Conditions: Alzheimer Disease Mild Cognitive Impairment
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 89
Healthy volunteers: yes

Brief summary:
A Phase 1 study designed to evaluate imaging characteristics of flortaucipir in the preclinical, prodromal and dementia phases of Alzheimer's disease.

Detailed description:
The Australian Imaging Biomarkers and Lifestyle Study (AIBL) is a multicenter multidisciplinary study of Alzheimer's disease and aging funded by the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Flagship Initiative, involving research centers in both Victoria and Western Australia. The goal of the A08 protocol was to further investigate the positron emission tomography (PET) imaging results with flortaucipir in patients across the AD spectrum from individuals with subjective memory complaints (SMC) to those with dementia, based on recruitment into the parent AIBL study.

Arms:
arm 1: Alzheimer's disease subjects receiving a flortaucipir PET scan at baseline and 12 months arm 2: Mild cognitive impairment subjects receiving a flortaucipir PET scan at baseline and 12 months arm 3: Subjective memory complainers receiving a flortaucipir PET scan at baseline and 12 months arm 4: Cognitively normal subjects receiving a flortaucipir PET scan at baseline and 12 months

Interventions: intervention 1: Flortaucipir F18 intervention 2: Brain PET scan
Intervention descriptions: intervention 1: IV injection, 240 megabecquerel (MBq) (6.5 mCi) intervention 2: positron emission tomography (PET) scan of the brain

Protocol document:
Prot_000.pdf: 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
of Alzheimer’s Disease”  
 
 
 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compounds: 
18F-AV-1451([F-18]T807) 
 
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4
,3-b]indole 
Title of Study: 18F-AV-1451-A08 
 
“18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases of Alzheimer’s 
Disease” 
Planned number of subjects (Enrolled): Approximately 120 
 
This study will be divided into the following groups: 
 
1. Approximately 25 cognitively healthy control subjects with no memory complaints 
2. Approximately 25 subjects with subjective memory complaints (SMC) and a negative 
amyloid scan 
3. Approximately 25 subjects with subjective memory complaints (SMC) and a positive amyloid 
scan 
4. Approximately 25 subjects with mild cognitive impairment (MCI) 
5. Approximately 20 subjects with Alzheimer’s disease (AD) 
 
Subjects will be recruited from the pool of participants participating in the Australian Imaging 
Biomarker and Lifestyle study of Ageing (AIBL).    
Name of compound and other imaging agents: 18F-AV-1451([F-18]T807)  
 
Dose: 
18F-AV-1451 ([F-18]T807):  240 MBq + 10% 
 
Route of Administration:  Intravenous (IV) bolus 
Study Phase:  I 
Study Centers:  Approximately 1  center in Australia 
Trial Objectives:  
Primary Objective: 
1. To determine the level of total brain tau deposits in men and women aged over 60 years 
with objective cognitive impairment (MCI and AD) and without objective cognitive 
impairment (healthy controls and subjects with SMC). 
Exploratory Objectives:  
1. To determine the prevalence and distribution of brain tau in men and women aged over 60 
years with and without subjective cognitive complaints. 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compounds: 
18F-AV-1451([F-18]T807) 
 
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4
,3-b]indole 
2. To relate the regional distribution of brain tau deposits to the presence of brain amyloid, 
current cognitive and brain function as well as brain atrophy. 
3. To relate the change over time in the levels of regional brain tau to baseline brain tau, 
baseline brain amyloid and change over time in cognition and function, and brain volume. 
4. To expand the 18F-AV-1451 safety database. 
Eligibility: 
Only subjects duly consented and enrolled in the AIBL study protocol will be considered for 
participation in this study. (See Section 5.3, Selection of Subjects)  
Study Design: 
This is a phase I study that will evaluate imaging characteristics of 18F-AV-1451 in the preclinical, 
prodromal and dementia phases of Alzheimer’s disease.  
AIBL subjects who have previously had beta-amyloid imaging in the form of florbetapir (18F) 
Positron Emission Tomography (PET) imaging  will be contacted to participate and must provide 
informed consent before starting any 18F-AV-1451-A08 study procedures. In addition to consenting 
to study procedures, participants will consent to have amyloid PET images and data, Magnetic 
Resonance Imaging (MRI) images and data, and cognitive data made available to this study to allow 
analysis and comparison. Other AIBL participants who have had other types of amyloid imaging will 
be recruited when required to reach the study target enrollment numbers. Screening assessments may 
take place over several days and will include demographic information and safety assessments.  
Subjects who qualify for the study will return to the clinic at a later date for a 18F-AV-1451 PET scan. 
To optimally compare to the AIBL cognitive evaluation, the 18F-AV-1451 PET scan will be obtained 
within +/- 2 months of the planned (or obtained) cognitive evaluation in AIBL.  
 
Subjects will have a follow-up 18F-AV-1451 PET scan at 12 (+/- 3) months following the initial 
18F-AV-1451 scan. A brief cognitive evaluation will be performed on the day of the follow-up 
18F-AV-1451 scan or on a separate visit within 2 months of the follow-up scan. 
 
