Clinical trial NCT02278354
Conditions: Alzheimer's Disease
Sponsor: Avid Radiopharmaceuticals
Start date: 2015-02-18; Completion date: 2017-02-03
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Subjects enrolled in the Professional Fighters Brain Health Study (PFBHS) will receive flortaucipir to explore its use as a biomarker for brain injury related to repetitive head trauma and to examine the relationship between clinical presentation and tau deposition.

Detailed description:

Arms: arm 1: Active professional fighters (with and without cognitive impairment) receiving a flortaucipir PET scan arm 2: Retired professional fighters (with and without cognitive impairment) receiving a flortaucipir PET scan
Interventions: intervention 1: Flortaucipir F18 intervention 2: Brain PET scan
Intervention descriptions: intervention 1: IV injection, 370 megabecquerel (MBq) (10 mCi) intervention 2: positron emission tomography (PET) scan of the brain 75-105 minutes post injection

Protocol documents:
Prot_000.pdf: 


Protocol 18F-AV-1451-A11: “18F-AV-1451 PET Imaging in Professional Fighters”  
 
 
 
Page 2 of 38 
 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451([F-18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-p
yrido[4,3-b]indole 
Title of Study: 18F-AV-1451-A11 
 
“18F-AV-1451 PET Imaging in Professional Fighters”  
Planned number of subjects (Enrolled): Approximately 30 
 
This study will be divided into the following groups: 
1. Approximately 15 active professional fighters (boxers and mixed martial artists) who have had 
at minimum 10 professional fights. 
a. Approximately 10 with cognitive impairment 
b. Approximately 5 without cognitive or behavioral complaints 
2. Approximately 15 retired professional fighters (boxers and mixed martial artists). 
a. Approximately 10 with cognitive impairment 
b. Approximately 5 without cognitive or behavioral complaints 
 
Subjects will be recruited from the pool of participants in the Professional Fighters Brain Health 
Study (PFBHS).    
Name of compound: 18F-AV-1451([F-18]T807) 
Dose: 370 MBq (10 mCi) 
Route of Administration:  Intravenous (IV) bolus 
Study Phase:  I 
Study Centers:  1-3 centers in the United States 
Trial Objectives:  
The primary objectives of this study are: 
• To explore the use of 18F-AV-1451 as a biomarker for brain injury related to repetitive head 
trauma; and 
• To examine the relationship between clinical presentation and tau deposition as measured 
by 18F-AV-1451 uptake in active and retired professional fighters. 
 
A secondary objective of this study is: 
• 
To expand the 18F-AV-1451 safety database. 
Eligibility: 
Only subjects duly consented and enrolled in the PFBHS protocol (conducted by the Cleveland Clinic 
with Dr. Charles Bernick as Principal Investigator) will be considered for participation in this study 
(see Section 5.3, Selection of Subjects).  
 


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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451([F-18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-p
yrido[4,3-b]indole 
Study Design: 
This is a phase I study that will evaluate imaging characteristics of 18F-AV-1451 in active and retired 
professional fighters enrolled in the PFBH study.  
 
Subjects enrolled in the PFBH study will be contacted to participate and must provide informed 
consent before starting any 18F-AV-1451-A11 study procedures. In addition to consenting to study 
procedures, participants will consent to have Magnetic Resonance Imaging (MRI) images/data, 
including volumetric, functional and standard clinical sequences, and cognitive/behavioral data as 
part of the PFBHS made available to this study to allow for analysis and comparison. Screening 
assessments may take place over several days, within 90 days of the 18F-AV-1451 Positron Emission 
Tomography (PET) scan, and will include demographic information, cognitive testing and safety 
assessments. Subjects may be permitted to return for the 18F-AV-1451 PET scan after the 90 day 
window with sponsor approval if the investigator does not recognize any significant medical changes. 
If a volumetric MRI has not been performed as part of PFBHS within six months of the 18F-AV-1451 
PET imaging visit, a volumetric MRI is to be performed as part of this study’s screening assessments. 
 
Subjects who qualify for the study will return to the clinic at a later date for the 18F-AV-1451 PET 
imaging visit. For the 18F-AV-1451 PET imaging visit, an intravenous catheter will be placed for IV 
administration of 18F-AV-1451 Injection.  Subjects will receive a single IV bolus injection with a 
target dose of 370 MBq (10 mCi) of 18F-AV-1451 Injection followed by a saline flush. At 
approximately 75 minutes following injection, a continuous 30-minute brain scan will begin. Adverse 
events will be monitored continuously during the imaging session. A physician or a 
licensed/credentialed medical professional (i.e., a PET technologist, imaging center nurse or a 
regional equivalent) designated by the site principal investigator must assess or evaluate the subject 
prior to injection and prior to discharge from the imaging center. If a designee performs this activity, 
a physician must be available to provide medical consultation. 
 
All professional fighters > 50 years of age and other participants in whom, and in the opinion of the 
investigator, the clinical presentation suggests a possible diagnosis of Alzheimer’s disease (AD) will 
return to the clinic for a florbetapir F 18 PET imaging visit. The PET imaging visits must be 
performed no more than 60 days apart. For the florbetapir F 18 PET imaging visit, an intravenous 
catheter will be placed for IV administration of Florbetapir F 18 Injection. Subjects will receive a 
single IV bolus injection target dose of 370 MBq (10 mCi) of Florbetapir F 18 Injection followed by a 
saline flush. At approximately 50 minutes following injection, a continuous 10-minute brain scan will 
begin. Adverse events will be monitored continuously during the imaging session. A physician, or 
physician designee, must evaluate the subject for adverse events prior to injection and prior to 
discharge from the imaging center. 
 
A follow-up phone call to the subject, or informant where applicable, will be conducted between 2 or 
3 business days of each imaging day, but not before 48 hours post-injection, to confirm subject 
well-being and to collect information about any new adverse events.  If both of these days are not 
business days, the follow-up phone call can occur the following business day. 


Protocol 18F-AV-1451-A11: “18F-AV-1451 PET Imaging in Professional Fighters”  
 
 
 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451([F-18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-p
yrido[4,3-b]indole 
 
Analyses will explore the relationship among 18F-AV-1451 uptake measurements, florbetapir SUVR 
(where applicable), cognitive and neuropsychiatric measurements, and other collected biomarkers in 
subjects, and will explore if the 18F-AV-1451 uptake measurements are different across patient 
enrollment groups. 
Assessments and Endpoints: 
All subjects will have a screening visit, a 18F-AV-1451 PET imaging visit, and a follow-up phone call 
after the imaging visit. All professional fighters > 50 years of age and other participants in whom, and 
in the opinion of the investigator, the clinical presentation suggests a possible diagnosis of AD will 
also have a florbetapir F 18 PET imaging visit and a follow-up phone call after the imaging visit.  
 
Details of additional assessments that will be performed at each visit are detailed in Section 7.1.   
Statistical Methods:   
Descriptive Statistics will be applied to describe the 18F-AV-1451 uptake and florbetapir SUVR 
distribution by subject enrollment groups (active/retired professional fighters and cognitive 
impaired/normal). ANOVA test, or comparable non-parametric tests such as Kruskall-Wallis test 
when ANOVA’s pre-requisites are not met, will be conducted to detect the differences 
in 18F-AV-1451 uptake measurements across the enrollment groups. If an overall difference is 
detected, then a two sample t-test, or Wilcoxon rank sum test when the pre-requisite of t-test is not 
met, will be applied to test if there are differences seen in 18F-AV-1451 uptake measurements 
between pair-wised enrollment groups.  Additional exploratory analyses will be applied to explore the 
relationship among 18F-AV-1451 uptake measurements, cognitive and neurological measurements, 
and other collected biomarkers in the study subjects.  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 18F-AV-1451-A11: “18F-AV-1451 PET Imaging in Professional Fighters”  
 
 
 
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TABLE OF CONTENTS 
 
 
 
 
 
 
 
  Page 
 
            ABBREVIATIONS AND DEFINITIONS                                                         7              
 
1. 
INTRODUCTION 
10 
 
2. 
TRIAL OBJECTIVES 
12 
 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 
12  
 
4. 
TEST DRUG AND CONTROL AGENTS 
13 
4.1 
Descriptive Name:  18F-AV-1451                     
13 
4.2 
Descriptive Name:  Florbetapir F 18              
13 
4.3 
Radioactive Labeling                                     
13 
4.4 
Decay Characteristics                                                                             13 
4.5 
Formulation and Dose Florbetapir F 18 Injection 
14  
4.6 
Formulation and Dose 18F-AV-1451 Injection 
14 
4.7 
Packaging Florbetapir F 18 Injection  
15 
4.8 
Packaging 18F-AV-1451 Injection                                                          15 
4.9 
Storage and Handling Florbetapir F 18 Injection                       
15 
4.10 
Storage and Handling 18F-AV-1451 Injection     
15 
 
5. 
INVESTIGATIONAL PLAN                                                                          15 
5.1 
Overall Design and Plan of Trial                                                            15 
5.2 
Planned Dosage and Duration of Treatment 
16 
5.2.1 Dosage and Administration 
16 
5.2.2 Rationale for Dosage 
17 
5.3 
Selection of Subjects 
17 
5.3.1 Inclusion Criteria 
17 
5.3.2 Exclusion Criteria 
18 
5.4 
Prior and Concomitant Therapy 
18 
5.5 
Removal of Subjects from Trial 
18 
5.6 
Premature Termination of Trial/Closure of Center 
19 
 
6. 
WARNINGS/PRECAUTIONS 
19 
 
7. 
PROCEDURES AND METHODS 
19 
7.1 
Assessment Periods 
19 
7.1.1 Screening Visit 
19 
7.1.2 Imaging Visit(s) 
20  
7.2 
Observations and Measurements 
21 
7.3 
Protocol for Image Collection 
24 
7.4 
Good Clinical Practice and Monitoring 
24 
7.5 
Informed Consent and Subject Information 
24 
7.6 
Documentation  
25 


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7.7 
Adverse Events 
25 
7.7.1 Adverse Event Monitoring 
26 
7.7.2 Adverse Event Definitions 
26 
7.7.3 Adverse Event Documentation 
28 
7.7.4 Reporting of Serious Adverse Events 
28 
 
8. 
STATISTICAL ANALYSIS                                                                              29 
8.1 
General Statistical Considerations                                                          29 
8.2 
Safety Analysis 
29 
8.3 
Image Analysis 
30 
 
9. 
USE OF DATA AND PUBLICATION 
30 
 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
31 
10.1 
Institutional Review Board (IRB) 
31 
10.2 
Informed Consent 
31 
10.3 
Protocol Adherence 
31 
10.4 
Documents Necessary for Initiation of the Trial 
31 
10.5 
Study Drug Control 
32 
10.6 
Data Collection 
32 
10.7 
Adverse Events 
32 
10.8 
Records Retention 
33 
 
11. 
APPENDICES 
34  
11.1 
References 
34 
11.2 
Trial Flow Chart 
36 
 
INVESTIGATOR STATEMENT 
37 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AD 
ADR 
Alzheimer’s disease 
Adverse Drug Reaction 
Adverse Event 
(AE) 
 
amu 
ANOVA 
Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. 
Atomic mass unit 
A collection of statistical models used to analyze the differences between 
group means and their associated procedures 
Audit 
 
 
 
 
β+ 
A systematic and independent examination of the trial-related activities 
and documents to determine whether the evaluated trial-related activities 
were conducted, and the data were recorded, analyzed, and accurately 
reported according to the protocol, applicable standard operating 
procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s). 
Beta decay 
Case Report Form 
(CRF) and 
electronic Case 
Report Form 
(eCRF) 
A printed or electronic form for recording study participants’ data during a 
clinical study, as required by the protocol. 
CNS 
Central Nervous System 
CRO 
Contract Research Organization: A person or organization (commercial, 
academic, or other) contracted by the sponsor to perform one or more of the 
sponsor’s trial-related duties and functions.  
CTE 
ECG 
 
EDTA 
Chronic Traumatic Encephalopathy 
Electrocardiogram 
 
(ethylenediaminetetraacetic acid) is the most commonly used 
anticoagulant in evacuated tubes 
Efficacy 
 
 
Efficacy is the ability of a treatment to achieve a beneficial intended result. 
 
End of Synthesis 


Protocol 18F-AV-1451-A11: “18F-AV-1451 PET Imaging in Professional Fighters”  
 
 
 
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EOS 
FDA 
US Food and Drug Administration  
FDG 
18F - Fluorodeoxyglucose 
GCP 
hERG 
IB 
 
Good Clinical Practice 
human Ether-à-go-go-Related Gene 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
Institutional 
Review Board 
/Independent 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that the 
safety, welfare and human rights of the subjects participating in a clinical 
study are protected. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
IV 
Intravenous 
Kd 
keV 
Dissociation Constant 
Kiloelectronvolt 
MBq 
 
Megabecquerel 
 
mCi 
MedDRA 
Millicurie 
Medical Dictionary for Regulatory Activities 
MHD 
MMSE 
 
Maximum Human Dose 
Mini-Mental State Examination 
MRI 
Magnetic Resonance Imaging 
mSv 
 
MW 
N 
Millisivert, a derived unit of ionizing radiation dose in the International 
System of Units 
Molecular weight 
Number, or total 


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NDA 
NLT 
NORM-JECT® 
New Drug Application 
Not Less Than 
syringes which are latex-free, contain no rubber, no silicone oil, styrene or 
DEHP and are DNA-free 
NOAEL 
No Observable Adverse Effect Level 
PET 
PFBHS 
pH 
PHF tau 
PhRMA 
Positron Emission Tomography 
Professional Fighters Brain Health Study 
a measure of the acidity or basicity of an aqueous solution 
Paired Helical Filament tau 
Pharmaceutical Research and Manufacturers of America 
v/v 
QT 
 
QTcF 
 
Percentage solution 
A measure of the time between the start of the Q wave and the end of the T 
wave 
Fredericia's repolarization correction formula of the QT interval 
 
SAP 
SAS 
SD 
Serious Adverse 
Event (SAE) 
 
 
 
SOP 
Statistical Analysis Plan 
Statistical Analysis System 
Standard Deviation 
A SAE is an AE that results in one of the following outcomes or constitutes 
one of the following events: death, Initial or prolonged inpatient 
hospitalization, life-threatening experience (that is, immediate risk of 
dying); Persistent or significant disability/incapacity; Congenital 
anomaly/birth defect; Considered significant by the investigator for any 
other reason. 
Standard Operating Procedure 
 
SUVR 
SOC 
TBI 
TdP 
 
 
Standard Uptake Value Ratio 
System Organ Class 
Traumatic Brain Injury 
Torsades de Pointes 
 
 
 


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1. INTRODUCTION  
Traumatic brain injury (TBI) is a major public health concern with 1.7 million people 
in the United States suffering a TBI each year (Faul et al., 2010).  There is longstanding 
evidence linking a history of TBI to increased risk for Alzheimer’s disease (AD) 
(Graves et al., 1990), and emerging concern that a single TBI could initiate long-term 
processes leading to dementia that is independent of AD (Johnson et al., 
2010).  Pathologically, amyloid-beta (Aβ) deposits have been identified following a 
single TBI in approximately 30% of patients (Huber et al., 1993; Ikonomovic et al., 
2004).   Plaques found acutely following TBI are typically diffuse, in contrast to the 
thioflavine-S-positive neuritic plaques characteristic of AD.  Thus far, neurofibrillary 
tangles (NFTs) have not been identified following a single TBI in humans; although the 
neuropathological evidence is sparse, with the only study examining this issue limited 
to patients dying within 4 weeks of injury (Smith et al., 2003). 
 
