADMINISTRATIVE PROCEDURES .......................................................................30 
14.1. 
Study Site Initiation ....................................................................................................30 
14.2. 
Study Funding .............................................................................................................30 
14.3. 
Study Completion .......................................................................................................30 
14.4. 
Publications .................................................................................................................30 
15. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................31 
15.1. 
External Contract Organizations .................................................................................31 
15.2. 
Changes to Final Study Protocol ................................................................................31 
15.3. 
Ethics Committee Notification of Study Completion or Termination ........................31 
15.4. 
Retention of Study Data ..............................................................................................31 
16. 
REFERENCES ...........................................................................................................32 
17. 
INVESTIGATORS SIGNED AGREEMENT OF STUDY PROTOCOL .................34 

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TSPO PET as a measure of post-stroke brain inflammation 
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1. 
 SPONSOR INFORMATION 
The regulatory sponsor is Imperial College London. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
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2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
BBB 
Blood-brain barrier 
BI 
Barthel index 
CRF 
case report form 
CRO 
contract research organization 
CNS 
Central nervous system 
CT 
computed tomography 
EC 
ethics committee 
EDC 
electronic data capture 
EU 
European Union 
LAR 
legally authorized representative 
LKN 
Last known normal 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board  
MoCA 
Montreal Cognitive Assessment 
MRI 
magnetic resonance imaging 
mRS 
Modified Rankin scale 
NIHSS 
National Institutes of Health stroke scale 
PET 
Positron emission tomography 
PHI 
protected health information 
RDC 
remote data capture 
SABR 
Safety and Benefit-Risk 
SAE 
serious adverse event 
SUSAR 
suspected unexpected serious adverse reactions 
TSPO 
Translocator protein 
UK 
United Kingdom 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
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3. 
SYNOPSIS 
Tracking Number: 
GBR-TYS-16-11060 
Protocol Title: 
TSPO PET as a measure of post-stroke brain inflammation: 
a natural history cohort 
Version Number: 
2.0 
Name of Study Treatment: 
Not applicable 
Study Indication: 
AIS 
Phase of Development: 
NA 
Rationale for the Study: 
Stroke is a leading cause of mortality and serious long-term 
disability. There is a substantial unmet medical need for new 
therapies that can improve outcomes in acute stroke. 
Experimental and pathologic data suggest that peri-infarct 
inflammation contributes to secondary injury after brain 
ischemia and that blocking inflammation could reduce the 
volume of brain infarction and improve clinical outcome.  
In a recently completed phase 2 placebo-controlled clinical 
trial, the administration of natalizumab (a potent inhibitor of 
leukocyte transmigration through the blood –brain barrier 
[BBB]) in the hyperacute phase of ischemic stroke was 
associated with beneficial effects in measures of functional 
outcome, but did not affect the rate of infarct volume growth 
during a 90-day assessment period. This apparent 
discrepancy between the lack of effect of anti-inflammatory 
therapy on lesion size and a substantial beneficial effect on 
functional outcome in ischemic stroke patients has raised 
further questions about the manifestation of 
neuroinflammation, its pathophysiological role  and its 
relation to patients’ functional outcome in stroke patients. 
The purpose of this imaging study is to characterize the 
subacute and longstanding extent of upregulation of the 
neuroinflammation marker TSPO on glial cells at two time 
points after stroke. The study will also explore the 
correlation of TSPO upregulation with measures of stroke 
severity and post-stroke functional outcomes. 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
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Study Objectives and 
Endpoints: 
The objectives of this study are: 
 To characterize TSPO glial expression in specific 
regions of interest defined on correlative brain MRI 
(ROIs; infarct, peri-infarct, thalamus) in the subacute 
(day 15+7) and chronic (day 90+/-7) phases after an 
ischemic stroke;  
 To determine the magnitude and variability of TSPO 
uptake at these ROIs during the assessment period;  
 To describe changes in TSPO expression between 15 
and 90 days 
 To explore the relationship between TSPO uptake, 
blood and infarct volume, and measures of Wallerian 
degeneration, 
 To characterize post-stroke TSPO glial expression in 
relation to measures of stroke severity (infarct size, 
volume and location; NIHSS) and functional 
outcome (mRS,BI, depression scale, MoCA) 
 To characterize post-stroke TSPO glial expression in 
relation to systemic inflammatory markers in blood  
The endpoints that relate to these objectives are:  
 PET-derived measures of TSPO radiotracer uptake 
in the infarct and peri-infarct areas at day 15 and day 
90 after a stroke 
 PET-derived measures of TSPO radiotracer uptake 
in ROIs distant from the infarct area (e.g. thalamus, 
hippocampi, amygdalae and midbrain) at day 15 and 
day 90 after a stroke 
 Correlation of PET-derived measures with clinical 
and imaging measures of stroke severity (stroke 
volume, size and NIHSS) and functional outcome 
(mRS Barthel index, MoCA, depression, ) at day 15 
and day 90 
 Correlation of infarct volume and MRI measures of 
white matter tract injury determined from DTI MRI 
with measures of thalamic TSPO uptake (time-
activity curve; measures of mean and max TSPO 
uptake on summed image sets fromTSPO PET 
 Correlation of PET derived measures with 
inflammatory markers in the blood (e.g. cytokines) 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
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Study Design: 
This is an exploratory, prospective, natural history, imaging 
cohort study. 
Study Location and Number 
of Sites: 
The recruiting site will be Imperial College Healthcare NHS 
Trust. All study scans will be performed by Imanova, 
Hammersmith Hospital 
Number of Planned Subjects: 
Between 15 and 25 subjects, with recruitment ending when 
15 participants have completed all study procedures.  
Study Population: 
Subjects aged 18-85 with a supratentorial ischemic stroke of 
moderate severity as measured by NIHSS >4 and evidence 
of infarction on clinical brain scan at time of stroke:  
 