Assessments and Endpoints: 
For each subject, the study will last for approximately 12 months. Participation will include 1 
Screening Visit and up to 4 Study Visits (two 18F-AV-1451 PET imaging visits and if applicable, a 
MRI visit, and a follow-up cognitive assessment). 
Details of additional assessments that will be performed at each visit are detailed in Section 7.1.   
Statistical Methods:   
Descriptive statistics and graphical displays by clinical diagnosis groups will be applied to describe 
the distribution of tau deposition as measured by 18F-AV-1451 uptake values.  Analyses will be 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compounds: 
18F-AV-1451([F-18]T807) 
 
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4
,3-b]indole 
conducted to assess the relationship among tau deposition measurements, cognitive function 
measurements, and other collected biomarkers both cross-sectionally and longitudinally.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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TABLE OF CONTENTS 
 
 
 
 
 
 
 
  Page 
 
            ABBREVIATIONS AND DEFINITIONS                                                         7              
 
1. 
INTRODUCTION 
9 
 
2. 
TRIAL OBJECTIVES 
11 
 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 
12  
 
4. 
TEST DRUG AND CONTROL AGENTS 
12 
4.1 
Descriptive Name:  18F-AV-1451                     
12 
4.2 
Radioactive Labeling                                     
12 
4.3 
Decay Characteristics                                                                             13 
4.4 
Formulation and Dose 18F-AV-1451 Injection 
13 
4.5 
Packaging 18F-AV-1451 Injection                                                          13 
4.6 
Storage and Handling 18F-AV-1451 Injection     
13 
 
5. 
INVESTIGATIONAL PLAN                                                                          14 
5.1 
Overall Design and Plan of Trial                                                            14 
5.2 
Planned Dosage and Duration of Treatment 
14 
5.2.1 Dosage and Administration 
14 
5.2.2 Rationale for Dosages 
14 
5.3 
Selection of Subjects 
15 
5.3.1 Inclusion Criteria 
15 
5.3.2 Exclusion Criteria 
16 
5.4 
Prior and Concomitant Therapy 
17 
5.5 
Removal of Subjects from Trial 
17 
5.6 
Premature Termination of Trial/Closure of Center 
17 
 
6. 
WARNINGS/PRECAUTIONS 
18 
 
7. 
PROCEDURES AND METHODS 
18 
7.1 
Assessment Periods 
18 
7.1.1 Screening Visit 
18 
7.1.2 MRI Visit 
18 
7.1.3 
18F-AV-1451 PET Imaging Visits 
19  
7.2 
Observations and Measurements 
20 
7.3 
Protocol for Image Collection 
23 
7.4 
Good Clinical Practice and Monitoring 
23 
7.5 
Informed Consent and Subject Information 
23 
7.6 
Documentation  
24 
7.7 
Adverse Events 
24 


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7.7.1 Adverse Event Monitoring 
25 
7.7.2 Adverse Event Definitions 
25 
7.7.3 Adverse Event Documentation 
27 
7.7.4 Reporting of Serious Adverse Events 
27 
 
8. 
STATISTICAL ANALYSIS                                                                              28 
8.1 
General Statistical Considerations                                                          28 
8.2 
Sample size estimation 
28 
8.3 
Image Analysis 
28 
8.4 
Primary objective analysis 
28 
8.5 
Analysis of exploratory objectives 
29 
8.6 
Safety analysis 
29 
 
9. 
USE OF DATA AND PUBLICATION 
30 
 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
30 
10.1 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) 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 
31 
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 
37 
 
INVESTIGATOR STATEMENT 
38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AD 
 
Alzheimer’s disease 
Adverse Event 
(AE) 
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. 
AIBL 
Australian Imaging Biomarker and Lifestyle study of Ageing 
ANCOVA 
Analysis of Covariance 
Audit 
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). 
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.  
CT 
Computed Tomography 
 
Efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended result.
FDA 
US Food and Drug Administration  
FDG 
18F - Fluorodeoxyglucose 
GCP 
Good Clinical Practice 


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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 
Dissociation Constant 
MBq 
Megabecquerel 
MCI 
Mild Cognitive Impairment 
MHD 
Maximum Human Dose 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No Observable Adverse Effect Level 
PET 
Positron Emission Tomography 
SMC 
Subjective Memory Complaint 
SUVR 
Standard Uptake Value Ratio 
TGA 
Therapeutic Goods Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION  
Molecular imaging biomarkers have the potential to aid in the diagnosis of patients 
with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) 
(Dubois, 2010; McKhann, 2011).  Positron emission tomography (PET) ligands such 
as florbetapir F 18 (Wong, 2010) may provide a minimally invasive estimate of cortical 
beta amyloid (Aβ) neuritic plaque deposition, a hallmark pathology, and a required 
element for the evaluation of AD neuropathologic diagnosis (Hyman 2012).  Multiple 
studies comparing amyloid PET scans to histopathologic assessment of amyloid 
burden, in subjects for whom biopsy samples were available or who came to autopsy 
after receiving a PET amyloid scan, support the relationship between PET amyloid 
imaging results and cortical neuritic plaque density (Clark 2011, 2012; Leinonen, 
2008; Sojkova, 2011; Kantarci, 2011; Burack, 2010).  The largest of these studies 
(Clark 2012) demonstrated a high sensitivity and specificity for florbetapir PET to 
discriminate subjects with subsequent autopsy findings of no or sparse neuritic plaques 
(amyloid negative) from those with moderate to frequent plaques (amyloid positive). 
The ability to image brain amyloid with compounds such as florbetapir is an important 
advance for diagnosis of neurological disease.  An amyloid negative florbetapir PET 
scan indicates the absence of a hallmark pathology and is inconsistent with a diagnosis 
of AD.  However, because amyloid is believed to accumulate very early in the disease 
process (Jack et al., 2010) and may be present in other diseases or in clinically normal 
elderly subjects (Sperling et al. 2011; Price and Morris, 1999), the density or 
distribution of amyloid in subjects with a positive scan is not associated with 
Alzheimer’s disease severity, has not been established to predict rate of future 
deterioration and has not been established as a tool to predict or monitor response to 
therapy. 
In contrast to Aβ neuritic plaques, the density and distribution of phosphorylated tau, 
aggregated in neurofibrillary tangles, increases with AD-related cognitive impairment 
and correlates with neurodegeneration (Duyckaerts et al., 1987; Brack et al., 2011; 
Nelson et al., 2012).  Thus, a PET imaging agent that binds to phosphorylated tau has 
potential application as a biomarker for disease severity/neurodegeneration and may be 
useful both for selecting patients for therapy and for monitoring disease progression in 
therapeutic trials. 
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 A negative tissue.  Scatchard analysis 
based on this heterogeneous autoradiography assay yielded an estimated Kd of 15 nM. 
A saturation binding experiment using purified Paired Helical Fragment-Tau isolated 
brains of AD patients yielded a Kd value of 0.7 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. 
18F-AV-1451 has been evaluated in two human studies under the exploratory IND 
(Chien, et. al.; 2013).  Adverse events reported have been mild and transient; none have 
been considered related to 18F-AV-1451 administration.   Preliminary evaluation of the 
PET images suggest that 18F-AV-1451 is eliminated from normal brain yielding only a 
diffuse pattern of background activity (Figure 1), whereas a regionally-specific gray 
matter distribution is observed in subjects with high probability AD (Figure 2).   
 