Emerging research suggests that tau pathology similar to that seen in Alzheimer’s 
disease may be more likely after even a single TBI episode (Johnson et. al, 2012). 
Chronic repetitive TBI has been linked to the pathological entity known as chronic 
traumatic encephalopathy (CTE).  CTE is a clinic-pathological entity characterized 
post mortem by tau pathology that has been linked to individuals exposed to repetitive, 
often mild or concussive, head injury such as boxers (Corsellis et al., 1973;  Dale et al. 
1991; Geddes et al., 1999) and professional football players (McKee et al., 2009; 
McKee et al., 2013). 
 
The Professional Fighters Brain Health Study (PFBHS) being conducted at the 
Cleveland Clinic Lou Ruvo Center for Brain Health is a longitudinal study that focuses 
on a sample of active and retired professional fighters, and compares them with a 
control cohort matched for age and level of education. The primary objective of the 
PFBHS is to determine the relationship between measures of head trauma exposure and 
other potential modifiers and changes in brain imaging, neurological and behavioral 
function over time (Bernick, 2013).  In this context, the addition of an imaging 
biomarker that could identify the presence of underlying tau pathology might be useful 
in understanding the etiology and evolution of CTE, and could potentially identify 
cases at risk for subsequent neurodegeneration or other clinically important outcomes 
with implications for management of CTE and/or TBI cases.     
 
18F-AV-1451 (originally named [F-18]T807 by Siemens Molecular Imaging 
Biomarker Research group) has been developed as a positron emitting 
radiopharmaceutical for in vivo imaging of tau protein aggregates (Xia et al., 2013).  
Autoradiography results using tissue sections from human brains showed a strong 
signal in the grey matter of cortical slices from tau positive brains, but weak or no 
binding in tau negative, Aβ positive, or tau and Aβ negative tissue.  Scatchard analysis 
based on this heterogeneous autoradiography assay yielded an estimated Kd of 15nM. 
A saturation binding experiment using purified PHF tau isolated from brains of AD 
patients yielded a Kd value of 0.54 nM. 
 


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AV-1451 was assessed in competitive binding assays against a panel of 72 of the most 
common central nervous system (CNS) targets and no clinically relevant inhibition was 
seen.   AV-1451 was positive in the in vitro hERG assay; however, in vivo 
cardiovascular safety pharmacology assessments in dogs showed no evidence of QT 
prolongation at doses up to 50x the intended maximum human dose (MHD).  
Nonetheless, until sufficient human cardiovascular safety data are available, initial 
clinical studies will exclude subjects with a history of risk factors for Torsades de 
Pointes and subjects taking drugs known to prolong the QT interval. 
In vivo safety pharmacology studies were also conducted in rats to determine potential 
effects on the CNS and respiratory systems. In these studies no clinically relevant 
effects were reported at doses exceeding 100x the intended MHD. Additionally, 
non-radioactive AV-1451 has been tested in single and repeat dose toxicology studies 
in rat and dog.  In each of these studies the no observable adverse effect levels 
(NOAELs) were the highest doses tested (150x MHD for single, 50x MHD for repeat).   
Potential genotoxicity of non-radioactive AV-1451 was tested in both in vitro and in 
vivo assays.  In the in vitro assays, AV-1451 tested positive for potential genotoxicity.   
However, in the in vivo rat micronucleus assay at doses up to 750x MHD (scaled 
allometrically), AV-1451 showed no evidence of genotoxicity. The different results in 
the in vitro genotoxicity assays and the in vivo micronucleus study are likely related to 
differences in the exposure conditions encountered by the target cells in the different 
test systems. In vivo, AV-1451 is cleared rapidly; however, the in vitro experiments 
employ static, prolonged exposure of cells to high concentrations of the test article. 
While the in vitro data show the potential for genotoxicity, the in vivo data provide 
assurance that genotoxicity is unlikely to occur at clinically-relevant doses for human 
diagnostic studies. 
Human dosimetry has been obtained in nine subjects.  Generally, the radiotracer 
distribution was consistent among the subjects and showed rapid hepatobiliary 
clearance.  There were three organs that received estimated doses higher than 0.05 
mSv/MBq. The organ that received the largest estimated dose was the upper large 
intestinal wall (0.0962 ± 0.0134 mSv/MBq), followed by the small intestine and the 
liver.  The Effective Dose was 0.0241 ± 0.0016 mSv/MBq. This results in an estimated 
Effective Dose of 8.92 mSv for an anticipated 370 MBq (10 mCi) injection and is 
comparable to the effective dose of approved 18F-labeled compounds such as 
fluorodeoxyglucose (FDG) and florbetapir F 18 injection. 
 
18F-AV-1451 may be useful as a marker of tau pathology in patients with AD and other 
neurodegenerative disorders (Figures 1 and 2).  Several preliminary studies 
using 18F-AV-1451 have been completed (e.g., Chien et al., 2013). Based on this 
rationale, the goal of this protocol is to perform 18F-AV-1451 PET imaging on active 
and retired professional fighters enrolled in the PFBHS protocol and explore its 
potential as a biomarker for brain injury related to repetitive head trauma.    
 


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Figure 1: 5
 female control subject (MMSE = 29) 
 
Figure 2: 
d male AD subject (MMSE = 18) 
2. TRIAL OBJECTIVES 
 
The primary objectives of this study are: 
 
• To explore the use of 18F-AV-1451 as a biomarker for brain injury related to 
repetitive head trauma; and 
• To examine the relationship between clinical presentation and tau deposition as 
measured by 18F-AV-1451 uptake in active and retired professional fighters. 
 
     A secondary objective of this study is: 
• To expand the 18F-AV-1451 safety database.  
 
3. SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 
 
The trial is sponsored by: 
 
Avid Radiopharmaceuticals 
3711 Market Street, 7th Floor 
Philadelphia, PA 19104 
Phone: +1 215-298-0700 
 
The medical contact is: 
 


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1-3 centers in the United States will participate in this trial. 
 
4. TEST DRUG AND CONTROL AGENTS  
 
4.1 Descriptive Name:  18F AV-1451  
  
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole  
 
MW = 262.27 amu 
 
 
4.2  Descriptive Name:  Florbetapir F 18     
4-[(1E)-2-[6-[2-[2-[2-(fluoro-18F)ethoxy]ethoxy]ethoxy]-3-pyridinyl]ethenyl]-N-
methyl- benzenamine 
 
 
 
 
 
 
MW= 359.4 amu 
 
4.3 Radioactive Labeling 
      The compounds are labeled with [18F] fluorine that decays by positron (β+) 
emission and has a half-life of 109.77 min.  The principal photons useful for 
diagnostic imaging are the 511 keV gamma photons, resulting from the interaction 
of the emitted positron with an electron. 
 
4.4 Decay Characteristics 
 
 
The time course of radioactive decay for Fluorine [18F] is shown below. 
 
N
N 
H 
O 
O 
O 
1 8 F 
1 8 F-AV-45


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Min. 
Fraction Remaining 
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
 
       
Physical decay chart for Fluorine [18F].  Half-life = 109.77 min. 
 
4.5 Formulation and Dose Florbetapir F 18 Injection 
 
Drug Product is formulated in 10% v/v ethanol, USP, 0.45% sodium ascorbate, 
USP, in 0.9% sodium chloride injection, USP.  Subjects will receive a single IV 
administration of approximately 370 MBq (10 mCi) of Florbetapir F 18 Injection 
immediately prior to imaging.  The mass dose of florbetapir in each human dose 
will be ≤ 50 µg (0.14 μmol) per 10 mCi dose in total volume not exceeding 10 mL.  
Florbetapir F 18 Injection expires at 10 hours post End-of-Synthesis (EOS) or when 
either the strength or specific activity shelf-life specifications (Not less than (NLT) 
37 MBq/mL (1 mCi/ml) or NLT 7.4 MBq/µg (0.2mCi/ μg), respectively) are met, 
whichever is soonest.   
 
Florbetapir F 18 Injection will be supplied from manufacturing facilities approved     
for commercial distribution under NDA 202-008. 
 
4.6 Formulation and Dose 18F-AV-1451 Injection 
18F-AV-1451 Injection is a clear solution containing 18F-AV-1451 (drug substance) 
formulated for intravenous bolus administration. Depending on the 
manufacturer, 18F-AV-1451 Injection will be formulated in: 
• aqueous 21 mM sodium phosphate solution containing up to 10% (v/v) 
ethanol, or  
• a solution containing  10% (v/v) ethanol, USP in 0.9% sodium chloride 
injection, USP. 
 
Drug product of either formulation is manufactured to meet one common set of 
specifications. 
 
The expiration time and date of 18F-AV-1451 Injection are provided on the outer 
label of each dose based on specific activity or strength. 18F-AV-1451 Injection 
should be stored at room temperature. 
 
 


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4.7 Packaging Florbetapir F 18 Injection 
Unit doses of Drug Product may be contained in a sterile, apyrogenic 10, 30 or 50 
mL clear Type I Borosilicate glass serum vial closed with a 20 mm Fluro 
Tec®-coated 4432/50-B2-40 gray elastomeric closure sealed with a 20 mm 
aluminum crimp seal, manufactured by Allergy Laboratories or may be contained 
in 2 mL, 5 mL, or 10 mL sterile apyrogenic NORM-JECT® 
polypropylene/high-density polyethylene syringes.  
 
4.8 Packaging 18F-AV-1451 Injection 
 
Each package of 18F-AV-1451 Injection includes a sterile apyrogenic sealed glass 
vial or sterile apyrogenic syringe containing 18F-AV-1451 Injection, a surrounding 
protective lead shield canister, and an outside delivery case. 
4.9 Storage and Handling Florbetapir F 18 Injection 
Florbetapir F 18 Injection is stored at 25ºC; excursions permitted to 15-30ºC. The 
product does not contain a preservative.  Florbetapir F 18 Injection should be stored 
within the original container or equivalent radiation shielding.  Florbetapir F 18 
Injection must not be diluted. 
4.10 
Storage and Handling 18F-AV-1451 Injection 
18F-AV-1451 Injection is stored at room temperature. 18F-AV-1451 Injection 
should be stored within the original container or equivalent radiation 
shielding.  18F-AV-1451 Injection must not be diluted. 
5. INVESTIGATIONAL PLAN 
5.1 Overall Design and Plan of Trial 
This is a phase I study that will evaluate imaging characteristics of 18F-AV-1451 in 
active and retired professional fighters enrolled in the PFBH study.  
Subjects enrolled in the PFBH study will be contacted to participate and must 
provide informed consent before starting any 18F-AV-1451-A11 study procedures. 
In addition to consenting to study procedures, participants will consent to have 
Magnetic Resonance Imaging (MRI) images/data, including volumetric, functional 
and standard clinical sequences, and cognitive/behavioral data as part of the 
PFBHS made available to this study to allow for analysis and comparison. 
Screening assessments may take place over several days, within 90 days of 
the 18F-AV-1451 PET scan, and will include demographic information, cognitive 
testing and safety assessments. Subjects may be permitted to return for 
the 18F-AV-1451 PET scan after the 90 day window with sponsor approval if the 
investigator does not recognize any significant medical changes. If a volumetric 
MRI has not been performed as part of PFBHS within six months of 
the 18F-AV-1451 PET imaging visit, a volumetric MRI is to be performed as part of 
this study’s screening assessments.   


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Subjects who qualify for the study will return to the clinic at a later date for 
the 18F-AV-1451 PET imaging visit. For the 18F-AV-1451 PET imaging visit, an 
intravenous catheter will be placed for IV administration of 18F-AV-1451 Injection.  
Subjects will receive a single IV bolus injection with a target dose of 370 MBq (10 
mCi) of 18F-AV-1451 Injection followed by a saline flush. At approximately 75 
minutes following injection, a continuous 30-minute brain scan will begin. Adverse 
events will be monitored continuously during the imaging session. A physician or a 
licensed/credentialed medical professional (i.e. a PET technologist, imaging center 
nurse or a regional equivalent) designated by the site principal investigator must 
assess or evaluate the subject prior to injection and prior to discharge from the 
imaging center. If a designee performs this activity, a physician must be available 
to provide medical consultation.  
All professional fighters > 50 years of age and other participants in whom, and in 
the opinion of the investigator, the clinical presentation suggests a possible 
diagnosis of AD will return to the clinic for a florbetapir F 18 PET imaging visit. 
The PET imaging visits must be performed no more than 60 days apart. For the 
florbetapir F 18 PET imaging visit, an intravenous catheter will be placed for IV 
administration of Florbetapir F 18 Injection. Subjects will receive a single IV bolus 
injection target dose of 370 MBq (10 mCi) of Florbetapir F 18 Injection followed 
by a saline flush. At approximately 50 minutes following injection, a continuous 
10-minute brain scan will begin. Adverse events will be monitored continuously 
during the imaging session. A physician, or physician designee, must evaluate the 
subject for adverse events prior to injection and prior to discharge from the imaging 
center. 
 