 
Duration of Treatment and 
Follow-up: 
Subjects will participate in this study for approximately 90 
days. No treatment will be started as part of the trial 
 
 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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4. 
SCHEDULE OF EVENTS  
Tests and Assessments 
Screening visit9 
Day 15 (±3 days) 
Day 90 (±7 days) 
Eligibility confirmation1 
X 
 
 
Sign Informed Consent Form2 
X 
 
 
Demographics and medical 
history 
X 
 
 
Physical and neurological 
examination 
X 
X 
X 
Vital signs3 
X 
X 
X 
Height (if available) and 
weight 
X 
 
 
Urine (or serum) pregnancy 
test4 
X 
X 
X 
Medications 
X 
 
 
NIHSS 
 
X 
X 
mRS 
 
X 
X 
BI 
 
X 
X 
Beck Depression Inventory 
 
X 
X 
Hematology and blood 
chemistry5,6 
X 
 
 
Blood sample for systemic 
inflammatory profile 
X 
X 
X 
Blood sample for TSPO 
polymorphism genotyping7 
X 
 
 
Confirmation of genotype 
eligibility criterion8 
 
X 
 
PET and MRI scanning 
 
X 
X 
Adverse Events reporting 
throughout 
 
1. All but genotype exclusion criterion, see bullet point 8 
2. Subjects will be consented prior to screening procedures  
3. Vital signs include temperature, blood pressure, pulse or heart rate and respiratory rate 
4. Women with childbearing potential only 
5. Liver function, renal function and CBC will be performed at screening. Results of tests performed as part of 
standard of care can be accepted. 
6. Renal function tests will be repeated before each PET MRI assessment in subjects older than 60 years of 
age or with known renal impairment 
7. SNP genotype confirmation is required to determine eligibility. Blood samples for this assessment will be 
collected at screening only after other eligibility criteria have been met 
8. Verification of the TSPO SNP genotype exclusion criterion will occur prior to or at the PET MRI 
acquisition day but will be confirmed before subjects undergo PET-MRI imaging acquisition. 

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TSPO PET as a measure of post-stroke brain inflammation 
 
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9. Up to 10 days from stroke onset  

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TSPO PET as a measure of post-stroke brain inflammation 
 
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5. 
INTRODUCTION 
5.1. 
Background 
Stroke is a leading cause of mortality and serious long-term disability. There is a substantial 
unmet medical need for new therapies that can improve outcomes in acute stroke.  Experimental 
and pathologic data suggest that peri-infarct inflammation contributes to secondary injury after 
brain ischemia and that blocking inflammation reduces the volume of brain infarction and 
improves clinical outcomes.1, 2  Hence, immunologic therapies have been investigated for 
treatment of ischemic stroke.3 Nevertheless, there is substantial uncertainty about the time course 
and anatomic distribution of inflammation after stroke as well as its contribution to functional 
outcomes.  
5.2. 
Rationale 
TSPO, previously known as the peripheral benzodiazepine receptor (PBR), is a cholesterol 
transport protein that is present mainly in the mitochondrial compartment where it facilitates 
flow of cholesterol into mitochondria during steroid synthesis. 4 TSPO is overexpressed by 
microglia and monocyte-derived cells during inflammation and has been extensively used as a 
measure of inflammation.  
In the brain, TSPO PET radioligands provide a measure of predominantly resident (activated) 
microglia and infiltrating monocyte-derived macrophages and, to a lesser extent, reactive 
astrocytes. 5 
Ischemic stroke is arguably one of the most robust examples of CNS inflammation following 
acute brain injury. As such, TSPO PET scans have been used to assess brain inflammation for 
over two decades. 11C-PK11195, a first generation radioligand, was used by several 
investigators to study the magnitude of inflammation after the occurrence of an acute ischemic 
stroke in humans. Table 1 below summarizes the key findings of these studies: 
Table 1: Literature on 11C-PK11195 PET imaging in human ischemic stroke 
Author/Date 
Number of 
subjects studied 
Key findings 
Ramsay 1991 
1 
Uptake in infarct zone at 13d and 20d 
Pappata 2000 
7 
All MCA stroke, imaged 2-24 months after 
stroke. Increased binding in ipsilateral thalamus 
and ipsilateral midbrain (not contralateral 
thalamus) 
Gerhard 2000 
5 
Uptake at 5-33 days 
Gerhard 2005 
6 
Early uptake in infarct zone 

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TSPO PET as a measure of post-stroke brain inflammation 
 