 
Figure 1: 
 female control subject (MMSE = 29) 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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Figure 2: 
male AD subject (MMSE = 18) 
 
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 5.78 mSv for an anticipated 240 MBq injection and is comparable to 
the effective dose of approved 18F-labeled compounds such as fluorodeoxyglucose 
(FDG) and florbetapir F 18 injection. 
 
The goal of this protocol is to further investigate the PET imaging results with                         
18F -AV-1451 in patients across the AD spectrum from individuals with subjective 
cognitive complaints to those with dementia.  To accomplish this goal, the protocol will 
investigate 18F-AV-1451 results in older cognitively unimpaired individuals and across 
a spectrum of participants who may have increased brain tau deposition; a) normal 
older individuals, b) individuals with subjective cognitive complaints, c) with MCI and 
d) persons with dementia. The findings will be analysed in view of the  brain amyloid 
status (typically using a florbetapir (18F) PET scan), MRI scans and cognitive 
assessments performed in the same AIBL participants.  
 
2. TRIAL OBJECTIVES 
 
Primary Objective: 
1. To determine the level of total brain tau deposits in men and women aged over 
60 years with objective cognitive impairment (MCI and AD) and without 
objective cognitive impairment (healthy controls and subjects with SMC). 
Exploratory Objectives:  
1. To determine the prevalence and distribution of brain tau in men and women 
aged over 60 years with and without subjective cognitive complaints. 
2. To relate the regional distribution of brain tau deposits to the presence of brain 
amyloid, current cognitive and brain function as well as brain atrophy. 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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3. To relate the change over time in the levels of regional brain tau to baseline 
brain tau, baseline brain amyloid and change over time in cognition and 
function, and brain volume.  
4. 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: 
 
Approximately 1 center in Australia will participate. 
 
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 Radioactive Labeling 
      The compound is 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. 


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4.3 Decay Characteristics 
 
 
The time course of radioactive decay for Fluorine [18F] is shown below 
 
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. 
 
 
4.4 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. 18F-AV-1451 Injection will be 
formulated in: 
 a solution containing  10% (v/v) ethanol, USP in 0.9% sodium chloride 
injection, USP. 
 
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. 
 
 
4.5 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. 
4.6 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. 
 


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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 
the preclinical, prodromal and dementia phases of Alzheimer’s disease.  
AIBL subjects who have previously had beta-amyloid imaging in the form of 
florbetapir (18F) PET imaging  will be contacted to participate and must provide 
informed consent before starting any 18F-AV-1451-A08 study procedures. In 
addition to consenting to study procedures, participants will consent to have 
amyloid PET images and data, MRI images and data, and cognitive data made 
available to this study to allow analysis and comparison. Other AIBL participants 
who have had other types of amyloid imaging will be recruited when required to 
reach the study target enrollment numbers. Screening assessments may take place 
over several days and will include demographic information and safety 
assessments.  
Subjects who qualify for the study will return to the clinic at a later date for a 
18F-AV-1451 PET scan. To optimally compare to the AIBL cognitive evaluation, 
the 18F-AV-1451 PET scan will be obtained within +/- 2 months of the planned (or 
obtained) cognitive evaluation in AIBL.  
 
Subjects will have a follow-up 18F-AV-1451 PET scan at 12 (+/- 3) months 
following the initial 18F-AV-1451 scan. A brief cognitive evaluation will be 
performed on the day of the follow-up 18F-AV-1451 scan or on a separate visit 
within 2 months of the follow-up scan. 
 
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 240 
MBq +/- 10% of 18F-AV-1451 Injection. 
 
5.2.2 Rationale for Dosages  
 
Human dosimetry has been obtained in nine subjects. The results estimated an 
Effective Dose of 0.024 mSv/MBq and is comparable to the effective dose of 
approved 18F-labeled compounds such as FDG and florbetapir F 18 injection.  
 
Compared with previous studies, reported in the Investigator’s Brochure, which 
employed a 370 MBq dose, we propose a slightly lower dose in this trial in 
order to minimize the total amount of radiation potentially administered to 
patients, who may receive multiple doses of radiotracers during the course of 


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the AIBL study participation. Thus, for the purposes of this trial, 18F-AV-1451 
will be administered IV in a radioactive dose of 240 MBq with an estimated 
Effective Dose of 6.2 mSv (including a nonclinical CT scan for attenuation 
correction).  This dose is expected to have acceptable image quality in 
preliminary human studies. No treatment related adverse events have been 
reported using doses up to 370 MBq. 
 