A follow-up phone call to the subject, or informant where applicable, will be 
conducted between 2 or 3 business days of each imaging day, but not before 48 
hours post-injection, to confirm subject well-being and to collect information about 
any new adverse events.  If both of these days are not business days, the follow-up 
phone call can occur the following business day. 
   
Analyses will explore the relationship among 18F-AV-1451 uptake measurements, 
florbetapir SUVR (where applicable), cognitive and neuropsychiatric 
measurements, and other collected biomarkers in subjects, and will explore if 
the 18F-AV-1451 uptake measurements are different across patient enrollment 
groups. 
 
5.2 Planned Dosage and Duration of Treatment 
 5.2.1 Dosage and Administration 
 
18F-AV-1451: 
 
All subjects will receive a single IV bolus administration of approximately 370 
MBq (10 mCi) of 18F-AV-1451 Injection. 


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Florbetapir F 18: 
 
Subjects will receive a single IV bolus administration of approximately 370 
MBq (10 mCi) of Florbetapir F 18 Injection. 
 
 
 5.2.2 Rationale for Dosage  
 
18F-AV-1451 will be administered IV in a radioactive dose of 370 MBq (10 
mCi) with a maximum human dose (MHD) limited to 20 µg of compound by 
weight.  This dose is 150 fold lower than the NOAEL observed in the rat single 
dose toxicity study and is 50 fold lower than the NOAEL observed in the rat and 
dog repeat dose toxicity studies. 
 
Human dosimetry has been obtained in nine subjects. The results estimated an 
Effective Dose of 8.92 mSv for an anticipated 370 MBq (10 mCi) injection and 
is comparable to the effective dose of approved 18F-labeled compounds such as 
FDG and florbetapir F 18 injection. 
 
The proposed dose has been shown to have acceptable image quality in 
previous human studies. No treatment related adverse events have been 
reported using this regimen.   
 
5.3 Selection of Subjects 
 
5.3.1 
Inclusion Criteria 
 
All subjects must meet all of the following criteria to enroll in this trial: 
 
1. Males that have consented, are currently enrolled in the PFBHS protocol, 
and have participated in a minimum of 10 professional fights; 
2. Can tolerate PET scan procedures; and 
3. Have the ability to provide informed consent for study procedures (if the 
patient is ineligible to give informed consent, based on local standards, the 
patient’s legal representative may consent on behalf of the patient, but the 
patient must still confirm assent). 
 
Subjects with cognitive impairment should meet the following criteria: 
 
1. Have subjective cognitive complaints or objective decline or impairment as 
determined by the investigator.  
 
 


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5.3.2 
Exclusion Criteria 
 
Subjects will be excluded from enrollment if they: 
1. Have behavior dysfunction that is likely to interfere with imaging. The 
investigator should carefully consider whether subjects with behavior 
dysfunction will be able to complete the imaging session(s) and may be 
enrolled only after discussion and with approval of the sponsor;  
2. Are claustrophobic or otherwise unable to tolerate the imaging procedure 
(use of mild sedatives are permitted to manage claustrophobia); 
3. Have current clinically significant cardiovascular disease, or clinically 
significant abnormalities on screening ECG (including but not limited to 
QTcF>450 msec. Subjects with QTcF>450 msec in the presence of bundle 
branch block may be enrolled after discussion with sponsor); 
4. A history of additional risk factors for Torsades de Pointes (TdP) (e.g.,  
heart failure,  hypokalemia, family history of Long QT syndrome) or are taking 
drugs that are known to cause QT-prolongation (a list of prohibited and 
discouraged medications is provided by the Sponsor); 
5. Have a current clinically significant infectious disease, endocrine or 
metabolic disease, pulmonary, renal or hepatic impairment, or cancer that the 
investigator believes would affect study participation or scan results; 
6. Have had a non-study related radiopharmaceutical imaging or treatment 
procedure within 7 days prior to the 18F-AV-1451 imaging session;  
7. Have current drug or alcohol dependence or alcohol dependence within the 
past 2 years; and 
8. In the opinion of the investigator, are otherwise unsuitable for a study of 
this type. 
 
5.4 Prior and Concomitant Therapy 
 
Except as noted in the exclusion criteria, all medications (prescription or 
over-the-counter) that have been started prior to screening may be continued during 
the course of the trial.  All medications, including investigational medications that 
are continued from the start of the trial, or that are started during the trial (other than 
the study medication), must be documented on the Concomitant Medication Page 
of the electronic Case Report Form (eCRF).   
 
5.5 Removal of Subjects from Trial 
 
Subjects must be removed from the trial if: 


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1. Informed consent is withdrawn; or 
2. The investigator or the sponsor believes it is in the best interest of the subject to 
be removed from the trial.   
Subjects may be withdrawn from the trial if a SAE occurs. The date and reason for 
discontinuation should be noted on the eCRF. Subjects who discontinue 
prematurely should be seen for a final evaluation.  
 
5.6 Premature Termination of Trial/Closure of Center 
 
The sponsor may discontinue the trial at any time.  Reasons for discontinuation of 
the trial may include, but are not limited to, new information on safety or efficacy, 
requests from regulatory authorities, or changes in business priorities.  Additional 
reasons for center closure may include, but are not limited to, excessive protocol 
violations, inadequate regard for subject safety, failure to follow recommended 
procedures (e.g., documentation), failure or inability to accommodate 
Avid/Contract Research Organization (CRO) monitors or to provide required 
access to data and source documents, staff turnover, inadequate staffing, and 
inadequate enrollment.  Except in cases affecting subject safety, the investigator 
may complete final study evaluations for ongoing subjects. In all cases of center, or 
study termination, appropriate steps will be taken to ensure the safety of study 
subjects. 
6. WARNINGS/PRECAUTIONS 
 
The most up-to-date and complete information regarding the use of 18F-AV-1451 
Injection can be found in the investigator's brochure.  
 
In brief, 18F-AV-1451 Injection is an experimental imaging agent that will be used at 
relatively low (tracer) doses.  Because 18F-AV-1451 Injection is under clinical 
investigation, it is recommended that subjects receiving 18F-AV-1451 Injection be 
followed closely by means of adverse event reporting. 
 
There are no data on the effects of 18F-AV-1451 Injection in human perinatal 
development.  For this reason, males enrolled in this study must agree to use adequate 
contraceptive methods, if they engage in sexual activity for at least 90 days after 
administration of 18F-AV-1451 Injection.   
 
7. PROCEDURES AND METHODS 
 
7.1 Assessment Periods (See Section 11.2, Trial Flow Chart) 
       
 
The study will consist of the following sequence of activities:  
 
7.1.1 
Screening Visit: 


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Subjects currently enrolled in the PFBH study protocol will be contacted to 
participate. Screening assessments may take place over several days, within 90 
days of the 18F-AV-1451 PET scan, and will include: 
• Informed Consent will take place before any 18F-AV-1451-A11 study 
procedures; 
• Demographics (birth year, gender, race, ethnicity, education, alcohol, drug 
use and smoking); 
• Medical history and concomitant medications; 
• Safety assessments: Vital signs (pulse rate, respiratory rate, supine blood 
pressure, height and weight), ECG (with results reviewed prior 
to 18F-AV-1451 administration), and safety labs (hematology, chemistry 
and urinalysis) including plasma thiamine (vitamin B1) level;  
• Mini-Mental State Examination (MMSE); 
• Digit span forward and backward;  
• Beck Depression Inventory II;  
• If a volumetric MRI has not been performed as part of PFBHS within six 
months of the 18F-AV-1451 PET imaging visit, a volumetric MRI is to be 
performed as part of this study’s screening assessments; and  
• A physician will see the subject during the screening assessments.   
 
7.1.2 
Imaging Visit(s)  
 
18F-AV-1451 PET Imaging Visit 
• A physician or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by 
the site principal investigator must assess or evaluate the subject prior to 
administration of 18F-AV-1451 Injection to determine if they are still 
suitable to undergo the scan. If a designee performs this activity, a 
physician must be available to provide medical consultation; 
• Vital signs will be taken (pulse rate, respiratory rate, supine blood pressure) 
at the following time points: 
 Prior to administration of 18F-AV-1451 Injection (Weight will also 
be collected) 
 Within 5 minutes after completion of injection of 18F- AV-1451 
Injection 
 After completion of the PET scan prior to discharge; 
• Subjects will receive a single IV bolus injection target dose of 370 MBq (10 
mCi) of 18F-AV-1451 Injection followed by a saline flush.  
• At approximately 75 minutes following injection, a continuous 30-minute 
brain scan will begin;   
• The injection site will be observed for excessive inflammation or damage to 
the surrounding tissue where the dose was injected; 
• Adverse events will be continuously monitored during the 18F-AV-1451 
PET imaging visit. Subjects who experience an adverse event will not be 


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discharged from the imaging center until the event has resolved or 
stabilized;  
• A physician or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by 
the site principal investigator must assess or evaluate the subject prior to 
discharge from the imaging center to evaluate the subject’s readiness for 
discharge. If a designee performs this activity, a physician must be available 
to provide medical consultation; and 
• A follow-up phone call to the subject, or informant where applicable, will 
be conducted within 2 or 3 business days of the imaging day, but not before 
48 hours post-injection, to confirm subject well-being and to collect 
information about any new adverse events.  If both of these days are not 
business days, the follow-up phone call can occur the following business 
day. 
 
Florbetapir F 18 PET Imaging Session   
All professional fighters > 50 years of age and other participants in whom, and 
in the opinion of the investigator, the clinical presentation suggests a possible 
diagnosis of AD will return to the clinic for a florbetapir F 18 PET imaging visit. 
The PET imaging visits must be performed no more than 60 days apart.  
• A physician, or physician designee, must see the subject prior to 
administration of Florbetapir F 18 Injection to determine if they are still 
suitable to undergo the scan; 
• Vital signs will be taken (pulse rate, respiratory rate, supine blood pressure 
and weight) immediately prior to injection of florbetapir F 18; 
• Subjects will receive a single IV bolus injection target dose of 370 MBq (10 
mCi) of florbetapir F 18 followed by a saline flush; 
• At approximately 50 minutes following injection, a continuous 10-minute 
brain scan will begin;   
• Adverse events will be continuously monitored during the Florbetapir F 18 
PET imaging visit. Subjects who experience an adverse event will not be 
discharged from the imaging center until the event has resolved or 
stabilized;  
• A physician, or physician designee, will see the subject prior to discharge 
from the imaging center to evaluate the subject’s readiness for discharge; 
and 
• A follow-up phone call to the subject, or informant where applicable, will 
be conducted within 2 or 3 business days of the imaging day, but not before 
48 hours post-injection, to confirm subject well-being and to collect 
information about any new adverse events.  If both of these days are not 
business days, the follow-up phone call can occur the following business 
day. 
7.2 Observations and Measurements 


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Informed Consent 
 
Potential subjects will be allowed to read a written informed consent form.  The 
principal investigator, or designee, will explain all study procedures, risks, and 
alternative therapies to the subject.  The subject will have an opportunity to have all 
questions answered.  The appropriate parties will then sign and date the informed 
consent form, indicating willingness to participate in the study (see Section 7.5). A 
copy of the signed informed consent will be given to the subject.  
 
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB) prior to use. 
 
Medical History  
The investigator or designee will obtain an updated history at the screening visit. 
• Relevant demographic information  
• Review of body systems 
• Social history 
• Medical and surgical history, including medical care for head trauma 
• Concurrent medications 
Whenever possible, the medical history will be confirmed by medical records. 
Vital Signs  
Vital signs (pulse rate, respiratory rate, supine blood pressure) will be taken as part 
of the screening visit and at the following time points: 
• Florbetapir F18 Imaging Visit 
o Prior to injection of florbetapir F 18 
• 
18F-AV-1451 Imaging Visit 
o Prior to the administration of 18F-AV-1451 Injection 
o Within 5 minutes after completion of injection of 18F-AV-1451 Injection  
o After the completion of imaging, prior to discharge.   
 
Height and Weight 
At both the screening visit and imaging visit (prior to 18F-AV-1451 and florbetapir 
F 18 administration) body weight will be measured, lightly clothed.  Height will 
only be measured as part of the screening visit. 
Electrocardiogram (ECG) 
A resting 12-lead electrocardiogram will be recorded as part of the screening visit. 
 


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Volumetric MRI 
If a volumetric MRI has not been performed as part of PFBHS within six months 
days of the 18F-AV-1451 PET imaging visit, a volumetric MRI is to be performed 
as part of this study’s screening assessments. The specific parameters for the MRI 
will be described in a separate document. 
 
Clinical Laboratory Tests  
 
Clinical laboratory evaluation will be performed at the site’s local laboratory as 
part of the screening visit. 
 
Tests will include: 
 
• 
Hematology (4 mL EDTA);  
 
 
• 
Chemistry (8.5 mL blood); 
 
• 
Urinalysis (10 mL, urine); and 
 
• 
Thiamine (vitamin B1; 4.0 mL blood).  
 
A list of analytes and reference range laboratory values will be provided by the site 
to Avid.  
 
Mini-Mental State Examination (MMSE)  
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive 
function in elderly patients.  The instrument is divided into 2 sections.  The first 
section measures orientation, memory, and attention.  The maximum score for the 
first section is 21.  The second section tests the ability of the patient to name 
objects, follow verbal and written commands, write a sentence, and copy figures.  
The maximum score for the second section is 9.  The range for the total MMSE 
score is 0 to 30.  The MMSE will be assessed during the screening visit. 
 
Digit span forward and backward (Wechsler Memory Scale-Revised (WMS-R)) 
Digit Span is composed of two tasks administered independently of each other: 
Digits Forward and Digits Backward. On both tasks, the examiner reads a series of 
number sequences to the subject. For each Digits Forward item, the subject is 
required to repeat the number sequence in the same order as presented. For Digits 
Backward, the subject is required to repeat the number sequence in the reverse 
order.  
 