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Late uptake in thalamus/Wallerian degeneration 
Price 2006 
4 stroke, 4 control 
Uptake in infarct, peri-infarct and contralateral 
brain increases from day 0-3, further at 7-14, 
and further at  day 25-30 
Radlinska 2009 
21 
Uptake along pyramidal tract as defined by DTI 
MRI within 2 weeks of acute ischemic stroke 
Thiel 2010 
18+ 6 controls 
Uptake at 2 weeks, persisting to 6 months 
Persistent uptake correlates with a worse 
clinical outcome 
As a summary, in these earlier TSPO PET studies there was an observable increase in PET 
radioligand uptake in the infarct zone at early time points, which increased up to 30 days after 
the stroke. 6, 7 In addition, development of an increased uptake at brain regions that are distant 
from the primary infarct area (i.e. thalamus and brainstem) was observable at later time points 
and seemed to be associated with areas of Wallerian degeneration, as demonstrated by 
concomitant acquisition of diffusion tensor imaging (DTI) on brain MRI. 8 Furthermore, the 
degree of microglial activation on 11C-PK11195 imaging appeared to be directly correlated with 
the degree of white matter fiber damage at MRI, which persisted in longitudinal TSPO PET 
assessments for up to six months after the index stroke. 5, 9  
Taken together, these findings provide scientific rationale to support that TSPO PET MRI is a 
valuable tool to assess dynamic changes in brain inflammation that occur after an event of acute 
ischemic brain injury, which could provide further insight on how brain inflammation relates to 
the natural history of the disease.  Given the small size, variability in imaging time points, and 
cross sectional nature of the majority of these studies, larger cohorts that measure longitudinal 
changes and key determinants of TSPO signal changes after stroke are needed to better 
understand neuroinflammation after stroke in humans.   
 
Rationale for radioligand selection 
Second-generation TSPO radiotracers have been developed to overcome some of the 
shortcomings of 11C-PK11195, the first-generation tracer. Specifically, the on-target to off-
target binding profile has been improved.   
These second-generation tracers were validated in numerous types of human CNS inflammation, 
including multiple sclerosis, trauma, HIV encephalopathy, and chronic neurodegenerative 
diseases such as Parkinson’s disease and Alzheimer’s disease. A second-generation tracer, 
PBR28, has been shown to effectively identify a sub-acute ischemic stroke in a case report 10.   
Despite the advantages of second-generation TSPO ligands in terms of image quality, a 
polymorphism (rs6971) in the gene encoding TSPO is responsible for existence of 3 classes of 
TSPO binders: Low-, Medium-, and High-affinity binders.11, 12  

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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Pharmacologic TSPO blockade in human studies has demonstrated that it is feasible to adjust 
image quantification to harmonize data between medium affinity binders (MAB’s) and high 
affinity binders (HAB’s).13  Low-affinity binders, which comprise no more than 10% of the 
population are usually excluded from TSPO PET studies due to poor signal-to-noise ratios. 
Hence, low-affinity binders will also be excluded in the present study. 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives and Endpoints 
The objectives of this study are: 
 To characterize TSPO glial expression in specific regions of interest defined on 
correlative brain MRI (ROIs; infarct, peri-infarct, thalamus) in the subacute (day 15+3) 
and chronic (day 90+7) phases after an ischemic stroke;  
 To determine the magnitude and variability of TSPO uptake at these ROIs during the 
assessment period;  
 To describe changes in TSPO expression between 15 and 90 days 
 To explore the relationship between TSPO uptake, blood and infarct volume, and 
measures of Wallerian degeneration; and, 
 To characterize post-stroke TSPO glial expression in relation to measures of stroke 
severity (infarct size, volume and location; NIHSS) and functional outcome (mRS, BI, 
MoCA, Beck depression inventory) 
 To characterize post-stroke TSPO glial expression in relation to systemic inflammation in 
blood 
 
Endpoints that correlate to these objectives are: 
 PET-derived measures of TSPO radiotracer uptake in the infarct and peri-infarct areas at 
day 15 and day 90 after a stroke; 
 PET-derived measures of TSPO radiotracer uptake in ROIs distinct from the infarct area 
(e.g.,  thalamus, hippocampi, amygdalae and midbrain) at day 15 and day 90 after a 
stroke; 
 Correlation of PET-derived measures with clinical and imaging measures of stroke 
severity (stroke volume, size and NIHSS) and functional outcome (mRS and BI) at day 
15 and day 90  
 Correlation of infarct volume and MRI measures of white matter tract injury determined 
from DTI MRI with measures of thalamic TSPO uptake (time-activity curve; measures of 
mean and max TSPO uptake on summed image sets from TSPO PET. 
 Correlation of PET derived measures with inflammatory markers in the blood (e.g. 
cytokines) 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a natural history cohort study evaluating patterns of brain inflammation and its 
relationship to qualifiers of stroke severity, functional outcome and stroke location. 
Patients participating in this study will be required to undergo physical examination, blood 
testing and PET-MRI imaging acquisition at distinct time points. 
7.2. 
Participation in this study will not influence the patients’ ability to receive 
standard of care treatment for stroke, as deemed necessary by the treating 
physician.Overall Study Duration and Follow-Up 
The study period will consist of screening and two time point PET and MRI assessments during 
an approximately 90-day follow-up period. The end of study is defined as final collection of 
data.  
7.3. 
Early Termination of Study 
The Sponsor-Investigator, after consultation with Biogen, may terminate this study at any time. 
 