5.3 Selection of Subjects 
 
5.3.1 
Inclusion Criteria 
 
Subjects who meet the following criteria are eligible to enroll in this trial as 
cognitively healthy controls: 
 
1. Met all eligibility criteria for this cohort in the AIBL study protocol; and  
2. Consented and currently enrolled in the AIBL study protocol with amyloid 
PET conducted or planned and MRI, cognitive and amyloid PET scan data 
can be made available to this study.  
 
Subjects who meet the following criteria are eligible to enroll in the arm of this 
trial reserved for subjects with subjective memory complaints: 
 
1. Met all eligibility criteria for this cohort in the AIBL study protocol; and  
2. Consented and currently enrolled in the AIBL study protocol with amyloid 
PET conducted or planned and MRI, cognitive and amyloid PET scan data 
can be made available to this study.  
 
Subjects who meet the following criteria are eligible to enroll in the arm of this 
trial reserved for subjects with MCI: 
 
1. Met all diagnostic and eligibility critiera for this cohort in the AIBL study 
protocol; 
2. Consented and currently enrolled in the AIBL study protocol with amyloid 
PET conducted or planned and MRI, cognitive and amyloid PET scan data 
can be made available to this study; and  
3. Have a reliable caregiver who is capable to provide correct information 
about the patient’s clinical symptoms.  
 
Subjects who meet the following criteria are eligible to enroll in the arm of this 
trial reserved for subjects with AD: 
 
1. Met all diagnostic and eligibility criteria for this cohort in the AIBL study 
protocol;  
2. Consented and currently enrolled in the AIBL study protocol with amyloid 
PET conducted or planned and MRI, cognitive and amyloid PET scan data 
can be made available to this study; and 


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3. Have a reliable caregiver who is capable to provide correct information 
about the patient’s clinical symptoms.  
 
Additionally, all subjects must meet all of the following criteria to be eligible to 
enroll in this trial: 
 
1. Male or female English speaking subject > 60 years of age; 
2. Have > 7 years of education; 
3. Have adequate visual and auditory acuity to complete neuropsychological 
testing; 
4. Can tolerate PET imaging procedures; 
5. Can tolerate MRI scan procedures;   
6. Have the ability to provide informed consent for study procedures (If the 
subject is ineligible to give informed consent, based on local standards, the 
subject’s legal representative may consent on behalf of the patient but the 
patient must still confirm assent). 
 
5.3.2 
Exclusion Criteria 
 
All subjects will be excluded from enrollment if they: 
1. Have a lifetime history of schizophrenia, schizoaffective disorder, or 
bipolar disorder; 
2. Have a history of electroconvulsive therapy;  
3. Have the presence of a metal device (e.g., any type of electronic, 
mechanical, or magnetic implant; cardiac pacemaker; aneurysm clips; 
implanted cardiac defibrillator) or potential ferromagnetic foreign body (metal 
slivers, metal shavings, other metal objects) that are contraindications for MRI; 
4. Are claustrophobic or otherwise unable to tolerate the imaging procedure 
(use of mild sedatives are permitted to manage claustrophobia); 
5. Have current clinically significant cardiovascular disease or clinically 
significant abnormalities on screening electrocardiogram (ECG) (including but 
not limited to QTc>450 msec); 
6. 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); 
7. Have a current clinically significant infectious disease, endocrine or 
metabolic disease, pulmonary, renal or hepatic impairment that the investigator 
believes would affect study participation (i.e. neuropsychological testing) or 
scan results; 
8. Have a history of cancer (other than skin or in situ prostate cancer) within 
the previous 5 years; 


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9. Have current drug or alcohol abuse/dependence; 
10. Have a history of alcohol abuse/dependence with 2 years of the onset of the 
symptoms of dementia; 
11. Are females of childbearing potential who are not surgically sterile, not 
refraining from sexual activity or not using reliable methods of contraception. 
Females of childbearing potential must not be pregnant or breastfeeding at 
screening. Females must agree to avoid becoming pregnant, and both females 
and males must agree to refrain from sexual activity or to use reliable 
contraceptive methods for 90 days following administration of 18F-AV-1451 
Injection; and 
12. 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 Case Report Form (CRF).   
 
 
5.5 Removal of Subjects from Trial 
 
Subjects must be removed from the trial if: 
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 CRF. 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 or inadequate staffing, and 
inadequate enrollment.  Except in cases affecting subject safety, the investigator 


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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.  However, because 18F-AV-1451 Injection is in the early 
stages of clinical investigation, it is recommended that subjects receiving 18F-AV-1451 
Injection be followed closely by means of adverse event reporting, vital signs, ECGs, 
and laboratory tests. 
 
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: 
Subjects currently enrolled in the AIBL (previously had amyloid imaging in the 
form of florbetapir (18F) PET imaging) study will be contacted to participate. 
Screening may take place over several days. All screening assessments should 
be performed within 60 days of the initial 18F-AV-1451 PET imaging session. 
Screening assessments will include: 
 Informed Consent; 
 Demographics (age, gender, race, ethnicity, education, alcohol, drug use 
and smoking); 
 Medical history and concomitant medications; 
 Physical and neurological examination; 
 Disease history (date/months since symptom onset, date/months since 
diagnosis) for cognitively impaired subjects; 
 Family history of neurologic disease; 
 Safety assessments: Vital signs (pulse rate, respiratory rate, supine blood 
pressure, height and weight), ECG, and safety labs (hematology, chemistry 
and urinalysis); and 
 A physician will see the subject during the screening visit.   
 