Beck Depression Inventory-II 


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The Beck Depression Inventory-II (Beck, Steer and Brown, 1996) is a 21-item, 
self-report rating inventory that measures characteristic attitudes and symptoms of 
depression.  
 
Physician Visit 
 
A physician must see the subject during the screening visit. A physician or a 
licensed/credentialed medical professional (i.e., a PET technologist, imaging center 
nurse or a regional equivalent) designated by the site principal investigator must 
assess or evaluate the subject prior to administration of 18F-AV-1451 Injection and 
prior to discharge from the imaging center. If a designee performs this activity, a 
physician must be available to provide medical consultation. A physician, or 
physician designee, must see the subject at baseline, prior to drug administration 
and at study end, prior to discharge from the florbetapir F 18 imaging session. At 
discharge, the physician or licensed/credentialed medical professional (or designee 
for the florbetapir F 18 imaging visit) should review all safety data and briefly 
examine/query the subject regarding potential adverse events or other treatment 
issues.   
 
7.3 Protocol for Image Collection 
 
The sponsor will prepare and distribute imaging manuals for 18F-AV-1451 and 
florbetapir F 18 image acquisition parameters and transmission procedures prior to 
site initiation.   
 
7.4 Good Clinical Practice and Monitoring 
All clinical studies performed under the direction of Avid/CRO will be conducted 
in accordance with applicable regulatory requirements and International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) and Avid/CRO 
Standard Operating Procedures (SOP).  
This includes: 
1. IRB approval:  An investigation will be initiated at a study site only after the 
IRB for that study site has given their written approval of the protocol and 
informed consent;    
2. Informed Consent:  Study procedures will not be initiated until the subject signs 
the informed consent form;   
3. Recording and monitoring of adverse events as outlined in Section 7.7.3 
including the notification of study site clinical investigators, local IRBs and the 
FDA regarding serious adverse event; 
4. Avid RP’s obligation to monitor the participating center on a regular basis; and 
5. The termination of a center or the trial if conditions apply, as outlined in Section 
5.6. 
 


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7.5 Informed Consent and Subject Information 
 
Potential subjects will be allowed to read a written informed consent form.  The 
principal investigator or designee will explain all study procedures, risks, and 
alternative therapies.  The subject will have an opportunity to have all questions 
answered by a physician.  The subject will then sign and date the informed consent 
form, indicating willingness to participate in the study.   
 
If the subject is not capable of giving consent, consent may be given by a legally 
authorized representative.  However, it is expected that all subjects entering this 
study should at least have the capacity to understand that they are engaging in a 
research study and should affirm that they do not object to participating, by signing 
on the Subject Assent line of the consent form.  If the legal guardian is also the 
informant, the guardian must still sign the informant line of the form, indicating 
their own willingness to participate as an informant. 
 
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB).  No study related procedures shall 
be performed prior to completion of the informed consent process, and signing of 
the consent form.  A copy of the signed informed consent should be given to the 
patient for their records. 
 
 
7.6 Documentation 
 
18F-AV-1451 and florbetapir F 18 PET scans will be saved in an appropriate 
electronic format as specified in the imaging manuals.  A copy of all scans, 
including the MRI scans conducted per PFBH study protocol, will be saved at the 
site/imaging center and a copy of each will be forwarded to the sponsor described 
in the imaging manuals.  All other data required by the protocol will be recorded in 
the eCRFs.  All data in the eCRFs will be substantiated by “source documents,” 
which consist of the subject’s medical files, laboratory result sheets, ECG tracings, 
etc.  All source documentation must be available to Avid, and its designees.  
Completed source documents and eCRFs may need to be made available and 
complete for an audit by the FDA, other international regulatory authorities, or 
Avid at any time.  The eCRFs and all other records must be filed in accordance with 
applicable laws and regulations (see Section 10.6). 
 
7.7 Adverse Events (AE) 
 
Avid’s standards for recording and reporting adverse events (AEs) are to be 
followed regardless of applicable regulatory requirements that may be less 
stringent.  All AEs must be fully recorded on the adverse event eCRFs. 
Investigators will be instructed to report to Avid, or its designee, their assessment 
of the potential relatedness of each AE to study drug or protocol procedure via 
electronic data entry.  If a patient’s treatment is discontinued as a result of an AE, 


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study site personnel must clearly report to Avid, or its designee, via electronic data 
entry the circumstances and data leading to any such discontinuation of treatment. 
In cases where the investigator notices an unanticipated benefit to the patient, study 
site personnel should report “unexpected benefit” with the actual event term to 
Avid, or its designee (for example, the complete actual term would be “unexpected 
benefit- sleeping longer”). 
 
Laboratory test abnormalities considered by the Investigator to be clinically 
relevant should be reported on the adverse event eCRFs.  Signs and symptoms of 
each AE should be described in detail (e.g., start and stop dates/time, 
severity/intensity, relationship to study drug, action taken, and event resolution).  
Additionally, any clinically significant findings from laboratory evaluations, vital 
sign measurements, or other study procedures including those that result in a 
diagnosis should be reported as an AE to Avid, or its designee.  
 
7.7.1 
 Adverse Event Monitoring 
  
Each patient must be carefully monitored for adverse events.  This includes 
clinical laboratory test variables.  An assessment must be made of the 
severity/intensity and relationship to the administration of the study drug. 
 
7.7.2 
 Adverse Event Definitions 
Adverse Events 
 
An adverse event is any undesirable experience occurring to a subject during a 
clinical trial, whether or not considered related to the study drug. 
 
For reporting purposes, Avid will distinguish among pre-existing conditions, 
trial-emergent adverse events and treatment-emergent adverse events.   
 
Pre-existing conditions (i.e., undesirable experiences, signs or symptoms that 
begin prior to the Screening Visit) will be recorded on the medical history 
eCRF pages. During the study, site personnel will record any change in the 
condition(s) and occurrence and nature of any AEs.  Signs and symptoms that 
are believed to be due to the pre-existing condition(s) (started prior to dose of 
study medication) do not have to be recorded in the AEs section of the eCRF, 
unless there is an increase in frequency and severity. 
 
Trial-emergent adverse events are undesirable experiences, signs or symptoms 
that begin, or worsen in intensity or frequency, after the informed consent, and 
prior to administration of the study drug at the imaging visit. Adverse events 
that occur between the florbetapir F 18 and the 18F-AV-1451 PET scans outside 
the 48 hour windows will also be considered trial-emergent adverse events. 
These will be recorded on the adverse event eCRFs. 
 


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Treatment-emergent adverse events are any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug 
related.  For the purposes of this study, untoward medical occurrences will be 
considered associated with the use of 18F-AV-1451, and thus be reported as 
adverse events, if they occur within 48 hours after 18F-AV-1451 administration. 
Untoward medical occurrences will be considered associated with the use of 
Florbetapir F 18 Injection, if they occur within 48 hours after Florbetapir F 18 
Injection administration.  
 
The end of study, for the purpose of adverse event reporting, is defined as 48 
hours after the last study drug administration (18F-AV-1451 or Florbetapir F 18 
Injection). 
 
Serious Adverse Event (SAE) 
 
A SAE is an AE that results in one of the following outcomes or constitutes one 
of the following events: 
• Death; 
• Initial or prolonged inpatient hospitalization (other than that required by 
protocol; “social hospitalization” or any hospitalization for non-medical 
reasons does not constitute a SAE); 
• A life-threatening experience (that is, immediate risk of dying); 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect; 
• Considered significant by the investigator for any other reason. 
                                          
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious adverse drug events when, 
based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
 
Unexpected Adverse Event 
 
An unexpected adverse event is an adverse event not previously reported or an 
adverse event that occurs with specificity, severity or frequency that is not 
consistent with the current IB. 
 


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Relationship to Study Drug 
 
Investigators will be instructed to report their assessment of the potential 
relatedness of each adverse event to protocol procedure or study drug.  The 
assessment of the relationship of an adverse event to the administration of the 
study drug is a clinical decision based on all available information at the time 
of the completion of the eCRF. 
 
Intensity/Severity of an Adverse Event 
 
In addition to assessing the relationship of the administration of the study drug 
to adverse events, an assessment is required, in order to determine the intensity 
(severity) of the event.  
 
The following classifications should be used: 
 
Mild:   
A mild adverse event is an adverse event, usually transient in nature and 
generally not interfering with normal activities. 
 
Moderate:   
A moderate adverse event is an adverse event that is sufficiently discomforting 
to interfere with normal activities. 
 
Severe:   
A severe adverse event is an adverse event that incapacitates the subject and 
prevents normal activities.   Note that a severe event is not necessarily a serious 
event; nor must a serious event necessarily be severe. 
 
7.7.3 Adverse Event Documentation 
 
All adverse events must be fully recorded on the adverse event eCRFs.  
Documentation must be supported by an entry in the subject file.  Laboratory 
tests, vital signs and ECG abnormalities considered by the Investigator to be 
clinically relevant should be reported on the adverse event eCRFs.  Signs and 
symptoms of each AE should be described in detail (e.g., start and stop dates, 
severity/intensity, relationship to study drug, action taken, and event 
resolution). 
 
Adverse events and laboratory test abnormalities fulfilling the definition of a 
serious adverse event should, in addition, be reported on the Serious Adverse 
Event Reporting Form. 
 
7.7.4 Reporting of Serious Adverse Events  
 


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Study site personnel must alert Eli Lilly, or its designee, of any SAE within 24 
hours of their awareness of the event via a sponsor-approved method.  Alerts 
issued via telephone are to be immediately followed with official notification 
on study-specific SAE forms.  
 
Serious adverse events occurring after a subject receives a dose of study drug 
will be collected until 48 hours after the  dosing of the study drug, regardless of 
the investigator’s opinion of causation.  Therefore, SAEs that occur later than 
48 hours after the dosing of the study drug are not required to be reported unless 
the investigator feels the events were related to either study drug or a protocol 
procedure. 
 
If a patient experiences a SAE after signing informed consent, but prior to 
receiving study drug, the event will NOT be reported unless the investigator 
feels the event may have been caused by a protocol procedure.  Previously 
planned (prior to signing the ICF) surgeries should not be reported as SAEs 
unless the underlying medical condition has worsened during the course of the 
study. 
 
 
 
8. STATISTICAL ANALYSIS 
 
8.1 General Statistical Considerations 
 
All statistical analyses will be performed using SAS® version 8.2 or higher. 
 
The study data collected under PFBHS protocol, such as but not limited to subjects’ 
demographic and baseline characteristics, history taking, neurological and 
behavioral evaluations, and MRI will be transferred to Avid for analysis purposes. 
 
Data will be summarized using descriptive statistics (number of subjects [N], mean, 
standard deviation [SD], median, quartiles, minimum, and maximum) for 
continuous variables and using frequency count and percentage for discrete 
variables.  The demographic and baseline characteristics data will be summarized 
for all subjects in the safety population according to clinical group.  Safety data will 
be summarized for all patients. 
 
Subject listings of all data from the eCRFs as well as any derived variables will be 
presented.  
 
Descriptive Statistics will be applied to describe the 18F-AV-1451 uptake and 
florbetapir SUVR distribution by subject enrollment groups (active/retired 
professional fighters and cognitive impaired/normal). ANOVA test, or comparable 
non-parametric tests such as the Kruskall-Wallis test when ANOVA’s 
pre-requisites are not met, will be conducted to detect the differences 


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in 18F-AV-1451 uptake measurements across the enrollment groups. If an overall 
difference is detected, then a two sample t-test, or Wilcoxon rank sum test when the 
pre-requisite of t-test is not met, will be applied to test if there are differences seen 
in 18F-AV-1451 uptake measurements between pair-wised enrollment groups.  
Additional exploratory analyses will be applied to explore the relationship 
among 18F-AV-1451 uptake measurements, cognitive and neurological 
measurements, and other collected biomarkers in the study subjects. 
 
Additional details concerning statistical analyses will be included in the Statistical 
Analysis Plan (SAP) to be completed per Avid SOP. 
 
8.2   Safety Analysis 
 
Vital sign measurements will be summarized by subject(s) and by evaluation time 
point(s).  Changes from baseline (pre-dose time point) values will be determined 
and summarized.    
 
Adverse events including injection site reactions will be summarized in terms of 
number and percentage of subjects experiencing an AE.  The summary will be 
further broken down by system organ class (SOC) and preferred term using 
Medical Dictionary for Regulatory Activities (MedDRA) terms.  Adverse events 
will also be presented by severity, relationship to treatment and seriousness.  All 
subjects who experience SAEs, or who discontinue due to AEs, will be 
summarized. 
 
Discontinuation  
 
All subjects who discontinued participation prior to completing the study will be 
listed and their discontinuation reasons will be tabulated. 
 
 Vital Signs 
 
 Changes in vital signs from baseline will be summarized. 
 
8.3 Image Analysis 
All 18F-AV-1451 PET images obtained starting at 75 minutes post injection will be 
analyzed. Additional details concerning image analyses will be included in a 
separate document to be completed prior to the end of the study.   
Florbetapir F 18 images will be analyzed as previously published (Clark et al. 2011, 
2012). 
 
9.     USE OF DATA AND PUBLICATION 


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Avid adheres to the Pharmaceutical Research and Manufacturers of America (PhRMA) 
Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results.  
A complete copy of these principles is available from Avid and can also be found at the 
PhRMA website (http://www.phrma.org).  Avid’s policy is briefly summarized below: 
 
• We commit to timely communication of meaningful results of controlled clinical 
trials, regardless of outcome.  
• As a sponsor, we may recommend that the Investigator(s) delay or decline 
publication in cases where the study design, conduct, or data are insufficient to 
allow meaningful interpretation.  Avid and the Investigator(s) will discuss the study 
design and data in advance of the study, and again after completion, and will strive, 
through appropriate scientific debate, to reach a consensus regarding the potential 
merits of publication. 
• Avid retains the right to review any manuscripts, presentations, or abstracts before 
they are submitted for publication. Where differences of opinion or interpretation 
exist regarding data planned for publication, the parties (Avid and the Investigator) 
should try to resolve them through appropriate scientific debate.  Avid retains the 
right to delay publication for up to 60 days to protect intellectual property.  
• Anyone who provides substantial contributions should receive appropriate 
recognition as an author or contributor when the manuscript is published.  
This is a multi-center study. A multi-center publication, reporting the primary analysis 
data set, should precede any other publications. 
10.    INVESTIGATOR’S REGULATORY OBLIGATIONS 
 
All clinical work conducted under this protocol is subject to Good Clinical Practice 
regulations; this may include an inspection by Avid and/or Health Authority 
representatives (FDA or international regulatory authorities) at any time. 
10.1  Institutional Review Board (IRB)  
 
The intent of the research program, the trial protocol, the patient 
information/informed consent form and any advertising material used to recruit 
subjects must be submitted to the clinical investigator’s local IRB and its approval 
must be obtained prior to its use.  A copy of the approval must be forwarded to Avid.  
When necessary, an extension or renewal of IRB approval must be obtained and 
also forwarded to Avid. 
 