7.4  
     Participant Identification and Recruitment 
Study Investigators who are members of the direct care team looking after the patient on the 
stroke ward, will identify them as potentially eligible. They will be approached by the 
Investigator and will have the study explained to them and be given a participant information 
sheet to read and consider. If they decide to take part after having any questions answered, the 
Investigator will take written informed consent before the patient has their screening visit.  
 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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8. 
STUDY POPULATION 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following inclusion criteria at 
screening: 
1. Able to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information in accordance with 
national and local subject privacy regulations   in accordance with all local and national 
regulations OR according to the local institutional review board’s (IRB’s)/ethics 
committee’s (EC’s) guidelines OR by another process compliant with applicable national 
laws and regulations and IRB/EC requirement 
2. Aged 18-85 years of age at the time of informed consent 
3. Clinical diagnosis of supratentorial acute ischemic stroke within the previous 10 days.  
Note: An acute brain CT or MRI scan must be available from the patient’s history to assess 
eligibility for the study and be consistent with the diagnosis of acute ischemic stroke. 
4. Score of at least 5 points on the NIHSS at Screening. 
5. Subjects of childbearing potential (male and female) must be willing and able to practice 
effective contraception during the study and for 4 weeks after their Day 90 appointment. 
6. Negative serum/ urine pregnancy test on all females of childbearing potential within 2 days 
before each PET study. 
8.2. 
Exclusion Criteria: 
Candidates will be excluded if any of the following exclusion criteria exist at screening, or at the 
time point specified in the individual criterion listed: 
1. Unable or unwilling to provide informed consent.  
2. Presence of acute intracranial hemorrhage on acute brain CT or MRI 
3. Inability to comply with study requirements (including implanted pacemaker). 
4. Subject has contraindications to undergoing MRI examination (including, but not limited 
to metal foreign bodies incompatible with MRI exposure, cardiac pacemakers, renal 
impairment that contraindicates gadolinium etc.) or PET scan. 
5. Subject has participated in a research and/or medical protocol involving nuclear 
medicine, PET or radiological investigations with radiation exposure that, when 
combined with the radiation exposure from the present study, would exceed 10 mSV in 
addition to the natural background radiation, in the previous 12 months. 
6. Other unspecified reasons that, in the opinion of the Investigator  make the subject 
unsuitable for enrollment. 
7. Nursing or pregnant females or females planning to become pregnant during study 
participation. 
8. Claustrophobic, unable to hold head continuously still for 90 minutes, or unwilling to 
undergo PET or MRI imaging and related procedures required for this study. 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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9. Genetic polymorphism consistent with low TSPO binding affinity (expected in 10% of 
the population).  

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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9. 
STUDY PROCEDURES 
Once the investigational site has been activated for study participation, subjects may be enrolled 
if they have met the inclusion criteria in Section 8.1 and have not been excluded based on the 
exclusion criteria in Section 8.2. 
9.1. 
Screening, Enrollment and Registration of Subjects 
Subjects must provide informed consent before any screening tests or assessments are 
performed.  When the subject signs the Informed Consent Form (ICF), the subject is considered 
to be enrolled in the study. Subjects will not be eligible for rescreening.  
Subjects will be registered at screening visit after the eligibility criteria, with the exception of the 
TSPO genotype, have been determined.  
Subjects will be registered and assigned a unique subject identification number after consent and 
before undergoing imaging acquisition.  Any subject identification numbers that are assigned 
will not be reused even if the subject does not undergo imaging. 
Subjects who withdraw from the study before completing Day 15 and Day 90 PET MRI scans 
may be replaced by discretion of the principal-investigator .  
9.2. 
Follow-up 
Subjects will be followed during a 90-day evaluation period during which time each participant 
is expected to undergo two visits where clinical assessment, blood sampling and PET-MRI scans 
will be conducted. Subjects will be called by study staff within 7 days after the 90 day study visit 
including the PET scan to inquire for potential adverse effects.  
Withdrawal of Subjects from the Study 
Subjects must be withdrawn from the study for any one of the following reasons: 
 The subject withdraws consent.   
 The subject is unwilling or unable to comply with the protocol. 
 The Physician withdraws the subject from the study for medical reasons. 
The reason for the subject’s withdrawal from the study should be recorded in the subject’s case 
report form (CRF) if provided by the subject.   
Participants who lose the capacity to consent during the trial will be withdrawn and have no 
further study procedures. The study team will retain the data and blood samples that are collected 
up until that point but no new data on the participant will be recorded.  
 

Protocol GBR-TYS-16-11060  
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TSPO PET as a measure of post-stroke brain inflammation 
 
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10. 
DATA COLLECTION 
10.1. 
Imaging Assessments 
PET and MRI 
 
10.1.1 Positron Emission Tomography (PET) 
PET imaging involves the estimation of the availability of a specific molecular target via the 
evaluation of the tissue kinetics of a specific molecule administered at tracer amounts and 
labelled with a positron emitting radionuclide. PET imaging allows the accurate estimation of the 
availability of the molecular target of interest before and after an intervention or over time. Each 
PET scan session in this study, will include the administration of [11C]PBR28, a PET 
radioligand suitable for the quantification of TSPO availability in the human brain. 
 
10.1.2 Magnetic Resonance Imaging (MRI) 
MRI involves the use of an intense magnetic field to quantify tissue anatomical characteristics. 
In this study MRI will be used to define the volume of the stroke affected areas, and 
physiological characteristics of the brain tissue relevant to stroke physiology. In addition, a 
Gadolinium conjugated contrast agent will be used to assess the regional integrity (i.e. 
permeability) of the blood-brain-barrier. Each MRI scanning session will be up to 90 min in 
duration and will include the administration of a Gadolinium-conjugated contrast agent.  
 