7.1.2 
MRI Visit 
MRI will be acquired within 6 months, either prior or after, the 18F-AV-1451 
PET scan. The subject’s AIBL MRI scan can be used as long as it is obtained 
within this timeframe. 


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7.1.3 
18F-AV-1451 PET Imaging Visits  
 
Initial 18F-AV-1451 PET Imaging Visit: 
To optimally compare to the AIBL cognitive evaluation, the 18F-AV-1451 PET 
scan will be obtained within +/- 2 months of the planned (or obtained) cognitive 
evaluation in AIBL. 
 
 A physician must see the subject prior to administration of 18F-AV-1451 
Injection to determine if they are still suitable to undergo the scan; 
 Vital signs will be taken (pulse rate, respiratory rate, supine blood pressure) 
at the following time points: 
 Immediately prior to administration of 18F-AV-1451 Injection 
(Weight will also be collected); 
 After completion of the 30-minute PET scan prior to discharge; 
 Subjects will receive a single IV bolus injection target dose of 240 MBq +/- 
10% of 18F-AV-1451 Injection followed by a saline flush;  
 A 5-minute brain scan (1 frame of 5 minute duration) will begin 
immediately following the administration of 18F-AV-1451 (however if 
there are logistical or technical reasons this scan cannot obtained, it will not 
be a protocol violation); 
 At approximately 75 minutes following injection, a continuous 30-minute 
brain scan (6 frames of 5 minute duration) 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 
discharged from the imaging center until the event has resolved or 
stabilized;  
 A physician 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 designated decision maker, 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. 
 
Follow-Up 18F-AV-1451 PET Imaging Visit: 
Subjects will have a follow-up 18F-AV-1451 PET scan at 12 (+/- 3) months 
following the initial 18F-AV-1451 scan. 
 
 A physician must see the subject prior to administration of 18F-AV-1451 
Injection to determine if they are still suitable to undergo the scan; 


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 Vital signs will be taken (pulse rate, respiratory rate, supine blood pressure) 
at the following time points: 
 Immediately prior to administration of 18F-AV-1451 Injection 
(Weight will also be collected); 
 After completion of the 30-minute PET scan prior to discharge; 
 Subjects will receive a single IV bolus injection target dose of 240 MBq +/- 
10%) of 18F-AV-1451 Injection followed by a saline flush;  
 A 5-minute brain scan (1 frame of 5 minute duration) will begin 
immediately following the administration of 18F-AV-1451 (however if 
there are logistical or technical reasons this scan cannot obtained, it will not 
be a protocol violation); 
 At approximately 75 minutes following injection, a continuous 30-minute 
brain scan (6 frames of 5 minute duration) 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 
discharged from the imaging center until the event has resolved or 
stabilized;  
 A physician 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 designated decision maker, 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. 
 A brief cognitive evaluation will be performed on the day of the follow-up 
18F-AV-1451 scan. If not able to be done on the day of scan it may be done 
on a separate visit within 2 months of the follow-up scan. The brief 
cognitive evaluation will consist of the Mini Mental State Examination 
(MMSE), Clinical Dementia Rating (CDR) scale, the alternative forms of 
California Verbal Learning Test-II (CVLT-II), Delis-Kaplan Executive 
Function System (D-KEFS) verbal fluency (letter and category), Boston 
Naming Test 30 Item, (Taylor) Complex Figure Test and Logical Memory 
– Wechsler Memory Scale – Revised.  
 
7.2 Observations and Measurements 
   
Informed Consent 
 
Potential subjects and legally authorized representatives, if applicable, 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 


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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 or legally authorized representative.  
 
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
prior to use. 
 
Medical History, Neurologic Disease 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 
 Concurrent medications 
 Neurologic Disease history (date/months since symptom onset and 
date/months since diagnosis) 
  Family history of neurologic disease 
 
Whenever possible, the medical history will be confirmed by medical records. 
 
Physical Examination  
 
A complete physical examination will be conducted at the screening visit.  
Clinically significant changes from screening will be recorded as adverse events for 
the relevant study period. 
 
Neurological Examination  
 
A neurological examination will be performed at the screening visit to evaluate 
cranial nerves, gait, sensory, and motor function, coordination and tendon reflexes.  
The investigator is to look for these specific signs: 
 Pyramidal signs (plantar extension reflex, Achilles tendon clonus); 
 Extrapyramidal signs (rigidity, wrist cogwheel phenomena, involuntary 
movements); and 
 Myoclonus. 
 
Vital Signs  
Vital signs (pulse rate, respiratory rate, supine blood pressure) will be taken as part 
of screening and at the following time points: 
 
18F-AV-1451 Imaging Visit 
o Immediately prior to the administration of 18F-AV-1451 Injection 
o After the completion the 30-minute PET scan prior to discharge.   
 
 


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Height and Weight 
At both screening and imaging visits (immediately prior to each 18F-AV-1451 
administration) body weight will be measured, lightly clothed.  Height will only be 
measured at screening. 
Electrocardiogram (ECG) 
A resting 12-lead electrocardiogram will be recorded as part of the screening visit. 
 
Clinical Laboratory Tests  
 
Clinical laboratory evaluation will be performed at screening.  
 
Tests will include: 
 
 Hematology (5 mL EDTA):  hemoglobin, hematocrit, RBC, WBC, MCH, 
MCHC, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, 
platelets, morphology, MCV, and RBC morphology.  
 
 Chemistry (6 mL blood):  total bilirubin, alkaline phosphatase, ALT (SGPT), 
AST (SGOT), urea nitrogen, creatinine, glucose, uric acid, calcium, 
phosphorus, total protein, albumin, total cholesterol, triglycerides, sodium, 
potassium, bicarbonate, chloride, magnesium, globulin, GGT. 
 