10.2 
 Informed Consent 
 
A signed, written informed consent must be obtained from each patient.  A copy of 
the signed informed consent should be given to the patient for their records.  A copy 
of the local IRB’s approved version of the informed consent form must be 
forwarded to Avid, or its designee, for review prior to being used to obtain patient 
consent. 
 


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10.3 
 Protocol Adherence 
 
 
The protocol must be read thoroughly and the instructions must be followed exactly.  
Where a deviation occurs, it must be documented, the sponsor/monitor informed, 
and a course of action agreed upon. 
 
10.4 
 Documents Necessary for Initiation of the Trial 
Avid must be provided with the following documents prior to the enrollment of any 
subjects: 
• 
Original signed and dated Statement of Agreement page; 
• 
Copy of the IRB and radiation safety committee approval (if applicable); 
• 
Copy of the IRB stamped approved consent form; 
• 
Name and location of the laboratory utilized for laboratory assays, and other 
facilities conducting tests, including laboratory certification number and 
date of certification if available;  
• 
List of reference range laboratory values; and 
• 
Any additional licenses required in order to order to use 18F-AV-1451. 
 
10.5 
Study Drug Control 
The receipt of clinical supplies (e.g. starting material for 18F-AV-1451) must be 
documented at the site.   
 
All drug supplies for this trial should be retained in a safe and secure place at all 
times during the trial.  18F-AV-1451 and Florbetapir F 18 Injections should be 
prepared by a qualified PET manufacturing site and administered by a qualified 
individual under the investigator’s supervision.  An up-to-date drug 
inventory/dispensing record must be maintained and all drug supplies must be 
justified.  After completion of the trial, all remaining clinical supplies must be 
returned to the sponsor, or their representative.   
 
10.6 
Data Collection 
 
Electronic case report forms (eCRFs) will be used for this trial.  Individual patient 
files should include appropriate source documents, including but not limited to 
patient’s medical records and laboratory test results.  The files should include 
information such as visit dates, records of medical history, examinations 
administered, laboratory, concomitant treatment, any adverse event encountered 
and other notes as appropriate.  These constitute “source data”.  All entries on the 
eCRFs must be backed up by source data.  Original electronic versions of imaging 
studies are also considered source data and should be kept on file by the 
site/imaging center, and appropriate copies should be forwarded to Avid as 
specified in the imaging manual.   
 


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Each patient’s source file should include an original signed informed consent form.  
When the trial is completed, the informed consent form should be kept on file with 
other trial related records. 
 
All original laboratory reports must be available for review in each patient’s file.  It 
is important that the original reports be available for review because of the 
possibility of inaccuracies or errors in transcribing data from original records to the 
eCRF. 
 
The eCRFs must be kept in order and up-to-date so that they always reflect the 
latest observations on the subjects that are enrolled in the trial.  The eCRFs must be 
completed for each patient enrolled in the trial and signed by the investigator.  This 
should be done as soon as possible after completion of the patient’s participation in 
the trial.  A monitor will verify the source data for all information on the eCRF. 
 
10.7 
Adverse Events 
 
All adverse events encountered during the clinical trial must be documented on the 
eCRF, whether or not considered drug-related. 
 
Eli Lilly must be notified immediately (as soon as possible, and in all cases within 
24 hours) of a drug experience, condition, development, or event, which is 
considered serious. Eli Lilly must be notified immediately of any findings with the 
use of the drug that may suggest significant hazards, contraindications, adverse 
drug reactions (ADRs) and precautions pertinent to the safety of the drug.  The 
investigator will be requested to complete a separate report form in addition to the 
information on the eCRF.  See section 7.7.4 for reporting serious adverse events 
 
If a SAE is determined to be unexpected (not previously reported or described by 
Avid), and study drug-related, Eli Lilly will notify the investigator in writing.  The 
investigator should forward this notification to the IRB within 24 hours of receipt. 
 
10.8 
Records Retention 
 
All correspondence (e.g., with Avid, IRB, etc.) relating to this clinical trial should 
be kept in appropriate file folders.  Records of subjects, source documents, and 
drug inventory sheets pertaining to the trial must be kept on file.  Records must be 
retained until the date a marketing application (NDA) is approved for the drug for 
the indication for which it is being investigated, or until 2 years following the date 
of clinical trial termination or completion, whichever is later.   If no application is to 
be filed, or if the application is not approved for such indication, records should be 
kept until 2 years following the date of clinical trial termination or completion. 
 
If an investigator moves, withdraws from an investigation, or retires, the 
responsibility for maintaining the records may be transferred to another person who 


Protocol 18F-AV-1451-A11: “18F-AV-1451 PET Imaging in Professional Fighters”  
 
 
 
Page 34 of 38 
 
will accept the responsibility.  Notice of transfer must be made to and agreed upon 
by Avid. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
11. APPENDICES 
 
11.1 References 
 
Beck A.T., Steer R.A. and Brown G.K. (1996) "Manual for the Beck Depression 
Inventory-II". San Antonio, TX: Psychological Corporation. 
 
Bernick C., Banks, S., Phillips, M., et al. “Professional Fighters Brain Health Study: 
Rationale and Methods”.  Am J Epidemiol. 2013; 178(2):280-6. 
 
 
Chien, D.T., Bahri, S., Szardenings, A.K., Walsh, J.C., Mu, F., Su, M.Y., Shankle, 
W.R., Elizarov, A., Kolb, H.C., “Early clinical PET imaging results with the novel 
PHF-tau radioligand [18F]-T807.” J Alzheimers Dis, 2013 Jan 1l34(2):467-68.  
 
Clark, C.M., Pontecorvo, M.J., Beach, T.G., Bedell, B.J., Coleman, R.E., Doraiswamy, 
P.M., Fleisher, A.S., Reiman, P.E.M., Sabbagh, M.N., Sadowsky, C.H., Schneider, 
J.A., Arora, A.,  Carpenter, A.P., Flitter. M.L., Joshi, A.D., Krautkramer, M.J., Lu, M., 
Mintun, M.A., Skovronsky, D.M.  “Florbetapir PET for Detection of Amyloid Neuritic 
Plaques, Comparison to Neuropathology at Autopsy: A Prospective Cohort Study.”  
The Lancet Neurology, 2012; 11: 669–78. 
 
Clark, C.M., Schneider, J.A., Bedell, B.J., et al. “Use of florbetapir-PET for imaging 
beta-amyloid pathology”. JAMA. 2011;305(3):275-283. 
 
Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol 
Med 3:270–303. 
 


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Dale GE, Leigh PN, Luthert P, Anderton BH, Roberts GW (1991) Neurofibrillary 
tangles in dementia pugilistica are ubiquitinated. J Neurol Neurosurg 
Psychiatry 54:116–118. 
 
Faul M, Xu L, Wald MM, Coronado VG (2010) Traumatic Brain Injury in the United 
States: Emergency Department Visits, Hospitalizations, and Deaths. Centers for 
Disease Control and Prevention, National Center for Injury Prevention and Control: 
Atlanta. 
 
Folstein, M.R., Folstein, S.E., and McHugh, P.R. “Mini Mental State: A practical 
method for grading the cognitive status of patients for the clinician.”  Journal of 
Psychiatric Research, 12: 189-198, 1975.  
 
Geddes JF, Vowles GH, Nicoll JA, Revesz T (1999) Neuronal cytoskeletal changes 
are an early consequence of repetitive head injury. Acta Neuropathol 98:171–178).  
 
Graves AB, White E, Koepsell TD, Reifler BV, van Belle G, Larson EB, Raskind 
M (1990) The association between head trauma and Alzheimer's disease. Am J 
Epidemiol 131:491–501. 
 
Huber AGK, Kelemen J, Cervod-Navarro J (1993) Density of amyloid plaques in 
brains after head trauma. J Neurotrauma 10(Suppl.):S180. 
 
Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee 
VM et al (2004) Alzheimer's pathology in human temporal cortex surgically excised 
after severe brain injury. Exp Neurol 190:192–203). 
 
Johnson VE, Stewart W, Smith DH (2010) Traumatic brain injury and amyloid-beta 
pathology: a link to Alzheimer's disease? Nat Rev Neurosci 11:361–370. 
 
Johnson VE, Stewart W, Smith DH (2012) Widespread Tau and Amyloid-Beta 
Pathology Many Years After a Single Traumatic Brain Injury in Humans Brain 
Pathology 22:142–149. 
 
 
McKee, A.C., Cantu, R.C., Nowinski, C.J., et al. “Chronic Traumatic Encephalopathy 
in Athletes: Progressive Tauopathy After Repetitive Head Injury”. J Neuropathol Exp 
Neuorl. July 2009; 68 (7):709-735. 
 
McKee, A.C., Stern, R.A., Nowinski, C.J., et al. “The spectrum of disease in chronic 
traumatic encephalopathy”. Brain. 2013; 136 (1):43-64. 
 
Smith C, Graham DI, Murray LS, Nicoll JA (2003) Tau immunohistochemistry in 
acute brain injury. Neuropathol Appl Neurobiol 29:496–502 
 


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Wechsler Adult Intelligence Scale F Revised. San Antonio, TX: Psychological 
Corporation, 1981. 
Wong, D.F., Rosenberg, P.B., Zhou, Y., et al. “In vivo imaging of amyloid deposition 
in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)”. 
J Nucl Med. 2010;51(6):913-920. 
 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent 
for Alzheimer’s disease,” Alzheimers Dement. 2013, 1-11. 
 


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11.2 Trial Flow Chart 
 
a. 
Screening may take place over several days.  All assessments must be performed within 90 days prior to the 18F-AV-1451 imaging session. Subjects may be permitted to return for the 18F-AV-1451 
PET scan after the 90 day window with sponsor approval if the investigator does not recognize any significant medical changes. 
b. 
A follow-up phone call to the subject, or information where applicable, will be conducted within 2 or 3 business days of each imaging day, but not before 48 hours post-injection, to confirm subject 
well-being and to collect information about any new adverse events.  If both of these days are not business days, the follow-up phone call can occur the following business day. 
c. 
For all professional fighters > 50 years of age and other participants in whom, and in the opinion of the investigator, the clinical presentation suggests a possible diagnosis of AD.  
d. 
Screening vital signs include pulse rate, respiratory rate, supine blood pressure, height and weight.  
e. 
Vital signs (pulse, respiratory rate, supine blood pressure) and weight will be taken prior to dose administration.   
f. 
Vital signs (pulse, respiratory rate, supine blood pressure) will be taken within 5 minutes after completion of injection of dose administration.  
g. 
Vital signs (pulse, respiratory rate, supine blood pressure) will be taken after completion of the PET scan prior to discharge.  
h. 
Safety labs to include hematology, chemistry and urinalysis including plasma thiamine (vitamin B1) level. 
i. 
ECG (with results reviewed prior to 18F-AV-1451 administration). 
j. 
If a volumetric MRI has not been performed as part of PFBHS within six monthsof the 18F-AV-1451 PET imaging visit, a volumetric MRI is to be performed as part of this study’s screening 
assessments. 
k. 
Subjects will receive a single IV bolus injection target dose of 370 MBq (10 mCi) of 18F-AV-1451 Injection followed by a saline flush.  
l. 
At approximately 75 minutes following 18F-AV-1451 injection, a continuous 30-minute brain scan will begin. 
m. 
Subjects will receive a single IV bolus injection target dose of 370 MBq (10 mCi) of florbetapir F 18 followed by a saline flush. 
n. 
At approximately 50 minutes following Florbetapir F 18 injection, a continuous 10-minute brain scan will begin. 
o. 
Or a licensed/credentialed medical professional (i.e. PET technologist, imaging center nurse or a regional equivalent) designated by the site principal investigator. If a designee performs this activity, 
the physician must be available to provide medical consultation.  
p. 
Or physician designee. 
Evaluations 
 
Screening 
Assessmentsa 
18F-AV- 1451 
Imaging Visit 
End of 18F-AV- 
1451 Imaging 
(prior to discharge) 
Follow-up 
Phone Callb 
Florbetapir 
F 18 
Imaging 
Visitc 
End of 
Florbetapir F 
18 Imaging 
(prior to 
discharge) 
Follow-up 
Phone Callb 
Signed Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
 
 
 
 
 
 
Vital Signs    
Xd 
Xe, f 
X g 
 
Xe  
 
 
Clinical Lab Tests  
Xh 
 
 
 
 
 
 
ECG 
Xi 
 
 
 
 
 
 
MMSE, Beck Depression Inventory II, 
Digit span forward/backward 
X 
 
 
 
 
 
 
MRI 
Xj 
 
 
 
 
 
 
PET Brain Scan 
 
X k, l 
 
 
X m, n 
 
 
Evaluation by a physician   
X 
Xo 
Xo 
 
Xp 
Xp 
 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 


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INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol 18F-AV-1451-A11: “18F-AV-1451 PET Imaging in Professional Fighters” 
 
 
Date and Version: 16 June 2015, Amendment 1 
 
 
I agree to conduct the study according to this protocol and to comply with its obligations, 
subject to ethical and safety considerations and all applicable regulations (ICH, CFR). 
 
I shall not disclose the confidential information contained in this protocol or any results 
obtained from the study, except for publication in accordance with Section 9 of this 
protocol, without written authorization from Avid. 
 