10.2 Summary of Risk Management for Imaging 
 
10.2.1 [11C]PBR28 
 
10.2.1.1 Pre-clinical safety and toxicology 
Safety and toxicity of PBR28 was studied in rodents and healthy human volunteers (n=10), at the 
National Institutes of Health (NIMH), USA. (National Institute of Health.html> February 2011). 
In an i.v. toxicity study in male and female Sprague-Dawley rats the NOAEL dose was 
determined to 
be 445 μg/kg for a single dose, and 88μg/kg for repeat dose administration. 
 
10.2.1.2 Clinical Safety 
In humans, pharmacological effects of [11C]PBR28 were monitored by performing vital signs 
and ECG monitoring, as well as blood tests (including full blood count, electrolytes, liver 
enzymes, creatinine) and standard urinalysis following i.v. injection of doses ≤10μg. No subject 
showed clinically 
significant changes in vital signs after administration of [11C]PBR28. Two subjects showed 
minor changes in laboratory tests, which could not be linked to administration of [11C]PBR28 
(Tracer Database Initiative). 

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10.2.2 Ionising Radiation Exposure 
Radiation dosimetry studies were conducted in order to estimate the radiation exposure following 
the administration of [11C]PBR28. The dosimetry of [11C]PBR28 was estimated in 7 human 
volunteers (4 male, 3 female) (Brown et al., 2007). Based on these data, the effective dose (ED) 
of [11C]PBR28 was estimated at 0.0066 mSv/MBq. Each volunteer will receive a maximum 
dose of 300 MBq of [11C]PBR28in each of their PET scans. The doses administered are adjusted 
to deliver the minimal radiation exposure compatible with a 
good quality PET signal. In addition, a low-dose CT scan of the head will be acquired to estimate 
attenuation correction prior to each PET scan.The radiation exposure due to the 2 scans with 
[11C]PBR28 will be 3.96 mSv, and 0.72 mSv from the 2 low-dose CT scans, yielding 4.68 mSv 
in total for the study. This exposure will place the study in category IIb of the International 
Commission on Radiological Protection (ICRP), an international workgroup on radiological 
protection. 
 
10.2.3 Intravenous cannulae 
Venous blood will be collected at screening to determine TSPO genotype and for routine 
safety tests. In addition a venous cannula will be inserted into a forearm or cubital vein for 
radiotracer administration and blood collection for pharmacokinetic analysis. Insertion of 
cannulae may lead to some transient pain and discomfort, and some bruising at the cannulation 
site.  
 
10.2.4 PET 
PET scans will be conducted according to GCP and GMP compliant procedures at the Imanova 
facility. Subjects will be screened for contraindications to PET scanning as per standard Imanova 
procedures. Before the start of each PET scan a venous cannula will be inserted into a forearm or 
cubital vein, for the administration of [11C]PBR28, and the subject will be positioned 
comfortably within the PET-CT scanner. A short low-dose CT of the brain will be conducted, 
and following this the PET emission data will be collected for approximately 90 minutes starting 
with the intravenous injection of [11C]PBR28. The primary discomfort arises from the need for 
subjects to lie supine during the scan. The scan will be stopped or abandoned if the subject is 
unable to complete the scan. 
 
10.2.5 MRI 
As a standard procedure, MR images will be evaluated by a radiologist. In the unlikely event of 
an unexpected and clinical significant finding on structural MRI which may require further 
investigation, participants and/or their General Practitioner will be informed, with the 
participant’s consent. There are no known risks to subjects associated with MRI scanning, 
provided subjects have no contraindications to MRI as listed in the exclusion criteria. Some 
participants may find the PET and MRI scanning environments claustrophobic. Participants with 
severe anxiety in confined spaces will be excluded from the study. Furthermore, potential risks 
associated with metallic implants injury will be eliminated by screening during study enrolment 
and prior to the scan. 

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10.2. 
Clinical Assessments 
After providing informed consent, the medical history will be documented in a CRF. Patients 
will also undergo a neurological examination. On the day of the PET and MRI examinations, the 
patients will be asked for the any events in the interim period since the screening examination. 
They will undergo a physical examination with a focus on neurological findings. Specifically, 
they will be assessed using the following tools: mRS:  The mRS measures independence, rather 
than neurological function, with specific tasks pre- and post stroke 14-17.  The scale consists of 
7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death.  The 
premorbid mRS will be scored through interviews with the participant and/or family caregiver.  
Raters will be required to be certified in the use of the mRS.  The mRS will be completed by a 
telephone interview for any subjects who fail to attend their Day 90 Follow-Up or Early 
Termination visit.  The mRS takes less than 5 minutes to administer. 
BI:  The BI consists of 10 items that measure a person’s daily functioning, specifically the 
activities of daily living and mobility 18-20.  The items include feeding, moving from wheelchair 
to bed and returning, grooming, transferring to and from a toilet, bathing, walking on a level 
surface, going up and down stairs, dressing, and maintaining continence of bowels and bladder.  
The assessment can be used to determine a baseline level of functioning and can be used to 
monitor change in activities of daily living over time.  The items are weighted according to a 
scheme developed by the authors.  The person receives a score based on whether they have 
received help while doing the task.  The scores for each of the items are summed to create a total 
score up to a maximum of 100.  The higher the score, the more “independent” the person is.  The 
BI takes less than 5 minutes to administer. 
NIHSS:  The NIHSS is a reliable tool for rapidly evaluating the effects of acute cerebral 
infarction 21.  Raters will be required to be certified in the use of the NIHSS.  A trained observer 
rates the subject’s ability to answer questions and perform activities relating to level of 
consciousness, language, visual-field loss, extraocular movement, motor strength, ataxia, 
dysarthria, sensory loss, and extinction and inattention (formerly neglect).  There are 15 items.  
Ratings for each item are scored with 3 to 5 grades, with 0 as normal and a maximum possible 
total severity score of 42 for all items.  There is an allowance for untestable items.  The test takes 
approximately 10 minutes to complete.  
MoCA:  The Montreal Cognitive Assessment (MoCA) is designed as a rapid screening 
instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and 
concentration, executive functions, memory, language, visuoconstructional skills, conceptual 
thinking, calculations, and orientation. Time to administer the MoCA is approximately 10 
minutes. The total possible score is 30 points. A score of 26 or above is considered normal.  
Beck’s Depression Inventory: The Beck Depression Inventory Second Edition (BDI-II) is a 21-
item self-report instrument intended to assess the existence and severity of symptoms of 
depression. Each of the 21 items corresponding to a symptom of depression is summed to give a 
single score for the BDI. There is a four-point scale for each item ranging from 0 to 3. On two 
items (16 and 18) there are seven options to indicate either an increase or decrease of appetite 
and sleep. Cut score guidelines for the BDI are given with the recommendation that thresholds be 
adjusted based on the characteristics of the sample, and the purpose for use of the BDI. Total 
score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. 

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Venous Blood Samples 
Genetic Testing: At the screening visit, participants will have a blood sample of up to 15mls 
taken which will processed at Hammersmith Hospital for TSPO Polymorphism genotyping. The 
results will confirm whether the participants meet the full eligibility criteria of the trial.  If the 
results show genetic polymorphism consistent with low TSPO binding affinity (expected in 10% 
of the population) those participants will be considered screen fails and will not be included in 
the trial. The test is purely to determine eligibility, the samples will be destroyed in accordance 
with local guidelines after testing is complete. Haematology and Chemistry: Participants will 
have a full blood count, renal and kidney function tests at screening if they have not had recent 
testing done as part of clinical care. It is expected that most participants will not require this.  
Systemic Inflammatory Markers: To assess systemic inflammatory markers, venous blood 
samples of 15ml will be takenon both days of the PET und MRI examinations. Blood will be 
rapidly frozen and stored in -80 specimen freezers at Imperial College London.Cytokines in 
blood will be measured using Multiplex ELISA. Samples will be processed on site at Imperial 
College London and any remaining samples will be stored for future use by the research team but 
will not be transferred out of Imperial College London.  
 

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11. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING 
Throughout the course of the study, every effort must be made to remain alert to possible adverse 
events (AEs).  If an AE occurs, the first concern should be for the safety of the subject.  If 
necessary, appropriate medical intervention will be provided. At the signing of the ICF, each 
subject or his/her legally authorized representative and/or main caregiver  must be given the 
names and telephone numbers of study site staff for reporting AEs and medical emergencies. 
11.1. 
Definitions 
11.1.1. 
Adverse Event (AE) 
The present study is observational. No drugs will be given as a therapeutic intervention. 
Therefore, only adverse reactions related to study procedures including PET and MRI scanning, 
blood sampling and clinical examination will be recorded.  
11.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that  
 results in death 
 in the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred in 
a more severe form, might have caused death 
 requires inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity, or 
 results in a congenital anomaly/birth defect. 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
11.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the study site must document all of the following: 
 The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 
 The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 

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Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment. 
 The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.  
If a subject is hospitalized due to local requirements for administration of standard of care, the 
hospitalization should not be considered an SAE unless one of the requirements in Section 11.1.2 
is met. 
11.2. 
Safety Classifications 
11.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria of an SAE as defined in Section 11.1.2 
 The relationship of the event to study intervention as defined in Section 11.2.1  
 The severity of the event as defined in Section 11.2.2 
11.2.2. 
Severity of Events  
The following definitions should be considered when evaluating the severity of AEs and SAEs:  
Severity of Event 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s) but may be given because of personality of subject. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
11.3. 
Monitoring and Recording Events 
11.3.1. 
Adverse Events 
Adverse events will be collected during the period between informed consent and  7 days after  
the second follow-up visit (about 90+7 days after the index stroke). :  
  
11.3.2. 
Serious Adverse Events 
Any SAE experienced by a subject after the subject signs the informed consent form (ICF) and 
before the final follow-up visit is to be recorded on an SAE Form. For reporting timelines and 
procedures, see Section 11.3.3. 

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Subjects will be followed for all SAEs until 7 days after the second MRI and PET scan (i.e. 
90days after the index stroke)  
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. 
11.3.3. 
Immediate Reporting of Serious Adverse Events 
The Investigator will notify the local ethics committee per local requirements and report 
applicable events to Heath Authorities as required by local legislation.  
The study site must formally notify Biogen SABR within 24hours of the study site staff 
becoming aware of the SAE. It is the Sponsor-Investigator’s responsibility to ensure that the 
SAE reporting information and procedures are used and followed appropriately. Site Principal 
Investigators must report SAE to the Sponsor-Investigator within 24 hours of becoming aware of 
the event. 
11.3.4. 
Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded and 
reported on the appropriate CRF.  All causes of death must be reported as SAEs.  The 
Investigator should make every effort to obtain and send death certificates and autopsy reports to 
Biogen SABR.  
11.4. 
Procedures for Handling Special Situations 
11.4.1. 
Reporting Pregnancy 
The Investigator should refer to the approved local label for guidance if female subjects become 
pregnant.  
11.4.2. 
Medical Emergency  
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care. 
11.5. 
Chief Investigator Responsibilities 
The Sponsor- Investigator’s responsibilities include the following (refer to Section 11.3.1for 
details): 
 Review all AEs to determine seriousness and fulfillment of collection criteria  
 Monitor and record all SAEs 
 Determine the onset and resolution dates of each SAE 
 Record all pregnancies. 
 Complete the appropriate form for each SAE and fax or email it to Biogen SABR 
within 24 hours of the study site staff becoming aware of the event. 