 Urinalysis (10 mL, urine):  Samples will be used to assess glucose, RBC, 
WBC, specific gravity, pH, protein, ketones, urobilinogen, blood, nitrite, 
microscopic, color, bilirubin, casts, epithelial cells, leukocyte, esterase, and 
bacteria.   
 
Neuropsychological Testing 
A brief cognitive evaluation will be performed on the day of the follow-up 
18F-AV-1451 scan or on a separate visit within 2 months of the follow-up scan. The 
brief cognitive evaluation will consist of the MMSE (Folstein et al., 1975), CDR 
(Morris et al., 1993), the alternative forms of California Verbal Learning Test-II 
(CVLT-II) (Delis et al., 2000), D-KEFS verbal fluency (letter and category) (Delis 
et al., 2001), Boston Naming Test (BNT) 30 Item (Saxton et al., 2000), (Taylor) 
Complex Figure Test (Hamby et al., 1993) and Logical Memory – Wechsler 
Memory Scale – Revised (Wechsler, 1987). 
 
Physician Visit 
 
A physician must see the subject at baseline, prior to each 18F-AV-1451 
administration and at study end, prior to discharge from each 18F-AV-1451 imaging 
session. At discharge, the physician should review all safety data and briefly 
examine/query the subject regarding potential adverse events or other treatment 
issues.   


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7.3 Protocol for Image Collection 
 
The sponsor will prepare and distribute imaging manuals for 18F-AV-1451 imaging 
parameters and scan transmission procedures prior to site initiation. The MRI, if 
applicable, imaging parameters should follow the Alzheimer’s Disease 
Neuroimaging Initiate (ADNI) MRI protocol.   
 
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/IEC approval:  An investigation will be initiated at a study site only after 
the IRB/IEC 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 
and/or their   legally authorized representative (as appropriate) 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/IECs 
and the FDA, TGA or other international regulatory authorities 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. 
 
7.5 Informed Consent and Subject Information 
 
Potential subjects, or their legally authorized representative (as appropriate), 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 and legally authorized representative 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 capable of giving informed consent then the subject should sign on 
the consent line of the informed consent form.  When applicable, the legally 
authorized representative should sign as well, indicating that they have witnessed 
the subject’s consent, and further agree to participate as an informant. 
 


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Subjects with AD are potentially a vulnerable population with compromised mental 
capacity. Investigators should take extra care to evaluate a patient’s ability to give 
consent. 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.   
 
All informed consent forms must be approved by Avid or designee, and by the 
appropriate IRB/IEC.  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 and/or their 
legally authorized representative for their records. 
 
7.6 Documentation 
 
18F-AV-1451 and MRI scans will be saved in an appropriate electronic format as 
specified in the imaging manuals.  A copy of all scans, including the florbetapir 
(18F) and MRI scans conducted in the AIBL study protocol, will be saved at the 
site/imaging center and a copy of each will be forwarded to the sponsor or to the 
designated imaging core lab as 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 designees.  Completed source documents and eCRFs may 
need to be made available and complete for an audit by the FDA or other 
international regulatory authorities or Avid at any time.  CRFs 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, 
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, 


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severity/intensity, relationship to study drug, action taken, and outcome).  
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 
and/or physical exam 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 under 
study (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. Additionally, signs or symptoms or changes in pre-exisiting 
conditions that occur outside the trial defined adverse event reporting period 
will be recorded in medical history. 
An adverse event is 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 administration of 18F-AV-1451.  Adverse events 
associated with the use of 18F-AV-1451 will be recorded as treatment emergent 
relative to the respective drug.  Adverse experiences that occur after 
administration of 18F-AV-1451 but outside the 48 hour reporting window will 
not be reported unless the investigator believes they are attributable to the drug. 
In order to capture possible adverse effects of trial participation, trial-emergent 
adverse events will also be reported as any untoward medical occurrences 
occurring, during the study period but not during the 48 hour window following 
the administration of 18F-AV-1451.  For the purpose of trial-emergent adverse 
events, the study period will be defined as beginning with the signing of 
consent and ending immediately before the administration of 18F-AV-1451. 


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The end of study for the purpose of adverse event reporting is defined as 48 
hours after the administration of 18F-AV-1451. 
 
Serious Adverse Event (SAE) 
 
An 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 an 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 investigator’s brochure. 
 
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 of the intensity (severity) of the 
event.  
 
The following classifications should be used: 
 


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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 
test, 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/time, severity/intensity, relationship to study drug, action taken, and 
outcome). 
 
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  
 
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 receive 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 an 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 


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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 AIBL protocol, such as but not limited to subjects’ 
demographic and baseline characteristics, history taking, clinical assessments,  
neuropsychological evaluations,  florbetapir (18F) and MRI scan will be transferred 
to study investigator and study sponsor (Avid) for analysis purpose. 
 
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 electronic case 
report forms (eCRFs) as well as any derived variables will be presented.  
 