 
 
______________________________________              ___________________________ 
Printed Name                                                                    Date 
 
 
 
______________________________________ 
Signature 
 

SAP_001.pdf: 
Statistical Analysis Plan: 18F-AV-1451-A11     
 
 
                   Confidential 
 
1 
 
 
  
 
 
STATISTICAL ANALYSIS PLAN 
 
 
DATE OF PLAN: 
09-June-2017 
 
BASED ON: 
18F-AV-1451-A11 Protocol 13 July 2015, Amendment 1 
 
STUDY DRUG: 
18F-AV-1451 ([F-18]T807) 
 
PROTOCOL NUMBER: 
18F-AV-1451-A11 
 
STUDY TITLE: 
18F-AV-1451 PET Imaging in Professional Fighters 
 
SPONSOR: 
Avid Radiopharmaceuticals 
Philadelphia, Pennsylvania USA 
215-298-0700 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


09 JUN 2017




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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVES ................................................................................................9 
2.1. 
Primary Objective .........................................................................................................9 
2.2. 
Secondary Objective .....................................................................................................9 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
Overview .....................................................................................................................10 
3.2. 
Sample Size Justification ............................................................................................11 
3.3. 
Patient Selection Criteria ............................................................................................11 
4. 
STUDY DURATION AND VISIT SCHEDULE ......................................................12 
5. 
CLINICAL AND IMAGING ASSESSMENTS ........................................................13 
5.1. 
Screening and Baseline Clinical Assessments ............................................................13 
5.2. 
Imaging Assessments ..................................................................................................13 
5.2.1. 
Flortaucipir PET Imaging Visit ..................................................................................13 
5.2.2. 
Florbetapir PET Imaging Visit ...................................................................................14 
5.3. 
Post-Baseline Assessments .........................................................................................14 
5.4. 
Final Evaluation or Premature Termination Visit ......................................................15 
6. 
DEFINITIONS AND CONVENTIONS ....................................................................16 
6.1. 
Data Conventions ........................................................................................................16 
6.2. 
General Summary Table and Individual Patient Data Listing Considerations ...........16 
6.3. 
Calculations Using Dates ............................................................................................16 
6.4. 
Visit Windows Relative to the First Dose of Study Medication ................................16 
7. 
ANALYSIS POPULATIONS ....................................................................................17 
7.1.1. 
Enrolled Population ....................................................................................................17 
7.1.2. 
Safety Analysis Population .........................................................................................17 
7.1.3. 
Efficacy Analysis Population .....................................................................................17 
8. 
DISPOSITION AND WITHDRAWALS ...................................................................18 
9. 
BASELINE PATIENT DATA ...................................................................................19 
9.1. 
Baseline Demographics and Characteristics ...............................................................19 
9.1.1. 
Missing Baseline Data ................................................................................................19 
9.2. 
Medical and Surgical History .....................................................................................19 
9.3. 
Prior and Concomitant Medication .............................................................................20 


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9.3.1. 
Missing and Partially Missing Start and Stop Dates ..................................................20 
9.4. 
Electrocardiogram & Routine Laboratory Data .........................................................20 
9.5. 
MRI .............................................................................................................................21 
9.5.1. 
Missing and Partially Missing Start and Stop Dates ..................................................21 
9.6. 
Baseline Vital Signs ....................................................................................................21 
9.6.1. 
Imputation for Missing Scale Items ............................................................................21 
10. 
EFFICACY ANALYSIS ............................................................................................22 
10.1. 
Primary Efficacy Analysis ..........................................................................................22 
10.1.1. 
Efficacy Variable ........................................................................................................22 
10.1.2. 
Hypothesis Tests .........................................................................................................22 
10.1.3. 
Primary Analysis ........................................................................................................23 
10.1.4. 
Exploratory Analysis ..................................................................................................24 
11. 
SAFETY AND TOLERABILITY ..............................................................................25 
11.1. 
Exposure to Study Drugs ............................................................................................25 
11.1.1. 
Unit Conversion and Volume Calculation ..................................................................25 
11.2. 
Adverse Events ...........................................................................................................25 
11.2.1. 
All AEs .......................................................................................................................25 
11.2.2. 
All TEAEs ..................................................................................................................26 
11.2.3. 
Severity .......................................................................................................................26 
11.2.4. 
Relationship to Study Medication ..............................................................................26 
11.2.5. 
Relationship to Study Procedure ................................................................................26 
11.2.6. 
Serious Adverse Events ..............................................................................................27 
11.2.7. 
Adverse Events Leading to Death ..............................................................................27 
11.2.8. 
Missing and Partial AE Onset Dates ..........................................................................27 
11.3. 
Vital Signs ..................................................................................................................27 
11.4. 
Potentially Clinically Significant Results ...................................................................28 
12. 
INTERIM ANALYSES ..............................................................................................29 
APPENDIX I: ALGORITHMS TO HANDLE MISSING AND PARTIAL DATES ..................30 
1.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........30 
1.2. 
Missing and Partial AE Onset Dates ..........................................................................32 
APPENDIX II: SAS CODE TEMPLATE FOR ANALYSIS .......................................................34 
1.1. 
Sample Code for Efficacy Analysis ............................................................................34 
1.1.1. 
Descriptive Statistics ..................................................................................................34 


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1.1.2. 
Hypothesis #1 and #2 ..................................................................................................34 
1.1.3. 
Hypothesis #3 .............................................................................................................34 
1.1.4. 
Hypothesis #4 .............................................................................................................34 
1.2. 
Sample Code for Exploratory Endpoint .....................................................................35 
1.3. 
Sample code for TEAE Tables by descending frequency ..........................................35 
 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: Visit Schedule ..................................................................................................................12 
Table 3: Potentially Clinically Significant Criteria .......................................................................28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AD 
Alzheimer’s Disease 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomic Therapeutic Chemical 
bpm 
Beats per minute 
cm 
centimeter 
CTE 
Chronic Traumatic Encephalopathy 
ECG 
Electrocardiogram 
kg 
Kilogram 
max 
maximum 
MBq 
Megabecquerels 
mCi 
Millicurie 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
mmHg 
Millimeters of Mercury 
MMSE 
Mini Mental State Exam 
MRI 
Magnetic Resonance Imaging 
MUBADA 
Multi-Block Barycentric Discriminant Analysis 
n 
Number of subjects 
PCS 
Potentially Clinically Significant 
PET 
Positron Emission Tomography 
PFBHS 
Professional Fighters Brain Health Study 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
System Organ Class 
SUVr 
Standard Uptake Value Ratio 
TBI 
Traumatic Brain Injury 
TEAE 
Treatment Emergent Adverse Event 


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1. 
INTRODUCTION 
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease marked by 
widespread accumulation of hyperphosphorylated tau (p-tau), predominantly as 
neurofibrillary and astrocytic tangles. CTE has been found most often in professional athletes 
involved in contact sports (e.g. boxing, American football) who have been subjected to 
repetitive brain trauma, including mild traumatic brain injury (TBI) or even asymptomatic, 
subconcussive trauma.  
The Professional Fighters Brain Health Study (PFBHS) being conducted at the Cleveland 
Clinic Lou Ruvo Center for Brain Health is a longitudinal study that focuses on a sample of 
active and retired professional fighters, and compares them with a control cohort matched for 
age and level of education. The primary objective of the PFBHS is to determine the 
relationship between measures of head trauma exposure and other potential modifiers and 
changes in brain imaging, neurological and behavioral function over time. In this context, the 
addition of an imaging biomarker that could identify the presence of underlying tau 
pathology might be useful in understanding the etiology and evolution of chronic traumatic 
encephalopathy (CTE), and could potentially identify cases at risk for subsequent 
neurodegeneration or other clinically important outcomes with implications for management 
of CTE and/or TBI cases.  
Flortaucipir (18F-AV-1451) may be useful as a marker of tau pathology in patients with 
Alzheimer’s Disease (AD) and other neurodegenerative disorders.  Several preliminary 
studies using flortaucipir have been completed (e.g., Chien et al., 2013). Based on this 
rationale, the goal of this protocol is to perform flortaucipir PET imaging on active and 
retired professional fighters enrolled in the PFBHS protocol and explore its potential as a 
biomarker for CTE. 
The purpose of this statistical analysis plan (SAP) is to describe the statistical analyses for 
this protocol.  The SAP should be read in conjunction with the protocol.  
 
 
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objectives of this study are: 
• To explore the use of flortaucipir as a biomarker for brain injury related to repetitive 
head trauma; and 
• To examine the relationship between clinical presentation and tau deposition as 
measure by flortaucipir uptake in active and retired professional fighters. 
2.2. 
Secondary Objective 
The secondary objective of this study is to expand the flortaucipir and florbetapir safety 
databases.  


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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a phase I study that will evaluate imaging characteristics of flortaucipir in active and 
retired professional fighters enrolled in the PFBHS. 
 
Subjects enrolled in the PFBHS will be contacted to participate and must provide informed 
consent before starting any 18F-AV-1451-A11 study procedures. In addition to consenting to 
study procedures, participants will consent to have Magnetic Resonance Imaging (MRI) 
images/data, including volumetric, functional and standard clinical sequences, and 
cognitive/behavioral data as part of the PFBHS made available to this study to allow for analysis 
and comparison. Screening assessments may take place over several days, within 90 days of the 
flortaucipir Positron Emission Tomography (PET) scan, and will include demographic 
information, cognitive testing and safety assessments. Subjects may be permitted to return for the 
flortaucipir PET scan after the 90 day window with sponsor approval if the investigator does not 
recognize any significant medical changes. If a volumetric MRI has not been performed as part 
of PFBHS within six months of the flortaucipir PET imaging visit, a volumetric MRI is to be 
performed as part of this study’s screening assessments. 
 
Subjects who qualify for the study will return to the clinic at a later date for the flortaucipir PET 
imaging visit. For the flortaucipir PET imaging visit, an intravenous catheter will be placed for 
IV administration of flortaucipir Injection. Subjects will receive a single IV bolus injection with 
a target dose of 370 MBq (10 mCi) of flortaucipir Injection followed by a saline flush. At 
approximately 75 minutes following injection, a continuous 30-minute brain scan will begin. 
Adverse events (AE) will be monitored continuously during the imaging session. A physician or 
a licensed/credentialed medical professional (i.e., a PET technologist, imaging center nurse or a 
regional equivalent) designated by the site principal investigator must assess or evaluate the 
subject prior to injection and prior to discharge from the imaging center. If a designee performs 
this activity, a physician must be available to provide medical consultation. 
 
All professional fighters > 50 years of age and other participants in whom, and in the opinion of 
the investigator, the clinical presentation suggests a possible diagnosis of AD will return to the 
clinic for a florbetapir PET imaging visit. The PET imaging visits must be performed no more 
than 60 days apart. For the florbetapir PET imaging visit, an intravenous catheter will be placed 
for IV administration of florbetapir. Subjects will receive a single IV bolus injection target dose 
of 370 MBq (10 mCi) of florbetapir (Florbetapir Injection) followed by a saline flush. At 
approximately 50 minutes following injection, a continuous 10-minute brain scan will begin. AE 
will be monitored continuously during the imaging session. A physician, or physician designee, 
must evaluate the subject for AE prior to injection and prior to discharge from the imaging 
center. 
 
A follow-up phone call to the subject, or informant where applicable, will be conducted between 
2 or 3 business days of each imaging day, but not before 48 hours post-injection, to confirm 
subject well-being and to collect information about any new adverse events. If both of these days 
are not business days, the follow-up phone call can occur the following business day. 


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3.2. 
Sample Size Justification 
No formal sample size calculation was performed. The study will stop enrolling subjects 
according to administrative consideration and decisions.  
3.3. 
Patient Selection Criteria 
Subjects who currently consented and enrolled in the PFBHS protocol, can tolerate PET scan 
procedures, and have the ablility to provide informed consent for study procedures will be 
provided opportunity to participate this study. 
Refer to Protocol Section 5.3, Selection of Subjects, for the detail of inclusion/exclusion details. 


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4. 
STUDY DURATION AND VISIT SCHEDULE 
The study participants will have a screening visit and two imaging visits. The details of these 
visits are shown below. 
Table 2: Visit Schedule 
a. 
Screening may take place over several days.  All assessments must be performed within 90 days prior to the 18F-AV-1451 imaging session. 
Subjects may be permitted to return for the 18F-AV-1451 PET scan after the 90 day window with sponsor approval if the investigator does 
not recognize any significant medical changes. 
b. 
A follow-up phone call to the subject, or information where applicable, will be conducted within 2 or 3 business days of each imaging day, 
but not before 48 hours post-injection, to confirm subject well-being and to collect information about any new adverse events.  If both of 
these days are not business days, the follow-up phone call can occur the following business day. 
c. 
For all professional fighters > 50 years of age and other participants in whom, and in the opinion of the investigator, the clinical presentation 
suggests a possible diagnosis of AD.  
d. 
Screening vital signs include pulse rate, respiratory rate, supine blood pressure, height and weight.  
e. 
Vital signs (pulse, respiratory rate, supine blood pressure) and weight will be taken prior to dose administration.   
f. 
Vital signs (pulse, respiratory rate, supine blood pressure) will be taken within 5 minutes after completion of injection of dose 
administration.  
g. 
Vital signs (pulse, respiratory rate, supine blood pressure) will be taken after completion of the PET scan prior to discharge.  
h. 
Safety labs to include hematology, chemistry and urinalysis including plasma thiamine (vitamin B1) level. 
i. 
ECG (with results reviewed prior to 18F-AV-1451 administration). 
j. 
If a volumetric MRI has not been performed as part of PFBHS within six monthsof the 18F-AV-1451 PET imaging visit, a volumetric MRI 
is to be performed as part of this study’s screening assessments. 
k. 
Subjects will receive a single IV bolus injection target dose of 370 MBq (10 mCi) of 18F-AV-1451 Injection followed by a saline flush.  
l. 
At approximately 75 minutes following 18F-AV-1451 injection, a continuous 30-minute brain scan will begin. 
m. 
Subjects will receive a single IV bolus injection target dose of 370 MBq (10 mCi) of florbetapir followed by a saline flush. 
n. 
At approximately 50 minutes following florbetapir injection, a continuous 10-minute brain scan will begin. 
o. 
Or a licensed/credentialed medical professional (i.e. PET technologist, imaging center nurse or a regional equivalent) designated by the site 
principal investigator. If a designee performs this activity, the physician must be available to provide medical consultation.  
p. 
Or physician designee. 
Evaluations 
 
Screening 
Assessme
ntsa 
Flortaucipir 
Imaging Visit 
End of 
Flortaucipir 
Imaging 
(prior to 
discharge) 
Follow-
up Phone 
Callb 
Florbeta
pir 
Imaging 
Visitc 
End of 
Florbetap
ir 
Imaging 
(prior to 
discharge) 
Follow-
up 
Phone 
Callb 
Signed Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
 
 
 
 
 
 
Vital Signs    
Xd 
Xe, f 
X g 
 
Xe  
 
 
Clinical Lab Tests  
Xh 
 
 
 
 
 
 
ECG 
Xi 
 
 
 
 
 
 
MMSE, Beck Depression 
Inventory II, Digit span 
forward/backward 
X 
 
 
 
 
 
 
MRI 
Xj 
 
 
 
 
 
 
PET Brain Scan 
 
X k, l 
 
 
X m, n 
 
 
Evaluation by a physician   
X 
Xo 
Xo 
 
Xp 
Xp 
 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 


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5. 
CLINICAL AND IMAGING ASSESSMENTS 
5.1. Screening and Baseline Clinical Assessments 
Subjects currently enrolled in the PFBHS protocol will be contacted to participate. Screening 
assessments may take place over several days, within 90 days of the flortaucipir PET scan, and 
will include: 
• 
Informed Consent will take place before any 18F-AV-1451-A11 study procedures; 
• 
Demographics (birth year, gender, race, ethnicity, education, alcohol, drug use and 
smoking); 
• 
Medical history and concomitant medications; 
• 
Safety assessments: Vital signs (pulse rate, respiratory rate, supine blood pressure, height 
and weight), electrocardiogram (ECG) (with results reviewed prior to flortaucipir 
administration), and safety labs (hematology, chemistry and urinalysis) including plasma 
thiamine (vitamin B1) level; 
• 
Mini-Mental State Examination (MMSE); 
• 
Digit span forward and backward; 
• 
Beck Depression Inventory II; 
• 
If a volumetric MRI has not been performed as part of PFBHS within six months of the 
flortaucipir PET imaging visit, a volumetric MRI is to be performed as part of this 
study’s screening assessments; and 
• 
A physician will see the subject during the screening assessments. 
5.2. 
Imaging Assessments 
5.2.1. 
Flortaucipir PET Imaging Visit 
Subjects who qualify for the study will return to the clinic at a later date for the flortaucipir PET 
imaging visit. For the flortaucipir PET imaging visit, an intravenous catheter will be placed for 
IV administration of flortaucipir Injection. 
• 
A physician or a licensed/credentialed medical professional (i.e., a PET technologist, 
imaging center nurse or a regional equivalent) designated by the site principal 
investigator must assess or evaluate the subject prior to administration of Flortaucipir 
Injection to determine if they are still suitable to undergo the scan. If a designee performs 
this activity, a physician must be available to provide medical consultation; 
• 
Vital signs will be taken (pulse rate, respiratory rate, supine blood pressure) at the 
following time points: 
o Prior to administration of Flortaucipir Injection (weight will also be collected) 
o Within 5 minutes after completion of injection of Flortaucipir Injection 
o After completion of the PET scan prior to discharge; 
• 
Subjects will receive a single IV bolus injection target dose of 370 MBq (10 mCi) of 
flortaucipir Injection followed by a saline flush. 
• 
At approximately 75 minutes following injection, a continuous 30-minute brain scan will 
begin; 
• 
The injection site will be observed for excessive inflammation or damage to the 
surrounding tissue where the dose was injected; 


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• 
AEs will be continuously monitored during the flortaucipir PET imaging visit. Subjects 
who experience an AE will not be discharged from the imaging center until the event has 
resolved or stabilized; 
• 
A physician or a licensed/credentialed medical professional (i.e., a PET technologist, 
imaging center nurse or a regional equivalent) designated by the site principal 
investigator must assess or evaluate the subject prior to discharge from the imaging 
center to evaluate the subject’s readiness for discharge. If a designee performs this 
activity, a physician must be available to provide medical consultation; and 
• 
A follow-up phone call to the subject, or informant where applicable, will be conducted 
within 2 or 3 business days of the imaging day, but not before 48 hours post-injection, to 
confirm subject well-being and to collect information about any new AEs. If both of 
these days are not business days, the follow-up phone call can occur the following 
business day. 
5.2.2. 
Florbetapir PET Imaging Visit  
All professional fighters > 50 years of age and other participants in whom, and in the opinion of 
the investigator, the clinical presentation suggests a possible diagnosis of AD will return to the 
clinic for a florbetapir PET imaging visit. The PET imaging visits must be performed no more 
than 60 days apart. 
• 
A physician, or physician designee, must see the subject prior to administration of 
Florbetapir Injection to determine if they are still suitable to undergo the scan; 
• 
Vital signs will be taken (pulse rate, respiratory rate, supine blood pressure and weight) 
immediately prior to injection of florbetapir; 
• 
Subjects will receive a single IV bolus injection target dose of 370 MBq (10 mCi) of 
florbetapir followed by a saline flush; 
• 
At approximately 50 minutes following injection, a continuous 10-minute brain scan will 
begin; 
• 
AEs will be continuously monitored during the florbetapir PET imaging visit. Subjects 
who experience an AE will not be discharged from the imaging center until the event has 
resolved or stabilized; 
• 
A physician, or physician designee, will see the subject prior to discharge from the 
imaging center to evaluate the subject’s readiness for discharge; and 
• 
A follow-up phone call to the subject, or informant where applicable, will be conducted 
within 2 or 3 business days of the imaging day, but not before 48 hours post-injection, to 
confirm subject well-being and to collect information about any new AEs. If both of 
these days are not business days, the follow-up phone call can occur the following 
business day. 
5.3. 
Post-Baseline Assessments 
Besides the clinical assessments at screening visit and relative imaging assessments, there will be 
no post-baseline assessments in this study. 


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5.4. 
Final Evaluation or Premature Termination Visit 
There will be only one clinical and imaging assessment visit in this study, and will not include 
any premature termination visit. 


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6. 
DEFINITIONS AND CONVENTIONS 
6.1. 
Data Conventions 
Data will be summarized using descriptive statistics (number of subjects [n], mean, 
standard deviation [SD], median, minimum (min), and maximum (max)) for continuous 
variables and using frequency count and percentage for discrete variables.  
All analysis will be performed using SAS version 9.2 or higher. 
6.2. 
General Summary Table and Individual Patient Data Listing 
Considerations 
The tables and listings will be numbered using a decimal system to reflect main levels of unique 
tables and listings and sub-levels of replicate tables and the listings with two digits per level 
(e.g., Table XX.YY.ZZ…). Tables will be presented starting with 14 and individual patient data 
listings are presented starting with 16.  
6.3. 
Calculations Using Dates 
The date of study drug (flortaucipir) administration in this study will be considered relative day 
1, and the day before the dose of study drug will be relative day -1.  Relative days will be 
calculated as follows only when the full assessment date is known (i.e., partial dates will have 
missing relative days): 
• 
For days on or after the first dose of study drug:  (Assessment Date – Exposure Date) + 1. 
• 
For days before the first dose of study drug: Assessment Date – Exposure Date 
6.4. 
Visit Windows Relative to the First Dose of Study Medication 
No visit windowing will be performed for this study.  
 


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7. 
ANALYSIS POPULATIONS 
7.1.1. 
Enrolled Population 
All subjects who meet the inclusion/exclusion criteria and have consented to be enrolled in this 
study, and have baseline data captured in the eCRF database will consist of the enrolled 
population.   
7.1.2. 
Safety Analysis Population 
The safety analysis population will consist of all subjects who received at least one injection of 
flortaucipir or florbetapir. 
7.1.3. 
Efficacy Analysis Population 
This population includes all subjects in safety population for whom valid image data are 
available for the flortaucipir visit(s). All primary and exploratory analyses will be based on this 
population. 


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8. 
DISPOSITION AND WITHDRAWALS 
The entire enrollment population will be represented in the disposition table. The disposition 
table be reported overall and broken down by enrolling diagnosis and include a summary of: 
• Total number of enrolled patients 
• Total number of patients in safety population 
• Number and percentage of completed patients (defined as completing scan procedure and 
receiving follow-up safety phone call) 
• Number and percentage of patients in efficacy population 
• Number and percentage of discontinued patients 
The disposition table will also include details on discontinuation reasons: 
• Adverse Event 
• Death 
• Lost to Follow-up 
• Other 
• Physician Decision 
• Protocol Violation 
• Study Terminated by Sponsors 
• Technical Problems 
• Withdraw by Subject 
Efficacy, completed and discontinued percentages will be based on the safety population. 
Percentages outlining discontinuation reasons will be based on the number of discontinued 
subjects. Discontinued reasons will be presented in a table by descending total frequency. 


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9. 
BASELINE PATIENT DATA 
9.1. 
Baseline Demographics and Characteristics  
Demographic data and other baseline characteristics will be presented for the flortaucipir safety 
analysis population in a table. 
The most recent value prior to a subject’s initial injection of flortaucipir will be considered the 
baseline value, and will be reported in the demographics table. The following data from the will 
be reported in the baseline and demographics table: 
• Age (years) 
• Gender 
• Race 
• Ethnicity 
• Highest Level of Education 
• Alcohol use 
• Tobacco use 
• Recreational Drug Use 
• Height (cm)  
• Weight (kg) 
• MMSE 
• Beck Depression Inventory II 
• Digit span forward/backward 
9.1.1. 
Missing Baseline Data 
No imputation will be performed on missing baseline demographic data. 
9.2. 
Medical and Surgical History 
Medical and Surgical History information will be presented for the safety analysis population.  
Medical and Surgical History will be coded using MedDRA Version 17. Medical History 
findings are defined as those conditions which stop prior to or at Screening. 
Medical and surgical history will be presented in a listing including: 
• System Organ Class (SOC) 
• Condition/Disease 
• Start Date 
• End Date 
• Condition Still Present (Y/N) 


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Medical and Surgical History data will be presented by System Organ Class (SOC) and Preferred 
Term (PT), sorted in descending frequency. 
9.3. 
Prior and Concomitant Medication 
Medications will be presented for the safety analysis population and coded using WHODRUG 
V2014Q1 or higher. Preferred Anatomic Therapeutic Chemical (ATC) coding will be applied. 
Medications will be presented by ATC Level 1, ATC Level 4. 
 ‘Prior’ medications are medications which started and stopped prior to the flortaucipir injection. 
‘Concomitant’ medications are medications that started prior to, on or after the flortaucipir 
injection and ended on or after the date of the flortaucipir injection or were ongoing at the end of 
the study. 
Prior and concomitant medications will be presented in a listing including: 
• Preferred term 
• Indication 
• Total daily dose 
• Dose unit 
• Frequency 
• Route 
• Start date 
• End date 
• Ongoing  (Y/N) 
• Used for AE (Y/N) 
For table summaries, the ATC Level 1s will be sorted by descending frequency of the total 
number of subjects with at least one medication. Within each ATC Level 1, the ATC Level 4s 
will be sorted by descending frequency of the total number of patients with at least one 
medication in each category. 
9.3.1. 
Missing and Partially Missing Start and Stop Dates 
See appendix 1.1 for specific algorithms to impute missing start and stop dates. 
9.4. 
Electrocardiogram & Routine Laboratory Data 
A resting 12-lead ECG and clinical laboratory evaluations will be performed at screening.  
Safety labs performed at screening will include hematology, chemistry and urinalysis including 
plasma thiamine (vitamin B1) level. 
This ECG and laboratory data will be summarized in listing with the following information for 
the safety analysis population: 
• Collected at Screening (Y/N) 


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• Collection Date 
• Collection Time 
9.5. 
MRI 
If a volumetric MRI has not been performed as part of PFBHS within six months days of the 
flortaucipir PET imaging visit, a volumetric MRI is to be performed as part of this study’s 
screening assessments. 
MRI data will be summarized in a listing and table for the following regions (normalized to 
intracranial volume) 
• Whole Brain Volume 
• Total Gray Volume 
• Hippocampal Volume 
• Ventricle Volume 
9.5.1. 
Missing and Partially Missing Start and Stop Dates 
See appendix 1.1 for specific algorithms to impute missing start and stop dates. 
9.6. 
Baseline Vital Signs 
Baseline vital signs will be presented in a listing, and will include: 
• Pulse rate (bpm) 
• Respiratory rate (breaths/minute) 
• Supine blood pressure (mmHg) 
• Height (cm)  
• Weight (kg)  
9.6.1. 
Imputation for Missing Scale Items 
No imputation method will be used for missing baseline vital sign data. 


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10. 
EFFICACY ANALYSIS 
10.1. 
Primary Efficacy Analysis 
10.1.1. 
Efficacy Variable 
The relationship of flortaucipir uptake will be evaluated both quantitatively (SUVr) and 
qualitatively using assessments from a visual read of the signals from images, classifying 
scans as ‘No uptake’, ‘Mild uptake’, ‘Moderate uptake’, and ‘Intense uptake’. 
The flortaucipir PET SUVr will be generated as an average SUVr across selected AAL 
defined regions and a weighted average (MUBADA) SUVr based on regions used in other 
studies to discriminate among AD and control groups.  
Efficacy analyses will be conducted separately on these two sets of SUVr and the 
qualitative read. 
10.1.2. 
Hypothesis Tests 
There are no formal hypothesis testing planned for this study. All the statistical hypothesis 
testing described below are for exploratory purpose only. 
10.1.2.1. Hypothesis #1: Difference in Quantitative Flortaucipir Uptake Between 
Cognitive Groups 
The mean flortaucipir SUVr difference between cognitive statuses (cognitively impaired vs 
without cognitive or behavioural complaint) will be tested with the following hypothesis. 
CN
CI
H
µ
µ
=
:
0
 
CN
CI
A
H
µ
µ
≠
:
 , 
Where:  
• μCI is the mean flortaucipir SUVr in the cognitively impaired group 
• μCN is the mean flortaucipir SUVr in the cognitive normal group 
10.1.2.2. Hypothesis #2: Difference in Quantitative Flortaucipir Uptake Between Fighter 
Groups 
The mean flortaucipir SUVr difference between fighting groups (active vs retired) will be tested 
with the following hypothesis. 
t
Act
H
Re
0 :
µ
µ
=
 
t
Act
A
H
Re
:
µ
µ
≠
, 
Where: 


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• μAct is the mean flortaucipir SUVr in the active fighters 
• μRet is the mean flortaucipir SUVr in retired fighters 
 
10.1.2.3. Hypothesis #3: Association of Qualitative Flortaucipir Uptake and Cognition 
The association of flortaucipir uptake (‘No uptake’, ‘Mild uptake’, ‘Moderate uptake’, ‘Intense 
uptake’) and cognitive status (‘Cognitively Impaired’, ‘Cognitive Normal’) will be tested with 
the following hypothesis. 
 