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 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen SABR within 24 hours of the study site staff becoming 
aware of new information. 
 Ensure all SAE reports are supported by documentation in the subjects’ medical 
records. 
 Report SAEs Biogen, local ethics committees, Health Authorities, other Investigators 
and entities as required by local law. 
 

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12. 
STATISTICAL CONSIDERATIONS 
12.1. 
Sample Size Justification 
This is a natural disease progression study.  Quantitative data on the uptake in and around 
infarcts and changes over time are not available to base a power calculation on. Therefore, 
sample size has been determined pragmatically, based on feasibility.  The main purpose is to 
pilot characterization of the magnitude and variability of the change in a normalized measure of 
the TSPO radioligand uptake in the target regions between baseline (14 days) and 90 days post 
infarction in untreated patients.  We chose to use a pseudo-reference region quantification as it 
avoids the need for radial artery cannulation in these patients. In addition, this method has a 
significantly better test-retest variability than the fully quantitative methods using metabolite 
corrected arterial plasma input function (~4-5% vs ~20%)..22  .  While such an approach may 
lead to an underestimation of any changes seen,23 due to potential changes in signal in the 
pseudo-reference region, we believe it is justified in this situation where a focal change in signal 
is expected, and will be compensated for by reduced signal variability.  
The magnitude of the signal change between days 14 and 90 is unknown but it is expected that 
changes above 10% will be detectable given the small test/retest variability of [11C]PBR28. 
12.2. 
Analysis Population 
All eligible subjects who have completed at least one PET-MRI scan will be included in the 
analysis 
12.3. 
Methods of Analysis 
In general, summary statistics will be presented. Continuous variables will be summarized using 
descriptive statistics, and categorical variables will be presented using frequency distributions. 
12.4. 
Endpoints Analysis 
PET-derived measures including SUVR in the infarct and peri-infarct area, and ROIs distant 
from the infarct area at Day 15 and Day 90 will be summarized by visit. Various aspects of 
change over time including magnitude, variability and pattern will be assessed. The relationship 
between PET-derived measures and stroke severity (including stroke volume, size, NIHSS) will 
be examined using methods including linear correlation and regression. Also, the relationship 
between PET-derived measures and functional outcomes , markers of systemic inflammation and 
relationship between measures of white matter tract injury and measures of thalamic uptake will 
be explored. 
A detailed statistical analysis plan will be established before the beginning of the analysis. 

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13. 
ETHICAL REQUIREMENTS 
The Sponsor-Investigator must comply with all instructions, regulations, and agreements in this 
protocol and applicable International Conference on Harmonisation (ICH) guidelines and 
conduct the study according to local regulations. The subject’s privacy; physical, mental, and 
social integrity; and the confidentiality of his or her personal information will be strictly 
respected in accordance with the World Medical Association Declaration of Helsinki. 
13.1. 
Ethics Committee 
The Sponsor-Investigator will obtain ethics committee and HRA approval of the protocol, ICF, 
and other required study documents prior to starting the study.   
The Sponsor-Investigator will ensure that all aspects of institutional review are conducted in 
accordance with current governmental regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, tracking number, and ICF version, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol. 
Protocol amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually. At the completion or termination of the study, the investigational site must submit 
a close-out letter to the ethics committee. 
13.2. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative, as applicable, in accordance with local practice and 
regulations.   
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
In addition, subjects who have the capacity should provide their consent to participate in the 
study.  The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines. 
A copy of the signed and dated ICF must be given to the subject.   Confirmation of a subject’s 
informed consent must also be documented in the subject’s medical record prior to any testing 
under this protocol, including screening tests and assessments. 
The signed ICF will be retained with the study records.  Local regulations must be complied with 
in respect to the final disposition of the original (wet signature) and copies of the signed and 
dated ICFs. 

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13.3. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law. 
The subject will not be identified by name in the CRF or in any study reports, and these reports 
will be used for research purposes only.  Ethics committees and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the subject’s 
personal medical data confidential. 
Participants will be assigned a subject number by their recruiting physician and all data collected 
about them during the study will only be recorded under this subject number. A log of the subject 
numbers and the identities of the participants will be securely stored on an NHS Trust computer 
with password protection and will only be accessible by the members of the research team who 
also direct care team members. This will ensure that all participants cannot be identified by the 
research data collected.  
All physical documents will be stored anonymized at Charing Cross Hospital in locked filing 
cabinets with only the research team having access to them. Consent forms will be stored 
separately from the research data. After the end of the study, data will be archived in accordance 
with Imperial College London procedures and it will be stored for a minimum of 10 years.  
The clinical team (Including: study coordinators, Dr’s, PET and MRI technicians) will have 
access to patient details for the scanning procedures. They will enter the demographics of 
participants into the Imanova database. All scans taken will be anonymized at source and 
transferred electronically for storage on NHS Trust computers. Imanova keeps all archived data 
for 30 years.  
Selected individuals at Biogen will have access to anonymized data, such as brain scans. They 
will be securely stored on private company computers in line with the data protection act and 
Biogens own data security protocols. Biogen staff will not see any patient identifiable 
information and will not have the patient identity log to be able to identify patients from their 
study identification numbers.  
13.4. 
Compensation for Injury 
The Sponsor-Investigator must maintain appropriate insurance coverage for clinical trials and 
follow applicable local compensation laws. 
13.5. 
Conflict of Interest 
Investigators should address any potential conflicts of interest with the subject before the subject 
makes a decision to participate in the study. 
13.6. 
Registration of Study and Disclosure of Study Results 
The Sponsor-Investigator will register the study and post study results regardless of outcome on 
a publicly accessible website in accordance with the applicable laws and regulations. 
 