8.2 Sample size estimation 
Due to the exploratory purpose of this study, the sample size was determined 
outside statistical consideration. 
8.3 Image Analysis 
All 18F-AV-1451 PET images obtained starting at 75 minutes post injection will be 
analyzed.  The 18F-AV-1451 PET images will be spatially normalized to standard 
stereotactic atlas space using MNI brain atlas. The uptake in tau protein rich brain 
regions will be assessed with regions of interest (ROI, designed in MNI brain atlas) 
in terms for standard uptake value ratio (SUVR, normalized by cerebellar uptake). 
The spatially normalized images and the measured SUVR values will be used to 
accordingly for the following objectives.  
Mean, standard deviation, minimum and maximum of the SUVR values for all 
groups will be calculated.  
Exploratory analysis will include co-registration of MRI to 18F-AV-1451 PET 
images and partial volume correction of 18F-AV-1451 PET images using 
anatomical information from MRI data. 
8.4 Primary objective analysis 
 
Descriptive statistics will be applied to summarize the tau deposition as measured 
by 18F-AV-1451 uptake values by clinical enrollment groups. Box-and-Whiskers 
plots by clinical enrollment groups will be created to describe the tau deposition 


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distributions. ANOVA test will be applied to compare the tau deposition between 
subjects with objective cognitive impairment (MCI and AD) and subjects without 
objective cognitive impairment (healthy controls and subjects with SMC) at 
baseline, and at 12 months follow up visit. If the pre-requisites of ANOVA are not 
met then appropriate non parametric test such as Kruskal-Wallis test will be 
applied.  
   
8.5 Analysis of exploratory objectives 
 
Analysis covariance (ANCOVA) models will be applied to compare the change 
from baseline values in tau deposition as measured by 18F-AV-1451 uptake across 
clinical diagnosis groups and amyloid status, adjusting for baseline value and 
baseline age. If the prerequisites of ANCOVA model are met non-parametric tests 
such as  rank ANCOVA (RANCOVA) will be applied instead.  
 
Based on data availability, the change in tau deposition (as measured by 
18F-AV-1451 uptake) during the 12 months follow up period will be correlated to 
change in cognitive function measurements and other collected biomarkers during 
the same follow up period.  
  
Additional details concerning statistical analyses will be included in the Statistical 
Analysis Plan (SAP) to be completed prior to the end of enrollment into the study. 
 
8.6   Safety Analysis 
 
Safety laboratory test results and vital signs measurements will be summarized by 
subject and by evaluation time point.  Change from baseline (pre-dose time point) 
values will be determined and summarized.   Subjects whose laboratory values are 
outside the pre-determined upper and lower limits of normal will be identified and 
tabulated.  
 
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 study drug 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. 
 
 
 
 


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Laboratory Data 
 
Subjects whose laboratory values are outside threshold values will be identified and 
tabulated. 
 
 Vital Signs 
 
 Changes in vital signs from baseline will be summarized. 
 
 ECG 
 
Any subjects showing QTc > 500 will be highlighted. 
 
9.     USE OF DATA AND PUBLICATION 
 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).  Our 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 single center study. A single 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, TGA or international regulatory authorities) at any time. 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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10.1  Institutional Review Board/Independent Ethics Committee (IRB/IEC)  
 
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/IEC 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/IEC 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/IEC’s approved version of the informed consent form must be 
forwarded to Avid or designee for review prior to being used to obtain patient 
consent. 
 
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/IEC and radiation safety committee approval (if 
applicable); 
• 
Copy of the IRB/IEC 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.  Avid may be responsible for supplying 
these to the investigator if a central laboratory is used;  
• 
List of reference range laboratory values.  Avid may be responsible for this 
if a central laboratory is used; and 
• 
Any additional licenses required in order to order to use or 18F-AV-1451. 
 
10.5 
Study Drug Control 
The receipt of clinical supplies (i.e. 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 Injection should be prepared by a qualified 
PET manufacturing site and administered by a qualified individual under the 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
of Alzheimer’s Disease”  
 
 
 
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investigator’s supervision.  An up-to-date drug inventory/dispensing record must 
be maintained.  All drug supplies must be accounted for.  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 or a 
designated Imaging Core Lab as specified in the Imaging Manual.   
 
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 CRF.  See section 7.7.4 for reporting serious adverse events 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
of Alzheimer’s Disease”  
 
 
 
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If an 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/IEC within 24 hours of 
receipt. 
 
10.8 
Records Retention 
 
All correspondence (e.g., with Avid, IRB/IEC, 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 
will accept the responsibility.  Notice of transfer must be made to and agreed upon 
by Avid. 
 
 
 


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11. APPENDICES 
 
11.1 References 
 
 
Braak H, Thal DR, Ghebremedhin E, Del Tredici K. “Stages of the Pathologic Process 
in Alzheimer Disease: Age Categories from 1 to 100 Years.” J Neuropathol Exp Nerol, 
J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. 
 
Burack, M.A., Hartlein, J., Flores, H.P., Taylor-Reinwald, L., Perlmutter, J.S., Cairns, 
N.J. “In vivo amyloid imaging in autopsy-confirmed Parkinson disease with 
dementia”. Neurology. 2010;74(1):77-84. 
 
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. 
 
Delis, D.C., Kaplan, E., and Kramer, J.H. Delis-Kaplan Executive Function System 
(D-KEFS). The Psychological Corporation, San Antonio, TX (2001).  
 
Delis, D.C., Kramer, J.H., Kaplan, E., and Ober, B.A. California Verbal Learning Test 
a second edition. Adult version. Manual Psychological Corporation, San Antonio, TX 
(2000). 
 
Dubois B., Feldman H.H., Jacova C., et al. “Revising the definition of Alzheimer's 
disease: a new lexicon”. Lancet Neurol. 2010;9(11):1118-1127.   
 
Duyckaerts, C., Brion, J.P., Hauw, J.J., Flament-Durand, J.  “Quantitative assessment 
of the density of neurofibrillary tangles and senile plaques in senile dementia of the 
Alzheimer type.  Comparison of immunocytochemistry with a specific antibody and 
Bodian’s protargol method.”  Acta Neuropathol. 1987;(7):129-135. 
 
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.  
 


Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in the Preclinical, Prodromal and Dementia Phases 
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Hamby, S.L., Wilkins, J.W., and Barry, N.S. “Organizational Quality on the 
Rey-Osterrieth and Taylor Complex Figure Tests: A New Scoring System.” 
Psychological Assessment, 1993;5(1):27-33. 
 
Hyman, B.T., Phelps, C.H., Beach, T.G., et al. “National Institute on 
Aging-Alzheimer's Association guidelines for the neuropathologic assessment of 
Alzheimer's disease”. Alzheimers Dement. 2012;8(1):1-13. 
 
Jack, C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., 
Petersen, R.C., Trojanowski, J.Q.  “Hypothetical model of dynamic biomarkers of the 
Alzheimer’s pathological cascade.”  Lancet Neurol 9:119-128, 2010. 
 
Kantarci, K., Lowe, V.J., Boeve, B.F., Weigand, S.D., Senjem, M.L., Przybelski, S.A., 
et al. “Multimodality imaging characteristics of dementia with Lewy bodies”. 
Neurobiol Aging 2011: Oct 20. [Epub ahead of print]. 
 
Leinonen, V., Alafuzoff, I., Aalto S., Suotunen, T., Savolainen, S., Nagren, K., et al. 
“Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by 
positron emission tomography with carbon 11-labeled Pittsburgh Compound B”. Arch 
Neurol 2008; 65(10):1304–1309. 
 
McKhann, G.M., Knopman, D.S., Chertkow, H., et al. “The diagnosis of dementia due 
to Alzheimer's disease: recommendations from the National Institute on 
Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's 
disease”. Alzheimers Dement. May 2011;7(3):263-269.    
 
Morris, J.C. “The Clinical Dementia Rating (CDR): Current vision and scoring rules” 
Neurology 43:2412-2414, 1993. 
 
Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease 
neuropathologic changes with cognitive status: a review of the literature. J Neuropathol 
Exp Neurol. 2012 May;71(5):362-81. 
 
Price, J.L., Morris, J.C. ”Tangles and plaques in nondemented aging and “preclinical”  
Alzheimer’s disease.” Ann Neurol 45:358–368, 1999. 
 
Saxton, J., Ratcliff, G., Munro, C. A., Coffey, E.C., Becker, J.T., Fried L., and Kuller, 
L. “Normative data on the Boston Naming Test and Two equivalent 30-item short 
forms”. Clin Neuropsychol 2000;14(4):526-534. 
 
Sojkova J., Driscoll I., Iacono D., Zhou Y., Codispoti K., Kraut M., et al. “In vivo 
fibrillar beta-amyloid detected using [11C] PiB positron emission tomography and 
neuropathologic assessment in older adults”. Arch Neurol 2011;68(2):232–240. 
 
Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., 
Iwatsubo, T., Jack, C.R., Jr., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, 


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C.C., Siemers, E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, 
M., Wagster, M.V., Phelps, C.H. 2011. “Toward defining the preclinical stages of 
Alzheimer's disease: Recommendations from the National Institute on 
Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's 
disease”. Alzheimers Dement 7(3), 280-92.  
 
Wechsler D.A. Wechsler Memory Scale – Revised. New York, NY: Psychological 
Corp; 1987. 
 
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 60 days of the initial 18F-AV-1451 imaging visit. 
b. 
Screening vital signs include, pulse rate, respiratory rate, supine blood pressure, height and weight.   
c. 
Vital signs include pulse rate, respiratory rate, supine blood pressure, and weight. 
d. 
Vital signs include pulse rate, respiratory rate, and supine blood pressure. 
e. 
Will be acquired within 6 months, either prior or after, the 18F-AV-1451 PET scan. The subject’s AIBL MRI scan can be used as long as it is obtained within this timeframe. 
f. 
A 5-minute brain scan (1 frame of 5 minute duration) will begin immediately following the administration of 18F-AV-1451.  However, if there are logistical or technical reasons this scan cannot 
obtained, it will not be a protocol violation. 
g. 
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. 
h. 
A brief cognitive evaluation will be performed on the day of the follow-up 18F-AV-1451 scan or on a separate visit with 2 months of the follow-up scan. It will consist of the MMSE, CDR, the 
alternative forms of CVLT-II, D-KEFS verbal fluency (letter and category), Boston Naming Test 30 Item, (Taylor) Complex Figure Test and Logical Memory – Wechsler Memory Scale – Revised. 
 
 
Initial and Follow-Uph 18F-AV-1451 Imaging Visits 
Evaluations 
Screening 
Visita 
Pre-Dose
Immediately after 
injection 
75-105 minutes 
post-injection 
End of 18F-AV- 
1451 Imaging 
(prior to discharge) 
Follow-up 
Phone Callg 
Signed Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History/Neurologic 
Disease History 
X 
 
 
 
 
 
Concomitant Meds 
X 
 
 
 
 
 
Physical/Neurological Exam 
X 
 
 
 
 
 
ECG  
X 
 
 
 
 
 
Vital Signs    
Xb 
Xc 
 
 
Xd 
 
Safety Labs 
X 
 
 
 
 
 
MRIe 
 
 
 
 
 
 
PET Brain Scan 
 
 
Xf 
X 
 
 
Evaluation by a physician   
X 
X 
 
 
X 
 
Adverse Events  
X  
X 
X 
X 
X 
X 
Serious Adverse Events 
 X 
X 
X 
X 
X 
X 


Protocol 18F-AV-1451-A08 
 
 
 
 
 
Page 38 of 38 
 
INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol 18F-AV-1451-A08: “18F-AV-1451 PET Imaging in Preclinical, Prodromal and 
Dementia Phases of Alzheimer’s Disease” 
 
 
Date and Version: 28 February 2014 
 
 
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: