An Open Label, Multicenter Study, Evaluating the Safety and Imaging Characteristics of 18F-AV-1451 in Cognitively Healthy Volunteers, Subjects With Mild Cognitive Impairment, and Subjects With Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer's Disease
Sponsor: Avid Radiopharmaceuticals

18F-AV-1451-A05 Protocol Amendment 2 
 
An Open Label, Multicenter Study, Evaluating the Safety and Imaging Characteristics of 18F-
AV-1451 in Cognitively Healthy Volunteers, Subjects With Mild Cognitive Impairment, and 
Subjects With Alzheimer's Disease 
 
NCT02016560 
Approval date: 07 Aug 2015

/ 
Protocol 18F-AV-1451-A05 
Confidential 
Protocol Number: 18F-AV-1451-AOS 
An open label, multicenter study, evaluating the safety and imaging characteristics of 18F-
AV-1451 in cognitively healthy volunteers, subjects with Mild Cognitive Impairment, 
and subjects with Alzheimer's disease 
Date and Version: 
07 August 2015, Amendment 2 
Name of Compound: 
18F-AV-1451 ([F-18]T807) 
Sponsor: 
Avid Radiopha'tmaceuticals, Inc. 
Philadelphia, Pennsylvania USA 
Approvals/Signatures and Date: 
CONFIDENTIAL 
This material is the property of Avid Radiopharmaceuticals, Inc. (Avid). The information is 
confidential and is to be used only in connection with matters authorized by Avid and no part of it 
is to be disclosed to others without prior written permission from A vi d. 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
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-A05 
An open label, multicenter study, evaluating the safety and imaging characteristics of 18F-AV-
1451 in cognitively healthy volunteers, subjects with Mild Cognitive Impairment, and subjects 
with Alzheimer’s disease 
Planned number of subjects (Enrolled): 380 
The first Phase of the study will be divided into three groups: 
1. Cognitively healthy volunteer subjects  
a. Approximately 20 subjects ≥ 20 to ≤40 years of age 
b. Approximately 60 subjects ≥ 50 years of age 
2. Mild cognitive impairment (MCI) (n=80) 
3. Alzheimer’s disease (AD) subjects 
a. Approximately 60 subjects with an MMSE ≥ 20 
b. Approximately 10 subjects with an MMSE >10 and <20 
The second Phase of the study will enroll: 
4.   Approximately 150 subjects with cognitive impairment (MCI or demented subjects with 
a suspected neurodegenerative cause) and an MMSE ≥ 20 and ≤ 27.  For the purposes of 
ensuring a distribution of disease severity, a target of at least 1/3 of the enrolled subjects will 
have dementia.  
Name of compound: 18F-AV-1451(also known as [F-18]T807) 
Dose: 370 MBq (10 mCi) 
Route of Administration:  Intravenous (IV) bolus 
Study Phase:  II 
Study Centers:  Approximately 30 centers in the United States 
Trial Objectives: This study will be conducted in two phases, an exploratory phase and a 
confirmatory/validation phase, which will have separate subjects and analyses.  The first phase 
of this study will be comprised of a cross-sectional component and a longitudinal component. 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
18F-AV-1451([F-
18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
The second (confirmatory/validation) phase will focus on the relationship of baseline PET tau 
images to changes in longitudinal clinical measures. 
 
Exploratory Phase, Cross-sectional objectives: 
The primary objective of the cross-sectional component is: 
 To compare 18F-AV-1451 imaging results in subjects with AD to subjects with MCI and 
cognitively healthy older individuals 
The secondary objective of the cross-sectional component is: 
 To establish a database of cognitively healthy individuals to show the spectrum of 18F-
AV-1451 imaging results in cognitively healthy individuals across a range of age strata 
Exploratory objectives of the cross-sectional component are: 
 To determine whether greater degrees of cognitive impairment correlate with higher 18F-
AV-1451 uptake in subjects with an amyloid positive status 
 To explore whether tests of specific cognitive domains correlate with regional 18F-AV-
1451 uptake  
 To explore the relationships between  18F-AV-1451 uptake and biomarkers of 
neurodegeneration and neurological disease (CSF markers including tau, phospho-tau 
and beta-amyloid (Aβ), genetic markers, PET amyloid imaging, and brain atrophy 
assessed by volumetric MRI) 
 To expand the 18F-AV-1451 safety database 
Exploratory Phase, Longitudinal objectives: 
The primary objective of the first phase longitudinal component is: 
 To assess the rate of change of tau deposition as measured by 18F-AV-1451 uptake over 
time. 
Exploratory objectives of the first phase longitudinal component are: 
 To explore associations between changes in 18F-AV-1451 uptake in the brain and clinical 
and functional measures, as well as, biomarkers of neurodegeneration and neurological 
disease (CSF markers including tau, phospho-tau and beta-amyloid (Aβ), genetic 
markers, PET amyloid imaging, and brain atrophy assessed by volumetric MRI).   
 To expand the 18F-AV-1451 safety database 
Confirmatory Phase, Longitudinal objectives: 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
18F-AV-1451([F-
18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
The second phase of the study is designed to provide independent validation of the relationships 
observed in the exploratory analyses of the first phase.  In particular, the goal of the second 
phase is to confirm the relationship between 18F-AV-1451 uptake in the brain as measured by 
PET and the subsequent rate of cognitive decline observed over longitudinal follow up. 
 
Eligibility: 
Each of the groups is comprised of specific inclusion and exclusion criteria to determine patient 
eligibility.  See Section 5.3, Selection of Subjects. 
Study Design: 
This is a phase 2 cross-sectional and longitudinal observational study that will evaluate imaging 
characteristics of 18F-AV-1451 in control subjects and patients with MCI and AD. This study 
will be conducted in two phases, an exploratory/hypothesis generating phase and a 
confirmatory/validation phase, which will have separate subjects and analyses.   
All subjects will provide informed consent before starting any study procedures.  
For both the Exploratory and Confirmatory Phases, screening assessments may take place over 
several days and will include demographic information, cognitive testing, safety assessment, 
and MRI, including both volumetric and standard clinical sequences.  Raters administering the 
cognitive testing will be blinded to the 18F-AV-1451 scans for subjects in the Confirmatory 
Cohort. Subjects who qualify for the study will return to the clinic at a later date for a florbetapir 
F 18 PET imaging session and an 18F-AV-1451 PET imaging session.  Some subjects, who are ≥ 
50 years of age, in the exploratory phase may have the option to also participate in cerebrospinal 
fluid (CSF) collection by lumbar puncture (LP).  
Subjects who are ≥ 50 years of age will return for follow-up visits at 9 (+/-2) and 18 (+/-2) 
months following the initial 18F-AV-1451 scan. Cognitive assessments and updates to 
concomitant medications and medical history will be collected at each follow-up visit. Subjects 
in the Exploratory phase will also have follow-up 18F-AV-1451 scans and MRI, including both 
volumetric and standard clinical sequences. A sub-set of subjects in the Exploratory phase may 
have the option to have an additional resting state functional (rsf)MRI sequence scan in addition 
to the volumetric and standard clinical sequences at both the screening MRI and follow-up 
MRIs.  Subjects or their designated decision maker will be contacted by phone at 5 and 14 
months following the initial 18F-AV-1451 scan to collect updated concomitant medications and 
medical history. 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
18F-AV-1451([F-
18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Assessments and Endpoints: 
Each group will have a screening visit(s), a florbetapir F 18 PET imaging visit, a 18F-AV-1451 
PET imaging visit, and follow-up phone calls after each imaging visit.  
Florbetapir F 18 PET Imaging Session: 
For the florbetapir F 18 PET imaging session, subjects will receive a single IV bolus injection 
target dose of 370 MBq (10 mCi) of florbetapir F 18.  At 50 minutes following injection, a 
continuous 10-minute brain scan (2 acquisitions of 5 minute duration) will begin.   
18F-AV-1451 PET Imaging Session:  
For the 18F-AV-1451 PET imaging session, subjects will receive a single IV bolus injection 
target dose of 370 MBq (10 mCi) of 18F-AV-1451 At approximately 80 minutes post dose, 
scanning will begin. Four 5-minute acquisitions will be taken.  
For both imaging sessions adverse events will be monitored continuously during the imaging 
session. Subjects who experience any adverse event during an imaging session will not be 
discharged until the event has resolved or stabilized. 
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. 
In the Exploratory longitudinal component, subjects who are ≥ 50 years of age will have two 
longitudinal follow-up visits with 18F-AV-1451 PET imaging, MRI, cognitive assessments and 
updated medical history and concomitant medications. In the Confirmatory Cohort, longitudinal 
follow-up visits will consist of cognitive assessments and updated medical history and 
concomitant medications. No PET imaging or MRI is planned at the follow-up visits in the 
Confirmatory Cohort. Additional assessments that will be performed at each visit are detailed in 
Section 7.1.   
 
 
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Statistical Methods:   
In the exploratory study phase, descriptive statistics will be applied to describe the 18F-AV-1451 
SUVR distribution across age groups among cognitive healthy subjects. ANOVA analysis will 
be applied to detect the difference between clinical diagnosis groups. Analyses will be 
conducted to assess the relationship among 18F-AV-1451 uptake, cognitive function 
measurements, and other collected biomarkers. Longitudinal data from the exploratory study 
phase will be assessed periodically to determine the relationships between various 18F-AV-1451 
imaging parameters (e.g., composite and regional SUVr, voxel based statistics and visual 
interpretation) and the change from baseline in the various cognitive and functional assessments.  
These data will be used to generate hypotheses regarding the relationship between 18F-AV-1451 
PET tau imaging and cognitive/functional change that will be formally incorporated into an 
analysis plan and tested in the confirmatory phase of the study. 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................ 12 
2. 
TRIAL OBJECTIVES ...................................................................... 14 
2.1. 
Exploratory Phase, Cross-sectional objectives: ................................ 15 
2.2. 
Exploratory Phase, Longitudinal objectives: .................................... 15 
2.3. 
Confirmatory Phase, Longitudinal objectives: ................................. 15 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 16 
4. 
TEST DRUG AND CONTROL AGENTS ...................................... 16 
4.1. 
Descriptive Name:  18F AV-1451 ..................................................... 16 
4.2. 
Descriptive Name:  Florbetapir F 18 ................................................ 16 
4.3. 
Radioactive Labeling ........................................................................ 17 
4.4. 
Decay Characteristics ....................................................................... 17 
4.5. 
Formulation and Dose Florbetapir F 18 Injection ............................. 17 
4.6. 
Formulation and Dose 18F-AV-1451 Injection ................................. 18 
4.7. 
Packaging Florbetapir F 18 Injection ............................................... 18 
4.8. 
Packaging 18F-AV-1451 Injection .................................................... 18 
4.9. 
Storage and Handling Florbetapir F 18 Injection ............................. 18 
4.10. 
Storage and Handling 18F-AV-1451 Injection .................................. 18 
5. 
INVESTIGATIONAL PLAN ........................................................... 19 
5.1. 
Overall Design and Plan of Trial ...................................................... 19 
5.2. 
Planned Dosage and Duration of Treatment ..................................... 20 
5.2.1. 
Dosage and Administration .............................................................. 20 
5.2.2. 
Rationale for Dosages ....................................................................... 21 
5.3. 
Selection of Subjects ......................................................................... 21 
5.3.1. 
Inclusion Criteria .............................................................................. 21 
5.3.2. 
Exclusion Criteria ............................................................................. 23 
5.4. 
Prior and Concomitant Therapy ........................................................ 24 
5.5. 
Removal of Subjects from Trial ....................................................... 24 
5.6. 
Premature Termination of Trial/Closure of Center .......................... 24 
6. 
WARNINGS/PRECAUTIONS ........................................................ 25 
7. 
PROCEDURES AND METHODS .................................................. 25 
7.1. 
Assessment Periods .......................................................................... 25 
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7.1.1. 
Screening and Baseline Visit: ........................................................... 25 
7.1.2. 
Optional Cerebrospinal fluid (CSF) collection by Lumbar Puncture 
(LP) (Aβ, p-tau, t-tau); Exploratory Phase only ............................... 26 
7.1.3. 
Initial PET Imaging Visits: ............................................................... 27 
7.1.4. 
First and Second Longitudinal Follow-up Visits .............................. 28 
7.1.5. 
Longitudinal Follow-Up Phone Calls ............................................... 30 
7.2. 
Observations and Measurements ...................................................... 30 
7.3. 
Protocol for Image Collection .......................................................... 36 
7.4. 
Good Clinical Practice and Monitoring ............................................ 36 
7.5. 
Informed Consent and Subject Information ..................................... 36 
7.6. 
Documentation .................................................................................. 37 
7.7. 
Adverse Events (AE) ........................................................................ 37 
7.7.1. 
Adverse Event Monitoring ............................................................... 38 
7.7.2. 
Adverse Event Definitions ................................................................ 38 
7.7.3. 
Adverse Event Documentation ......................................................... 40 
7.7.4. 
Reporting of Serious Adverse Events ............................................... 40 
8. 
STATISTICAL ANALYSIS ............................................................ 40 
8.1. 
General Statistical Considerations .................................................... 40 
8.1.1. 
Sample Size Estimation .................................................................... 41 
8.1.1.1. 
Exploratory Phase ............................................................................. 41 
8.1.1.2. 
Confirmatory Phase .......................................................................... 41 
8.1.2. 
Exploratory Phase, Cross-sectional Component ............................... 42 
8.1.2.1. 
Primary Objective Analysis .............................................................. 42 
8.1.2.2. 
Secondary Objective Analysis .......................................................... 42 
8.1.2.3. 
Exploratory Objective Analyses ....................................................... 42 
8.1.3. 
Exploratory Phase, Longitudinal Component ................................... 42 
8.1.3.1. 
Primary Objective Analysis .............................................................. 42 
8.1.3.2. 
Exploratory objective analyses ......................................................... 43 
8.1.4. 
Confirmatory Phase .......................................................................... 43 
8.2. 
Safety Analysis ................................................................................. 43 
8.3. 
18F-AV-1451 Image Analysis ........................................................... 44 
9. 
USE OF DATA AND PUBLICATION ........................................... 44 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................. 45 
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10.1. 
Institutional Review Board (IRB) ..................................................... 45 
10.2. 
Informed Consent ............................................................................. 45 
10.3. 
Protocol Adherence .......................................................................... 45 
10.4. 
Documents Necessary for Initiation of the Trial .............................. 46 
10.5. 
Investigational Product Control ........................................................ 46 
10.6. 
Data Collection ................................................................................. 46 
10.7. 
Adverse Events ................................................................................. 47 
10.8. 
Records Retention ............................................................................. 47 
11. 
APPENDICES .................................................................................. 48 
11.1. 
References ......................................................................................... 48 
11.2. 
Trial Flow Chart ............................................................................... 50 
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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AD 
Alzheimer’s disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale- Cognitive Subscale 
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. 
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). 
CHO 
Chinese Hamster Ovary 
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 
 
DSST 
 
Digit Symbol Substitution Test 
 
Efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
FDA 
US Food and Drug Administration  
FDG 
18F - Fluorodeoxyglucose 
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GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
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 
MAO 
Monoamine Oxidase 
MBq 
Megabecquerel 
mCi 
Millicurie 
MCI 
Mild Cognitive Impairment 
MHD 
Maximum Human Dose 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No Observable Adverse Effect Level 
NOEL 
No Observable Effect Level 
PET 
Positron Emission Tomography 
SUVR 
Standard Uptake Value Ratio 
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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 (Dickson et al., 1997; Duyckaerts et a., 1987).  
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 15nM. A saturation binding experiment using purified 
Paired Helical Fragment Tau isolated brains of AD patients yielded a Kd value of 0.7 nM. 
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 
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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).  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).   
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Figure 1: 
 control subject (MMSE = 29) 
 
Figure 2: 
 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 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. 
The overarching goal of this protocol is to further investigate the spectrum of PET 
imaging results with 18F -AV-1451 in patients with cognitive decline and healthy 
controls.  To accomplish this goal, the protocol will investigate 18F-AV-1451 results in 
younger and older controls and patients with cognitive complaints ranging from mild 
cognitive impairment (MCI) to mild and moderate Alzheimer’s disease (AD). 
Additionally, this protocol will investigate correlations between 18F-AV-1451 PET 
imaging and other biomarkers associated with AD and will test the relationship between 
18F-AV-1451 PET imaging and cognitive decline over the 18 month study period. 
2. 
TRIAL OBJECTIVES 
This study will be conducted in two phases, an exploratory phase and a 
confirmatory/validation phase, which will have separate subjects and analyses.  The first 
phase of this study will be comprised of a cross-sectional component and a longitudinal 
component. The second (confirmatory/validation) phase will focus on the relationship of 
baseline PET tau images to change in longitudinal clinical measure. 
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2.1. 
Exploratory Phase, Cross-sectional objectives: 
The primary objective of the cross-sectional component is: 
 To compare 18F-AV-1451 imaging results in subjects with AD to subjects 
with MCI and cognitively healthy older individuals 
The secondary objective of the cross-sectional component is: 
 To establish a database of cognitively healthy individuals to show the 
spectrum of 18F-AV-1451 imaging results in cognitively healthy individuals 
across a range of age strata 
Exploratory objectives of the cross-sectional component are: 
 To determine whether greater degrees of cognitive impairment correlate with 
higher 18F-AV-1451 uptake in subjects with an amyloid positive status 
 To explore whether tests of specific cognitive domains correlate with regional 
18F-AV-1451 uptake  
 To explore the relationships between  18F-AV-1451 uptake and biomarkers of 
neurodegeneration and neurological disease (CSF markers including tau, 
phospho-tau and beta-amyloid (Aβ), genetic markers, PET amyloid imaging, 
and brain atrophy assessed by volumetric MRI) 
 To expand the 18F-AV-1451 safety database 
2.2. 
Exploratory Phase, Longitudinal objectives: 
The primary objective of the first phase of the longitudinal component is: 
 To assess the rate of change of tau deposition as measured by 18F-AV-1451 
uptake over time. 
The exploratory objectives of the first phase of the longitudinal component are: 
 To explore associations between changes in 18F-AV-1451 uptake in  the brain 
and clinical and functional measures, as well as, biomarkers of 
neurodegeneration and neurological disease (CSF markers including tau, 
phospho-tau and beta-amyloid (Aβ), genetic markers, PET amyloid imaging, 
and brain atrophy assessed by volumetric MRI) 
 To expand the 18F-AV-1451 safety database 
2.3. 
Confirmatory Phase, Longitudinal objectives: 
The second phase of the study is designed to provide independent validation of the 
relationships observed in the exploratory analyses of the first phase. In particular, the 
goal of the second phase is to confirm the relationship between 18F-AV-1451 uptake in 
the brain as measured by PET and the subsequent rate of cognitive decline observed over 
longitudinal follow up.  
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3. 
SPONSOR, INVESTIGATOR(S) AND OTHER 
PARTICIPANTS 
The trial is sponsored by: 
 
Avid Radiopharmaceuticals, Inc. 
 
The medical contact is: 
 
 
Approximately 30 centers in the United States 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. 
Descriptive Name:  Florbetapir F 18     
4-[(1E)-2-[6-[2-[2-[2-(fluoro-18F)ethoxy]ethoxy]ethoxy]-3-pyridinyl]ethenyl]-N-methyl- 
benzenamine 
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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 
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. 
N
N 
H 
O
O
O
18F
18F-AV-45
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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. 
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. 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Design and Plan of Trial 
This is a phase 2 cross-sectional and longitudinal observational study that will evaluate 
imaging characteristics of 18F-AV-1451 in control subjects and patients with MCI and 
AD. This study will be conducted in two phases, an exploratory/hypothesis generating 
phase and a confirmatory/validation phase, which will have separate subjects and 
analyses. Approximately 230 subjects will be enrolled in the Exploratory Phase of the 
study: 80 cognitively healthy volunteers, 80 subjects with MCI, 70 subjects with AD. 
Approximately 20 cognitively healthy volunteers will be ≥20 to ≤40 years of age. 
Approximately 60 cognitively healthy volunteers will be ≥ 50 years of age and will be 
distributed across age deciles (50-59, 60-69, 70-79 and >80). Approximately 150 subjects 
with cognitive impairment will be enrolled in the Confirmatory Phase.  
All subjects will provide informed consent before starting any study procedures.  
For both the Exploratory and Confirmatory Phases, screening assessments may take place 
over several days and will include demographic information, cognitive testing, safety 
assessment, and MRI, including both volumetric and standard clinical sequences.  Raters 
administering the cognitive testing will be blinded to the 18F-AV-1451 scans for subjects 
in the Confirmatory Cohort. Subjects who qualify for the study will undergo both a 
florbetapir F 18 PET imaging session and an 18F-AV-1451 PET imaging session.  Some 
subjects, who are ≥ 50 years of age, in the Exploratory Phase will have the option to 
participate in cerebrospinal fluid (CSF) collection by lumbar puncture (LP).  
Subjects who are ≥ 50 years of age will return for follow-up visits at 9 (+/-2) months and 
18 (+/-2) months following the initial 18F-AV-1451 scan. Cognitive assessments and 
updates to concomitant medications and medical history will be collected at each follow-
up visit. Subjects in the Exploratory Phase will also have follow up 18F-AV-1451 scans 
and MRI, including both volumetric and standard clinical sequences. A sub-set of 
subjects in the Exploratory Phase may have the option to have an additional resting state 
functional (rsf)MRI sequence scan in addition to the volumetric and standard clinical 
sequences at both the screening MRI and follow-up MRIs. All follow-up procedures 
should be collected within the specified visit window (See Section 7.1.4). Subjects or 
their designated decision maker will be contacted by phone at 5 and 14 months following 
the initial 18F-AV-1451 scan to collect updated concomitant medications and medical 
history. 
Avid personnel will be blinded to the Confirmatory Phase longitudinal cognitive data. 
Avid personnel will also remain blinded to the PET scans (both florbetapir and 18F-AV-
1451) performed on subjects in the Confirmatory Phase with the exception of periodic 
quality assurance (QA) assessments of a random subset of image data (not to exceed 20% 
unless issues identified that warrant additional review). These QA reviews will serve to 
ensure image quality and data integrity for the scans collected and managed by the 
imaging core laboratory.  Avid staff performing the PET scan QA assessment will not be 
aware of diagnostic group or cognitive test scores for the subjects/images being reviewed. 
 
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Florbetapir F 18 PET Imaging Session: 
For the florbetapir F 18 PET imaging session, 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 (2 acquisitions of 5 minute duration) will begin.   
Adverse events will be continuously monitored during the florbetapir F 18 PET 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.  Subjects who 
experience an adverse event will not be discharged from the imaging center until the 
event has resolved or stabilized. 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days of the post-injection of florbetapir F 18, 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. 
 
18F-AV-1451 PET Imaging Session(s):  
For the 18F-AV-1451 PET imaging session(s), an intravenous catheter will be placed for 
IV administration of 18F-AV-1451 Injection.  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 80 minutes post dose, a continuous 20-minute brain scan (4 
acquisitions of 5-minute duration) will be obtained. If at any point during the imaging 
session it is determined that the subject is not able to continue, or that it is not in the best 
interest of the subject to continue, imaging will be discontinued.  The image data that has 
been collected up to that point will be analyzed. Clinical laboratory tests will be obtained 
prior to injection and upon completion of each imaging session. Adverse events will be 
monitored continuously during the imaging session. Subjects who experience any adverse 
event during an imaging session will not be discharged until the event has resolved or 
stabilized. 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 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. 
5.2. 
Planned Dosage and Duration of Treatment 
5.2.1. 
Dosage and Administration 
Florbetapir F 18: 
Subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) 
of Florbetapir F 18 Injection. 
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18F-AV-1451: 
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 
mCi) of 18F-AV-1451 Injection. 
5.2.2. 
Rationale for Dosages  
This trial is designed to evaluate the brain tau protein imaging properties and safety of 
18F-AV-1451 to be used in subjects with cognitive impairment and healthy volunteers. 
18F-AV-1451 will be administered IV in a radioactive target dose of 370 MBq with a 
maximum human mass 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 preliminary 
human studies. No treatment related adverse events have been reported using this 
regimen.   
5.3. 
Selection of Subjects 
5.3.1. 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible to enroll in this trial as 
cognitively healthy volunteers:  
1. Male or female subjects ≥ 20 to ≤ 40 years of age  
(n = approximately 20)  
-OR-  
Male or female subjects ≥ 50 years of age  
(n = approximately 60) 
2. MMSE ≥ 29  
3. No significant history of cognitive impairment 
4. Can tolerate PET imaging procedures 
5. Can tolerate MRI scan procedures, and 
6. Subjects who signed an IRB approved informed consent prior to any study 
procedures. 
Subjects who meet all of the following criteria are eligible to enroll in the arm of this trial 
reserved for patients with MCI: 
1. Male or female subjects > 50 years of age 
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2. MMSE > 24 
3. Have MCI  consistent with NIA-Alzheimer’s Association working group’s 
diagnostic guidelines for AD: Alzheimer’s Dementia 7:270-9, 2011 (Albert 
2011), including the following: 
a. Have cognitive decline verified by the study physician.  
b. Evidence of objective impairment in one or more cognitive domains, with 
supporting evidence from objective testing if available,  
c. Preservation of independence in functional abilities,  
d. Not demented  
4. Have a study partner who has significant interaction with the subject and can 
report on the subject’s activities of daily living 
5. Can tolerate PET imaging procedures 
6. Can tolerate MRI scan procedures, and 
7. 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. This person may serve as the study partner as well). 
Subjects who meet all of the following criteria are eligible to enroll in the arm of this trial 
reserved for patients with AD: 
1. Male or female subjects  > 50 years of age 
2. MMSE > 10 
a. Approximately 60 subjects with an MMSE >20 
b. Approximately 10 subjects with an MMSE >10 and < 20 
3. Subjects with possible or probable AD based on the NIA-Alzheimer’s Association 
working group’s diagnostic guidelines for AD: Alzheimer’s Dementia 7:263-9, 
2011 
4. Have a study partner who has significant interaction with the subject and can 
report on the subject’s activities of daily living 
5. Can tolerate PET imaging procedures 
6. Can tolerate MRI scan procedures, and 
7. 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. This person may serve as the study partner as well). 
Subjects who meet all of the following criteria are eligible to enroll in the second phase 
of this trial: Confirmatory Cohort: 
1. Male or female subjects > 50 years of age (n = approximately 150) 
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2. Cognitively impaired subjects (MCI or dementia with a suspected 
neurodegenerative cause) with an MMSE ≥ 20 and ≤ 27. (For the purpose of 
ensuring a distribution of disease severity, a target of at least 1/3 of the enrolled 
subjects will have dementia). 
3. Have a study partner who has significant interaction with the subject and can 
report on the subject’s activities of daily living 
4. Can tolerate PET imaging procedures 
5. Can tolerate MRI scan procedures, and 
6. 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. This person may serve as the study partner as well). 
5.3.2. 
Exclusion Criteria 
Subjects will be excluded from enrollment if they: 
1. Have current clinically significant psychiatric disease.  Subjects with behavior 
dysfunction in AD may be entered only after discussion and with approval of the 
sponsor.  The investigator should carefully consider whether subjects with 
behavior dysfunction in AD will be able to complete the imaging session 
2. Have evidence of structural abnormalities such as major stroke or mass on MRI 
that is likely to interfere with interpretation of a PET scan on MRI 
3. Have a history of moderate or severe traumatic brain injury (TBI) by OSU TBI-
ID method or evidence of brain injury by MRI or CT imaging 
4. Are claustrophobic or otherwise unable to tolerate the imaging procedure 
5. Have current clinically significant cardiovascular disease or clinically significant 
abnormalities on screening ECG (including but not limited to Fridericia’s 
corrected QT (QTcF) >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, or cancer that the investigator 
believes would affect study participation or scan results 
8. Have a history of significant or ongoing alcohol abuse or substance abuse or 
dependence 
9. 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 (negative serum β-HCG at the time of 
screening and negative urine β-HCG within 24 hours prior to injection) or 
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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 
10. Have had a non-study related radiopharmaceutical imaging or treatment 
procedure within 7 days prior to the 18F-AV-1451 or florbetapir F18 imaging 
session 
11. Are receiving any investigational medications, or have participated in a trial with 
investigational medications within the last 30 days 
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 below, 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 that are continued from the start of the trial or that are started during the trial 
(other than the study medication) must be documented in the case record form on the 
Concomitant Medication Page of the Case Record Form (CRF).   
 Investigators must discuss with the sponsor and carefully consider whether subjects 
requiring psychotropic medications will be able to complete the imaging session. 
 Subjects who are taking drugs that are known to cause QT-prolongation may not be 
enrolled in the study (a list of prohibited and discouraged medications is provided by the 
Sponsor). 
Subjects may be permitted to enroll in a clinical trial with a potential disease modifying 
(anti-tau or anti-amyloid) investigational medication after discussion with the sponsor.  
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 serious adverse event 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/CRO monitors or to provide 
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required access to data and source documents, staff turnover or inadequate staffing, and 
inadequate enrollment.  Except in cases affecting subject safety, the investigators will be 
given a minimum of 30 days to 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 relatively little toxicological evaluation 
has been completed, and 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. 
There are no data on the effects of 18F-AV-1451 Injection in human perinatal 
development.  For this reason, females must avoid becoming pregnant.  Both females and 
males must use adequate contraceptive methods for 90 days after administration of 18F-
AV-1451 Injection.  18F-AV-1451 Injection must not be administered to females who are 
pregnant or lactating. 
7. 
PROCEDURES AND METHODS 
7.1. 
Assessment Periods  
See Section 11.2, Trial Flow Charts. 
This study will be comprised of a cross-sectional component and a longitudinal 
component. Subjects in both the Exploratory Phase and Confirmatory Phase will have 
screening visit(s), a florbetapir F 18 PET imaging visit, a 18F-AV-1451 PET imaging 
visit, and follow-up phone calls after each imaging visit. Subjects who are ≥50 years old 
will return for follow-up visits at 9 (+/-2) and 18 (+/-2) months following the initial 18F-
AV-1451 scan. Cognitive assessments and updates to concomitant medications and 
medical history will be collected at each follow-up visit. Subjects in the Exploratory 
Phase will also have follow-up 18F-AV-1451 scans and MRI. 
7.1.1. 
Screening and Baseline Visit: 
Screening may take place over several days.  All screening assessments should be 
performed within 30 days of the initial 18F-AV-1451 PET imaging session.  
Screening assessments will include: 
 Informed consent; 
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 Demographics (age, gender, race, ethnicity, education, alcohol, drug use, and 
smoking); 
 Medical history, physical and neurological exam, concomitant medications; 
 Disease history (date/months since symptom onset, date/months since 
diagnosis, family history of  neurologic disease) for cognitively impaired 
subjects; 
 Ohio State University Traumatic Brain Injury Identification Method (OSU 
TBI-ID); 
 Mini Mental State Exam (MMSE); 
 Safety assessments: Vital signs (pulse rate, respiratory rate, supine blood 
pressure, height and weight), ECG, safety labs(hematology, chemistry, and 
urinalysis); 
 Serum beta-hCG test  (for females of childbearing potential defined as pre-
menopausal or less than 2 years post-menopausal and not surgically sterile);  
 MRI imaging including standard clinical sequences and volumetric MRI;  
 A physician will see the patient during the screening visit. 
Baseline assessments may be performed at the screening visit or +/- 30 days of the initial 
18F-AV-1451 Imaging Visit. Raters administering the MMSE and baseline assessments 
described below will be blinded to the 18F-AV-1451 scans for subjects in the 
Confirmatory Cohort. 
Baseline assessments will include: 
 Alzheimer’s Disease Assessment Scale- Cognitive subscale (ADAS-Cog11); 
 Neuropsychological test battery (Digit Symbol Substitution Test (DSST), 
Digit span forward and backward ,Trail Making A and B, Logical Memory 
Test, Immediate and Delayed Recall Story A , Animal list generation, Boston 
Naming Test (BNT) (30 item), American National Adult Reading Test 
(ANART), Clock Drawing Test, Benton Judgment of Line Orientation test); 
 Subjects in the Confirmatory Cohort will also be administered the Clinical 
Dementia Rating (CDR) Scale;  
 Pfeffer Functional Activities Questionnaire (FAQ). For the MCI and AD 
groups only.  
7.1.2. 
Optional Cerebrospinal fluid (CSF) collection by Lumbar Puncture (LP) 
(Aβ, p-tau, t-tau); Exploratory Phase only  
Some subjects (depending on site participation) who are ≥ 50 years of age who qualify 
for the study will be offered to consent for optional CSF collection by LP.  The LP should 
be performed at least 48 hours apart from the PET imaging sessions and should be 
performed within +/- 60 days of the initial 18F-AV-1451 Imaging Visit. Each LP will be 
done by a qualified physician who is experienced in performing the procedure. Subjects, 
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or their designated decision maker, will call the investigator to report any adverse events 
associated with the LP procedure. 
7.1.3. 
Initial PET Imaging Visits: 
Subjects who qualify will have a florbetapir F 18 PET imaging session and their initial 
18F-AV-1451 PET imaging session. The imaging sessions must be performed at least 48 
hours apart, but not more than 60 days apart. The order of the scans is interchangeable. 
Florbetapir F 18 PET Imaging Session   
 For women of childbearing potential, a negative urine pregnancy test must be 
obtained within 24 hours prior to injection; 
 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 of approximately 370 MBq 
(10 mCi) +10% of florbetapir F 18 followed by a saline flush. A 10-minute(2 
acquisitions of 5 minute duration) continuous, dynamic PET brain scan will 
begin approximately 50 minutes following the dose administration; 
 A physician or physician designee will see the subject prior to discharge from 
the imaging center to evaluate the subject’s readiness for discharge; 
 A follow-up phone call to the subject, or designated decision maker, will be 
conducted between 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. 
18F-AV-1451 PET Imaging Session: Raters administering the MMSE and baseline 
assessments will be blinded to the 18F-AV-1451 PET scan for subjects in the 
Confirmatory Cohort. 
 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; 
 For women of childbearing potential, a negative urine pregnancy test must be 
obtained; 
 Vital signs will be taken  at the following time points: 
o immediately prior to administration of 18F-AV-1451 Injection 
o within 5 minutes after completion of injection of 18F- AV-1451 Injection 
o after completion of the PET scan, prior to discharge; 
 ECGs will be taken at the following time points:  
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o Two will be taken approximately 5 minutes apart immediately prior to 
(within approximately 10 minutes) 18F-AV-1451 Injection administration 
o One will be taken within five minutes after completion of injection  
o One will be taken after completion of the PET scan, prior to discharge; 
 Blood and urine samples will be collected for safety labs prior to 
administration of 18F-AV-1451 Injection and after completion of the PET scan 
prior to discharge; 
 Blood will be collected for evaluation of ApoE genotype; 
 Blood will be collected for storage and genetic analysis (participant may opt 
out) ; 
 Subjects will receive a single IV bolus injection of approximately 370 MBq 
(10 mCi) +10% of 18F-AV-1451 Injection followed by a saline flush. At 
approximately 80 minutes post dose, a continuous 20-minute brain scan (4 
acquisitions of 5 minute duration) will be obtained.); 
 The injection site will be observed for excessive inflammation or damage to 
the surrounding tissue where the dose was injected; 
 The subject will be requested to void after completion of the PET scan; 
 Adverse events will be continuously monitored during the 18F-AV-1451 study 
imaging session; 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 between 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. 
 
Longitudinal Visit Procedures 
The longitudinal component will consist of the following sequence of activities: 
7.1.4. 
First and Second Longitudinal Follow-up Visits  
Exploratory Phase: The first and second follow-up visits will consist of PET scan 
procedures, an MRI, cognitive assessments and updated medical history and concomitant 
medications. The first follow-up scan will occur 9 (+/-2) months following the subject’s 
initial 18F-AV-1451 scan. The second follow up scan will occur 18 (+/-2) months 
following the initial 18F-AV-1451 scan. The cognitive assessments and MRIs should be 
performed +/- 30 days of each corresponding 18F-AV-1451 PET imaging visit and within 
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the 9 (+/-2) months window. The cognitive assessments and MRI should take place in the 
same 30 day window. 
Confirmatory Phase Cohort: The first and second follow-up visits will consist of 
cognitive assessments and updated medical history and concomitant medications. The 
first follow-up visit will occur 9 (+/-2) months following the subject’s initial 18F-AV-
1451 scan. The second follow-up visit will occur 18 (+/-2) months following the initial 
18F-AV-1451 scan. 
Cognitive Assessments: Raters administering the below assessments will be blinded to 
the 18F-AV-1451 scans for subjects in the Confirmatory Cohort 
 Mini Mental State Exam (MMSE); 
 Alzheimer’s Disease Assessment Scale- Cognitive subscale (ADAS-Cog11); 
 Neuropsychological test battery (Digit Symbol Substitution Test (DSST), 
Digit span forward and backward ,Trail Making A and B, Logical Memory 
Test, Immediate and Delayed Recall Story A , Animal list generation, Boston 
Naming Test (BNT) (30 item), American National Adult Reading Test 
(ANART), Clock Drawing Test, Benton Judgment of Line Orientation test); 
 Clinical Dementia Rating (CDR) Scale; For the MCI and AD groups only. 
 Pfeffer Functional Activities Questionnaire (FAQ). For the MCI and AD 
groups only.  
Magnetic Resonance Imaging (MRI) (for Exploratory Phase cohort only)  
MRI, including both volumetric and standard clinical sequences, will be obtained at the 
first and second follow-up visits. 
18F-AV-1451 PET Imaging Session (for Exploratory Phase cohort only) 
The first follow-up scan will occur 9 (+/-2) months following the subject’s initial 18F-
AV-1451 scan. The second follow up scan will occur 18 (+/-2) months following the 
initial 18F-AV-1451 scan.  Procedures for the longitudinal follow-up scans will be 
identical to the initial 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; 
 Updated medical history and concomitant medications; 
 For women of childbearing potential, a negative urine pregnancy test must be 
obtained; 
 Vital signs will be taken at the following time points: 
o immediately prior to administration of 18F-AV-1451 Injection 
o within 5 minutes after completion of injection of 18F- AV-1451 Injection 
o after completion of the PET scan prior to discharge; 
 ECGs will be taken at the following time points:  
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o Two will be taken approximately 5 minutes apart immediately prior to 
(within approximately 10 minutes) 18F-AV-1451 Injection administration   
o One will be taken within five minutes after completion of injection 
o One will be taken after completion of the PET scan prior to discharge; 
 Blood and urine samples will be collected for safety labs prior to 
administration of 18F-AV-1451 Injection and after completion of the PET scan 
prior to discharge; 
 Subjects will receive a single IV bolus injection of approximately (370 MBq) 
10 mCi (+10%) of 18F-AV-1451 Injection followed by a saline flush. At 
approximately 80 minutes post dose, a continuous 20-minute brain scan (4 
acquisition of 5-minute duration).  
 The injection site will be observed for excessive inflammation or damage to 
the surrounding tissue where the dose was injected; 
 The subject will be requested to void after completion of the PET scan; 
 Adverse events will be continuously monitored during the 18F-AV-1451 study 
imaging session; 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 between 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. 
 
7.1.5. 
Longitudinal Follow-Up Phone Calls 
Subjects or their designated decision makers will be contacted by phone at 5 and 14 
months following the initial 18F-AV-1451 scan to collect updated concomitant 
medications and medical history. 
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 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 or 
legally authorized representative.  
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All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB) prior to use. 
Medical History, Neurologic Disease History  
The investigator or designee will obtain a case history at the screening visit. 
 Relevant demographic information  
 Review of body systems 
 Social history 
 Medical and surgical history 
 Concurrent medications 
 Neurologic Disease history (month and year of symptom onset, month and 
year of 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. 
MRI 
MRI, including both volumetric and standard clinical sequences will be obtained.  The 
MRI sequences and acquisition parameters will be described in a separate document.  If a 
comparable MRI has been performed within the last six months, for the screening MRI, 
and an electronic copy of the images is available for submission, it should be discussed 
with the sponsor whether the MRI need not be repeated. 
A sub-set of subjects in the Exploratory Phase may have the option to have a rsfMRI in 
addition to the volumetric and standard clinical sequences at both the screening MRI and 
follow-up MRIs. 
Electronic copies of MRI scans will be submitted to Avid or designated imaging core lab. 
Vital Signs  
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Vital signs (pulse rate, respiratory rate, supine blood pressure) will be taken at the 
following time points: 
 Screening visit 
 Florbetapir F18 Imaging Day 
o immediately prior to injection of florbetapir F 18 
 
18F-AV-1451 Imaging Day  
o Immediately 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   
Temperature will be obtained at the following time points: 
 
18F-AV-1451 Imaging Day  
o Immediately prior to the administration of 18F-AV-1451 Injection 
o After the completion of imaging prior to discharge   
Height and Weight 
At both the screening and imaging visits body weight will be measured, lightly clothed.   
Height will be measured at screening. 
Electrocardiogram 
A resting 12-lead electrocardiogram will be recorded at screening.  At the 18F-AV -1451 
imaging visits the ECGs will be taken at the following time points: 
 Two ECGs will be taken at approximately 5 minutes apart immediately prior 
(within approximately 10 minutes) to 18F-AV-1451 Injection administration. 
 One ECG will be taken immediately (within approximately five minutes) after 
completion of 18F-AV -1451 injection.  
 One ECG will be taken after completion of the PET scan prior to discharge. 
Clinical Laboratory Tests  
Clinical laboratory evaluation will be performed at screening, on imaging day: prior to 
administration of 18F-AV-1451 Injection, and after completion of 18F-AV-1451 imaging. 
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. 
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 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.  
 ApoE Genotyping (10 mL, blood) will be performed at the initial 18F-AV-
1451 imaging session for those subjects whose ApoE results are unknown. 
Genetic Samples 
A one-time blood collection (10 mL, blood) will be performed on the day of the initial 
18F-AV-1451 imaging session for genetic analysis. Where local regulations allow, 
samples will be stored and analysis may be performed on genetic variants thought to play 
a role in dementia or related diseases. Samples will only be used for investigations related 
to disease and drug or class of drugs under study in the context of this clinical program. 
They will not be used for broad exploratory unspecified disease or population genetic 
analysis.  
Samples will be identified by the patient number and stored for up to 15 years after the 
last patient visit for the study at a facility selected by the sponsor. The sample and any 
data generated from it can only be linked back to the patient by investigator-site 
personnel. Subjects may opt out of participation. 
Pregnancy Testing  
 Serum beta hCG, qualitative:  performed at screening for females of 
childbearing potential who are not surgically sterile.  A serum pregnancy test 
may also be obtained prior to injection at the Imaging Visit if required by the 
local site. 
 Urine beta hCG: performed at both the 18F-AV-1451 and florbetapir F 18 
imaging visit(s) prior to injection for females of childbearing potential 
(defined as pre-menopausal, less than 2 years post-menopausal or not 
surgically sterile). 
Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-ID) 
Tau pathology can be associated with Traumatic Brain Injury (TBI), therefore the OSU 
TBI-ID (Corrigan and Bogner 2007) short version will be used to screen for a history of 
traumatic brain injury. It is the briefest version that still provides several summary indices 
on which the original version was validated. To shorten the instrument, TBIs resulting in 
loss of consciousness are emphasized over less severe injuries. 
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. 
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Alzheimer’s Disease Assessment Scale—Cognitive subscale (ADAS-Cog 11)  
The ADAS (ADAS-Cog; Rosen et al. 1984) was designed to assess the severity of the 
dysfunction in the cognitive and noncognitive behaviors characteristic of persons with 
AD.  The cognitive subscale of the ADAS, the ADAS-Cog11, consists of 11 items 
assessing areas of function most typically impaired in AD:  orientation, verbal memory, 
language, and praxis.  The scale ranges from 0 to 70, with higher scores indicating greater 
disease severity.   
Digit Symbol Substitution Test (DSST) 
The DSST (Wechsler Adult Intelligence Scale F Revised, 1981) is a paper test of 
psychomotor performance in which the subject is given a key of numbers and matching 
symbols and a test section with numbers and empty boxes. Under each number the 
subject should write down the corresponding symbol as fast as possible. The score is the 
number of correct number-symbol matches made within the allowed time (90 seconds).  
The strategy to solve the DSST consists of sequential encoding and retrieval of numbers 
and corresponding symbols.  Incidental memory, visuo-motor coordination, perceptual 
organization, and selective attention are key factors that determine the final score 
(Wechsler Adult Intelligence ScaleFRevised, 1981).  The ability to sort out irrelevant 
information (e.g., symbols that may look alike) also impacts performance. This test has 
high test–retest reliability (Matarazzo and Herman, 1984).  
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.  
Trail Making A and B 
The trail making test (Reitan and Wolfson, 1985) is a test of executive function. Part A 
consists of 25 circles numbered 1 through 25 distributed over a sheet of paper. The 
subject is instructed to connect the circles by drawing a line as quickly as possible in 
ascending numerical order. Part B consists of 25 circles containing either numbers (1 
through 13) or letters (A-L).  The subject is instructed to connect the circles while 
alternating between numbers and letters in ascending order. The subject is timed. The 
time to complete Part A is a 150 second maximum and Part B is a 300 second maximum. 
Testing is stopped if the maximum time is reached.  
Logical Memory Test, Immediate and Delayed Recall, Story A (WMS-R) 
The logical memory test (Wechsler D. 1987) assesses the ability to recall a short story. 
Subjects are read a story and asked to recall the story immediately and after a delay. 
Animal list generation 
The animal list generation (Morris et al. 1989) is used to measure verbal fluency. The 
subject is asked to name as many animals as possible in 60 seconds.  
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Boston Naming Test (BNT) (30 item) 
The 30 item Boston Naming Test (Kaplan, et al. 1983) is a measure of the ability to 
orally label 30 line drawings of objects. The objects are presented to the subject in order 
of frequency, from most frequent to least frequent. 
American National Adult Reading Test (ANART) 
ANART (Grober and Sliwinski 1991) is a measure for estimating premorbid verbal 
intelligence. The subject is presented with a word list and asked to pronounce the words.    
Clock drawing test 
The clock drawing test (Goodglass and Kaplan 1983) has two components: a command 
condition and a copy condition. In the command condition, the subject draws a clock 
according to verbal instructions. In the copy condition, the subject copies a model clock 
drawn at the top of a form.  
Judgment of Line Orientation Test (JOLO) 
The JOLO (Benton 1978) is a non-motor measure of visual perceptual ability where there 
is no time demand. The task asks subjects to match two lines by their angel of orientation 
to a test set of lines presented below the stimulus lines.  
Pfeffer Functional Activities Questionnaire (FAQ), (Pfeffer et al. 1982) 
Functional status is conceptualized as the “ability to perform self-care, self- maintenance 
and physical activities.” FAQ was developed to assess instrumental activities of daily 
living involving higher level functional skills such as shopping alone, writing checks, 
remembering appointments..etc. FAQ asks informant to rate patient’s ability using the 
following scoring system: Dependent = 3; Requires assistance = 2; Has difficulty but 
does by self = 1; Normal = 0; Never did [the activity] but could do now = 0; Never did 
and would have difficulty now = 1The sum scores ranges from 0-30. 
Clinical Dementia Rating (CDR) Scale (Berg, 1988) 
The CDR examines 6 categories of cognitive functioning domains. Each domain is 
scored on a scale ranging from 0 to 3 (including 0.5). A global rating of dementia can be 
generated from the domain scores. A CDR Sum of Boxes can be generated from the total 
across domains.  
Physician Visit 
A physician must see the subject at screening, at baseline, prior to drug administration 
and at study end, prior to discharge from both the 18F-AV-1451 and florbetapir F 18 
imaging sessions.  At this time, the physician should review all safety data and briefly 
examine/query the subject regarding potential adverse events or other treatment issues.  A 
physician or physician designee can administer these assessments on the day of imaging 
for the florbetapir F 18 imaging session only. 
Optional Cerebrospinal fluid (CSF) collection  
Depending on site participation, subjects in the Exploratory Phase will be offered to 
consent for optional CSF collection by LP. Aβ, phospho-tau, and total tau will be 
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measured. 20 mL of CSF will be collected from each subject and divided into 1 ml 
conical vials. Samples will be shipped to a facility designated by the Sponsor. Samples 
will be identified by the patient number and stored for up to 15 years after the last patient 
visit for the study at a facility selected by the sponsor  
7.3. 
Protocol for Image Collection 
The sponsor will prepare and distribute a PET Imaging Manual for 18F-AV-1451 and 
florbetapir F 18. MRI image acquisition parameters and transmission procedures will be 
outlined in an MRI procedures manual.   
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 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. 
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. 
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 capable of giving informed consent then the subject should sign 
on the consent line of the informed consent form.  When applicable the legally authorized 
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representative should sign as well, indicating that they have witnessed the subject’s 
consent, and further agree to participate as an informant. 
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 
and/or their legally authorized representative for their records. 
7.6. 
Documentation 
18F-AV-1451 and florbetapir F 18 PET scans, as well as MRI scans, will be saved in an 
appropriate electronic format as specified in the imaging manuals.  A copy of all scans 
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 CRF.  All data in the CRF 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 CRFs may need to be made 
available and complete for an audit by the FDA or other international regulatory 
authorities or Avid at any time.  A ballpoint pen should be used to ensure that all copies 
are legible.  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 Page of the eCRF. Investigators will be instructed 
to report to Avid or its designee their assessment of the potential relatedness of each AE 
to investigational product 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 Page of the eCRF.  Signs and symptoms of each 
AE should be described in detail (e.g., start and stop dates/time, severity/intensity, 
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relationship to investigational product, 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 trial medication. 
7.7.2. 
Adverse Event Definitions 
Adverse Events 
For reporting purposes, Avid will distinguish among pre-existing conditions, treatment -
emergent adverse events and trial-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.  Signs and 
symptoms that are believed to be due to the pre-existing condition (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 or severity.  Additionally, signs or symptoms or changes 
in pre-exisiting conditions that occur outside the trial defined adverse event reporting 
period (e.g., between the end of the baseline/cross-sectional imaging period and the 9 
month follow-up imaging 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 18F-AV-1451 
administration, either at baseline or at the 9 or 18 month imaging visit. 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.  Adverse 
events associated with the use of 18F-AV-1451 or Florbetapir F 18 injection will be 
recorded as treatment emergent relative to the respective drug.  Adverse experiences that 
occur after administration of either drug 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 
baseline/cross-sectional imaging period but not during the 48 hour windows following 
the administration of 18F-AV-1451 or Florbetapir F 18 injection.  For this purpose, the 
baseline/cross-sectional imaging period will be defined as beginning with the signing of 
consent and ending 48 hours after the last of the screening/baseline procedures described 
in sections 7.1.1 – 7.1.3, including (but not limited to) neuropsychological testing, MRI, 
18F-AV-1451 or Florbetapir F 18 injection PET scanning and lumbar puncture. 
The end of study for the purpose of adverse event reporting is defined as 48 hours after 
the last administration (i.e., 18 month visit or early termination visit) of 18F-AV-1451. 
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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 Investigational Product 
Investigators will be instructed to report their assessment of the potential relatedness of 
each adverse event to protocol procedure, concomitant medication and/or investigational 
product.  The assessment of the relationship of an adverse event to the administration of 
the investigational product 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 investigational 
product to adverse events, an assessment is required of 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. 
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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 Page via the Electronic 
Data Capture (EDC) system.  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 page of the 
eCRF.  Signs and symptoms of each AE should be described in detail (e.g., start and stop 
dates, severity/intensity, relationship to investigational product, 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 investigational product 
will be collected until 48 hours after the  dosing of the investigational product, regardless 
of the investigator’s opinion of causation.  Therefore, SAEs that occur later than 48 hours 
after the dosing of the investigational product are not required to be reported unless the 
investigator feels the events were related to either investigational product or a protocol 
procedure. 
If a patient experiences an SAE after signing informed consent, but prior to receiving 
investigational product, 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. 
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 according to clinical 
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group (healthy volunteers and subjects with cognitive impairment) at recruitment for all 
subjects in the safety population.  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.  
Additional details concerning statistical analyses will be included in the Statistical 
Analysis Plan (SAP). 
8.1.1. 
Sample Size Estimation 
8.1.1.1. 
Exploratory Phase 
A total of 230 subjects (80 cognitively healthy volunteers, 80 MCI and 70 AD) will be 
enrolled in the Exploratory Phase study.   To explore the 18F-AV-1451 SUVR values 
across age strata among cognitively healthy subjects, these subjects will be divided into 5 
age groups as 20-40 years old, 50-59 years old, 60-69 years old, 70-79 years old and 80 
years old or above. There will be 15 subjects in each of the 50 or older age groups and 
about 20 subjects from age group 20-40 years old. From a preliminary analysis of study 
T807000, the standard deviation (SD) of SUVR from combination ROI was 0.06 for 
subjects with low probability of AD. Therefore assuming a 0.06 SD, a sample of 15 
subjects will give an approximately 90% probability to observe a 95% confidence 
interval (CI) as accurate as +/-0.04 around the point estimation.  
From previous studies, the amyloid positive rate is approximately 50% among MCI 
patients and approximately 80% from AD subjects. Therefore 80 MCIs and 70 ADs will 
likely result in 40 amyloid positive MCIs and 56 amyloid positive ADs. Also from study 
T807000, the combination ROI SUVR difference between CN and AD was 0.39, with a 
pooled SD of 0.27. Assume a pooled SD of 0.30, a sample of 60 CNs and 56 amyloid 
positive ADs will give a 90% power to detect a 0.18 difference between the CN and AD 
groups.  
8.1.1.2. 
Confirmatory Phase 
 