Protocol GBR-TYS-16-11060  
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14. 
ADMINISTRATIVE PROCEDURES 
14.1. 
Study Site Initiation 
Investigators must not screen or enroll any subjects into the study prior to all prerequisite study 
document completion and agreement by the Sponsor-Investigator and Biogen. 
14.2. 
Study Funding 
Biogen will financially support the work of the Sponsor-Investigator as it pertains to the conduct 
of this study.  All financial details are provided in the separate contract(s) between the 
institution, Sponsor-Investigator, and Biogen.   
14.3. 
Study Completion 
The ethics committee must be notified of completion or termination of the protocol.  Within 3 
months of protocol completion or termination, the investigator must provide a final clinical 
summary report to the ethics committee.  The Sponsor-Investigator will maintain an accurate and 
complete record of all submissions made to the ethics committee, including a list of all reports 
and documents submitted.   
14.4. 
Publications 
Details are included in the clinical trial agreement for this study. 

Protocol GBR-TYS-16-11060  
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15. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
15.1. 
External Contract Organizations 
Imanova next to the Hammersmith Hospital of  Imperial College in London has been selected to 
perform all study PET and MRI imaging acquisitions for this study.  
15.2. 
Changes to Final Study Protocol 
All protocol amendments must be submitted to the ethics committee and Regulatory Authorities 
as required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
In the event of a protocol modification, the subject consent form may require similar 
modifications (see Sections 13.1 and 13.2). 
It is the responsibility of the Chief Investigator to agree all revisions to the protocol with Biogen. 
Proposed amendments will be submitted for approval to the sponsor before being submitting to 
the Research Ethics Committee.  
15.3. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
15.4. 
Retention of Study Data 
The minimum retention time for study records will be 10 years, which is Imperial College 
London policy. 
 

Protocol GBR-TYS-16-11060  
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16. 
REFERENCES 
 
1. 
Shichita T, Sakaguchi R, Suzuki M and Yoshimura A. Post-ischemic inflammation in the 
brain. Front Immunol. 2012;3:132. 
2. 
Liesz A, Zhou W, Mracsko E, Karcher S, Bauer H, Schwarting S, Sun L, Bruder D, 
Stegemann S, Cerwenka A, Sommer C, Dalpke AH and Veltkamp R. Inhibition of lymphocyte 
trafficking shields the brain against deleterious neuroinflammation after stroke. Brain : a journal 
of neurology. 2011;134:704-20. 
3. 
Veltkamp R and Gill D. Clinical Trials of Immunomodulation in Ischemic Stroke. 
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 
2016. 
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Chen MK and Guilarte TR. Translocator protein 18 kDa (TSPO): molecular sensor of 
brain injury and repair. Pharmacol Ther. 2008;118:1-17. 
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Thiel A and Heiss WD. Imaging of microglia activation in stroke. Stroke. 2011;42:507-
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Gerhard A, Neumaier B, Elitok E, Glatting G, Ries V, Tomczak R, Ludolph AC and 
Reske SN. In vivo imaging of activated microglia using [11C]PK11195 and positron emission 
tomography in patients after ischemic stroke. Neuroreport. 2000;11:2957-60. 
7. 
Gerhard A, Schwarz J, Myers R, Wise R and Banati RB. Evolution of microglial 
activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. NeuroImage. 
2005;24:591-5. 
8. 
Radlinska BA, Ghinani SA, Lyon P, Jolly D, Soucy JP, Minuk J, Schirrmacher R and 
Thiel A. Multimodal microglia imaging of fiber tracts in acute subcortical stroke. Annals of 
neurology. 2009;66:825-32. 
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Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 33 
Gunn RN and Rabiner EA. Determination of [(11)C]PBR28 binding potential in vivo: a first 
human TSPO blocking study. J Cereb Blood Flow Metab. 2014;34:989-94. 
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2015;35:304-11. 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 34 
17. 
INVESTIGATORS SIGNED AGREEMENT OF STUDY PROTOCOL 
 
 
I have read the foregoing protocol, “TSPO PET as a measure of post-stroke brain inflammation: 
a natural history cohort” and agree to conduct the study according to the protocol and the 
applicable ICH guidelines and local regulations, and to inform all who assist me in the conduct 
of this study of their responsibilities and obligations. 
 
 
 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 35 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX 
 
 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 36 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 37 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 38 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 39 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 40 
 
 
 
 
 
 
 

Protocol GBR-TYS-16-11060  
Version 3.1 
 
TSPO PET as a measure of post-stroke brain inflammation 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of the 
Sponsor-Investigator. 
Page 41