H0: Cognitive status and qualitative flortaucipir uptake are independent 
HA: Cognitive status and qualitative flortaucipir uptake are not independent 
 
10.1.2.4. Hypothesis #4: Association of Qualitative Flortaucipir Uptake and Fighter 
Status 
The association of flortaucipir uptake (‘No uptake’, ‘Mild uptake’, ‘Moderate uptake’, ‘Intense 
uptake’) and fighter status (‘Retired’, ‘Active’) will be tested with the following hypothesis. 
 
H0: Fighter status and qualitative flortaucipir uptake are independent 
HA: Fighter status and qualitative flortaucipir uptake are not independent 
 
10.1.3. 
Primary Analysis 
Descriptive statistics for flortaucipir SUVr will be reported overall and by each enrolment group. 
Box-and-whisker plots of flortaucipir SUVr will be created to visually display tau distribution 
across these groups. 
Hypotheses 1 and 2 will be tested using a two-way ANOVA, with fighters status (active or 
retired) and cognitive status (impaired or normal) as two main factors. The comparisons of mean 
SUVr values will be compared through setting up proper contrasts.   
The descriptive statistics and ANOVA analysis will be summarized in a table and include the 
following: 
• n 
• Mean (SD) 
• Median 
• Min, Max 
• Overall P-value from ANOVA 
• P-values from each contrast 
Hypotheses 3 and 4 will be tested using Fisher’s exact test. The distributions for each enrollment 
group will be presented in a 4x2 contingency table along with the p-values from each test. 


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10.1.3.1. Statistical Considerations in Primary Analysis 
All hypothesis testing will be run at the 0.05 level of significance. Because this is a Phase I 
study, no correction for multiplicity will be applied to control for alpha. 
10.1.4. 
Exploratory Analysis 
A correlation analysis will be performed to investigate the relationship between flortaucipir 
SUVr and: 
• MMSE 
• Beck Depression Inventory II 
• Digit span forward/backward 
• MRI brain volumes (normalized to intracranial volume) 
o Whole brain volume 
o Gray volume 
o Hippocampal volume 
o Ventricle volume 
Contingent on a trending significance in the primary analysis (p < 0.1500 for contrasts), more 
correlation analysis will be performed to investigate the relationship between tau deposition as 
measured by flortaucipir SUVr and: 
• Years of fighting 
• Age when fighting began 
• Number of bouts 
• Number of losses 
• Number of wins 
• Number of draws 
• Number of knockouts  
A multivariate model may also be derived assuming strong relationships found in the primary 
and correlation analyses. 
10.1.4.1. Subgroup Analysis 
All correlation analysis conducted will be performed for each cognitive group separately, and 
results will be provided in a table. 


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11. 
 
SAFETY AND TOLERABILITY 
The safety analysis population will be used for all safety outcomes. There will be no statistical 
comparisons performed among the safety data. 
All safety analysis will be conducted separately for flortaucipir and florbetapir injections. 
11.1. 
Exposure to Study Drugs 
Exposure to study medication will be presented for the safety analysis population.  All exposure 
data will be presented in listings by visit to include: 
• Injection site (Left Arm, Left Hand, Right Arm, Right Hand, Unknown) 
• Net activity administered (MBq) 
• Date and time of the Injection 
• Saline flush administered (Y/N) 
The actual dose (MBq) of flortaucipir and florbetapir received will be summarized by enrolling 
diagnosis using descriptive statistics (n, mean, SD, median, min, and max) in a table. 
11.1.1. 
Unit Conversion and Volume Calculation 
All exposure tables and listings will display volume in MBq. Volume collected in mCi will be 
converted to MBq as follows: 
• 
mCi
MBq
×
= 37
 
11.2. 
Adverse Events 
An AE is any undesirable experience occurring to a subject during a clinical trial, whether or not 
considered related to the study drug.  
Treatment-emergent adverse events (TEAE) are any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related.  For the purposes of 
this study, untoward medical occurrences will be considered associated with the use of 
flortaucipir or florbetapir, and thus be reported as AEs, if they occur within 48 hours after 
administration of the respective PET tracer. AE that occur after the administration of study drug 
but outside the 48 hour reporting window will not be reported unless the investigator believes 
they are attributable to the drug. 
The end of study for the purpose of AE reporting is defined as 48 hours after the administration 
of flortaucipir injection or florbetapir injection (whichever occurs last). 
11.2.1. 
All AEs 
A summary of all AEs will be reported in a listing including: 
• SOC 
• PT 
• Start Date/time 


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• End Date/time 
• Severity 
• Relationship to Medication (Y/N) 
• Relationship to Study Procedure (Y/N) 
• Seriousness (Y/N) 
• Lead to Death (Y/N) 
11.2.2. 
All TEAEs 
A summary of TEAEs will be reported in the tables including: 
• Number of all TEAE 
• Number of patients with at least one TEAE 
The summary of TEAEs will be broken down further in descending frequency by SOC and PT. 
A subject will be counted once if the subject reported one or more events in a given level of 
summarization. 
11.2.3. 
Severity 
Severity is classed as mild/moderate/severe (increasing severity).  TEAEs with a missing 
severity will be classified as severe.  If a patient reports a TEAE more than once within that 
SOC/PT, the TEAE with the worst case severity will be used in the corresponding severity 
summaries.  
TEAE severity will be reported in a table in the same manner as outlined in 11.2.2.  
11.2.4. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as related or unrelated to study 
medication.  TEAEs with a missing relationship to study medication will be regarded as related 
to study medication.  If a patient reports the same AE more than once within that SOC/PT, the 
AE with the worst case relationship to study medication will be used in the corresponding 
relationship summaries.  
TEAE relationship to medication will be reported in a table in the same manner as outlined in 
11.2.2. 
11.2.5. 
Relationship to Study Procedure 
Relationship, as indicated by the Investigator, is classed as related or unrelated to protocol 
procedure.  TEAEs with a missing relationship to study procedure will be regarded as related to 
study procedure.  If a patient reports the same AE more than once within that SOC/PT, the AE 
with the worst case relationship to study medication will be used in the corresponding 
relationship summaries.  
TEAE relationship to medication will be reported in a table in the same manner as outlined in 
11.2.2. 


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11.2.6. 
Serious Adverse Events 
Serious TEAEs will be summarized in a similar manner as described in Section 11.2.2.  If a 
patient reported more than one serious TEAE with the same SOC or PT, the TEAE will be 
counted only once in that SOC or PT. 
11.2.7. 
Adverse Events Leading to Death 
TEAEs leading to death will be summarized in a similar manner as described in Section 11.2.2. 
11.2.8. 
Missing and Partial AE Onset Dates 
See appendix 1.2 for specific algorithms to impute missing start and stop dates 
11.3. 
Vital Signs 
The following Vital Signs measurements will be reported for this study: 
• Supine Systolic Blood Pressure (mmHg) 
• Supine Diastolic Blood Pressure (mmHg) 
• Supine Pulse Rate (bpm) 
• Respiratory Rate (breaths/min) 
Vital signs data will be summarized at screening, and [when applicable] at each imaging visit 
prior to the administration of injection (florbetapir or flortaucipir), within 5 minutes after 
completion of injection, and at the completion of the imaging visit prior to discharge. Changes 
from baseline (prior to injection) to each follow-up will be calculated. All vital sign data will be 
summarized by enrolling diagnosis in a table, and listing for the Safety population.  
 
 
 
 
 
 
 
 
 
 
 


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11.4. 
Potentially Clinically Significant Results 
Changes from baseline to all follow-ups in vital signs will be monitored for potentially clinically 
significance (PCS). Below are the criteria for PCS vital sign results. 
 
Table 3: Potentially Clinically Significant Criteria 
Parameter 
 
Potentially Clinically Significant Criteria 
Vital Sign 
 
Low 
High 
Systolic blood 
pressure 
mmHg 
≤ 90 and ≥ 20 
decrease 
≥ 180 and ≥ 20 
increase 
Diastolic blood 
pressure 
mmHg 
≤ 50 and ≥ 15 
decrease 
≥105 and ≥ 15 
increase 
Pulse rate 
bpm 
≤ 50 and ≥ 15 
decrease 
≥ 120 and ≥ 15 
increase 
Respiration rate 
Breaths/min 
≤ 10 
 
 


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12. 
INTERIM ANALYSES 
There is no interim analysis planned for this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I: ALGORITHMS TO HANDLE MISSING AND PARTIAL DATES 
1.1. MISSING AND PARTIAL CONCOMITANT AND OTHER 
MEDICATION START AND STOP DATES 
CONMED 
START 
DATE 
CONMED 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study med date, assign as prior  
If stop date ≥ study med date, assign as concomitant  
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med date, assign as prior 
If stop date ≥ study med date and start date, assign as 
concomitant 
Missing 
If stop date is missing could never be assumed a prior 
medication 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date < study med date, assign as prior 
If stop date ≥ study med date and start date, assign as 
concomitant 
Partial 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown) and impute stop date as latest possible date (i.e. 
last day of month if day unknown or 31st December if day 
and month are unknown), then: 
If stop date < study med date, assign as prior 
If stop date ≥ study med date and start date, assign as 
concomitant 
Missing 
Impute start date as earliest possible date (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), then: 
If stop date is missing could never be assumed a prior 
medication 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date ≥ study med start date, assign as concomitant 


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CONMED 
START 
DATE 
CONMED 
STOP 
DATE 
ACTION 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med date, assign as prior 
If stop date ≥ study med date, assign as concomitant 
Missing 
Assign as concomitant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2. MISSING AND PARTIAL AE ONSET DATES 
If the AE onset dates are missing, then the most conservative approach will be used to 
decide if the AE is TEAE or not, as detailed in the table below: 
AE ONSET 
DATE/TIME 
AE STOP 
DATE/TIME 
 
ACTION 
 
 
 
Partial, but 
known 
components 
show that it 
cannot be on 
or after an 
injection 
date/time 
and within 
48 hours 
post-
injection 
Known 
Not TEAE 
Partial 
Not TEAE 
Missing 
Not TEAE 
 
 
 
Partial, could 
be on or after 
an injection  
date/time 
and within 
48 hours 
post-
injection 
Known 
If stop date/time < flortaucipir (or florbetapir) 
injection date/time, then not TEAE 
If stop date/time >= flortaucipir (or 
florbetapir) injection date/time, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. 59 
if minutes unknown or 23:59 if hours and 
minutes unknown; last day of month if day 
unknown or 31st December if day and month 
unknown), then: 
If stop date/time < flortaucipir (or florbetapir) 
injection date/time, then not TEAE 
If stop date/time >= flortaucipir (or 
florbetapir) injection date/time, then TEAE 


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AE ONSET 
DATE/TIME 
AE STOP 
DATE/TIME 
 
ACTION 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date/time < flortaucipir (or florbetapir) 
injection date/time, then not TEAE 
If stop date/time >= flortaucipir (or 
florbetapir) injection date/time, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. 59 
if minutes unknown or 23:59 if hours and 
minutes unknown; last day of month if day 
unknown or 31st December if day and month 
unknown), then: 
If stop date/time < flortaucipir (or florbetapir) 
injection date/time, then not TEAE 
If stop date/time >= flortaucipir (or 
florbetapir) injection date/time, then TEAE 
Missing 
Assumed TEAE 
For the summarization of TEAEs by intensity, events recorded with missing intensity will 
be summarized as Severe.   
For the summarization of TEAEs by seriousness, events recorded with missing seriousness 
will be summarized as Serious. 
For the summarization of TEAEs by relationship to study drug or protocol procedure, 
events recorded with missing relationship will be summarized as Related. 
 
 
 
 
 
 
 
 


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APPENDIX II: SAS CODE TEMPLATE FOR ANALYSIS 
1.1. SAMPLE CODE FOR EFFICACY ANALYSIS 
1.1.1. DESCRIPTIVE STATISTICS 
PROC MEANS data = <data>; class COGGRP; 
output out= summ n=n_ mean=mean std=std median=median min=min max=max; 
RUN;  
QUIT; 
 
PROC MEANS data = <data>; class FIGHTGRP; 
output out= summ n=n_ mean=mean std=std median=median min=min max=max; 
RUN;  
QUIT; 
1.1.2. HYPOTHESIS #1 AND #2 
ods output contrasts=contrasts; 
PROC GLM data = <data>; 
class FIGHTGRP COGGRP; 
model SUVR = FIGHTGRP COGGRP FIGHTGRP*COGGRP; 
contrast "Active vs. Retired"     FIGHTGRP 1 -1; 
contrast "CI vs. CN"              COGGRP   1 -1; 
RUN;  
QUIT; 
1.1.3. HYPOTHESIS #3 
PROC FREQ data = <data>;  
table VISREAD*COGGRP /  fisher; 
RUN; 
1.1.4. HYPOTHESIS #4 
PROC FREQ data = <data>;  
table VISREAD*FIGHTGRP /  fisher; 
RUN; 
 
 
 
 


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1.2. SAMPLE CODE FOR EXPLORATORY ENDPOINT 
ods output PearsonCorr=corr; 
PROC CORR data = <data> pearsons;  
var <variable list>;  
RUN; 
 
1.3. SAMPLE CODE FOR TEAE TABLES BY DESCENDING 
FREQUENCY 
ods output crosstabfreqs=xtab; 
PROC FREQ data = <data> order=freq;  
table <SOC variable>*<Preferred Term variable>;  
RUN;