The final hypothesis and endpoint measurements for the Confirmatory Phase are yet to be 
determined and will depend on the discoveries from Exploratory Phase data. However the 
primary objective of the confirmatory phase is to validate the accuracy of 18F-AV-1451 
scans to predict clinically significant disease progression within 18 months from scan 
(e.g., cognitive function deterioration as measured by endpoints based on Exploratory 
Phase results).  For the purpose of sample size calculation, we assumed that the target 
success criteria would be at least 70% sensitivity and at least 70% specificity for 18F-AV-
1451 scans to detect this deterioration, with the lower bound of 95% confidence intervals 
(CI) above 50% for both sensitivity and specificity. Preliminary analysis of the 
exploratory phase cohort data showed that clinical assessments may have a relatively 
large variance. It is important to ensure that enough subjects will be in each group for 
sensitivity and specificity calculation (i.e., the subjects with or without a significant 
disease progression).  To that end, we assume at least 20% of the subjects will be in each 
group at the 18 month follow up.  With this assumption, a 5% two-sided type I error rate, 
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and that 95% CI will be calculated using Wilson score method, a sample of 115 subjects 
will provide an over 90% probability to observe lower bound of 95% CI above 50%, for 
both sensitivity and specificity.    Also assuming an approximate 20% drop out rate over 
the 18 months follow up, this study will aim to enroll 150 subjects in total.    
 
8.1.2. 
Exploratory Phase, Cross-sectional Component 
8.1.2.1. 
Primary Objective Analysis 
ANOVA analysis will be applied to detect the difference between clinical diagnosis 
groups. If an overall difference is detected, pair-wised comparisons will be conducted. If 
the pre-requisites of ANOVA test are not met, Kruskal Wallis and Wilcoxon rank sum 
test will be conducted instead. 
8.1.2.2. 
Secondary Objective Analysis 
Descriptive statistics will be applied to describe the tau SUVR distribution across age 
groups among cognitive healthy subjects. These data will also be graphically displayed.  
8.1.2.3. 
Exploratory Objective Analyses 
Correlation analysis will be conducted to determine whether greater degrees of cognitive 
impairment are associated with higher 18F-AV-1451 uptake in subjects with an amyloid 
positive status.  
Correlation analysis will be conducted to assess the relationship between regional tau 
deposition measurements with cognitive function measurements and other collected 
biomarkers.  
The association between baseline values in 18F-AV-1451 uptake in brain and clinical 
function measures, as well as, biomarkers of neurodegeneration and neurological disease 
will be explored using the methods described below in 8.1.3.2.  
Subgroup and/or covariate analyses will also be planned accordingly by amyloid beta 
status, age groups, and etc. The specific analyses to address these objectives will be 
described in the Statistical Analysis Plan (SAP) 
8.1.3. 
Exploratory Phase, Longitudinal Component 
8.1.3.1. 
Primary Objective Analysis 
The primary objective of longitudinal component is to assess the rate of change of tau 
deposition as measured by 18F-AV-1451 over time. The tau measurement change from 
baseline at each follow up visit will be estimated using Mixed Model Repeated Measures 
(MMRM). The MMRM model will include the following fixed effects: baseline value, 
clinical group, visit, clinical group by visit interaction, and baseline age. Visit will be 
considered as a categorical variable. An unstructured covariance matrix will be used to 
model the within-subject correlation. Least squared means (LSM) and standard error for 
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the tau value change from baseline will be calculated for each clinical group at every 
follow up visit.  
8.1.3.2. 
Exploratory objective analyses 
The association between change and/or baseline values in 18F-AV-1451 uptake in brain 
and clinical function measures, as well as, biomarkers of neurodegeneration and 
neurological disease (CSF markers including tau, phosphor-tau and beta-amyloid (Aβ), 
genetic markers, PET amyloid imaging, brain atrophy assessed by volumetric MRI, and 
resting connectivity assessed with rsfMRI) will also be assessed using MMRM analyses. 
Marginal logistic regression and time to event analyses will also applied when 
appropriate, such as to investigate the odds ratio of ADAS score change over 4 with the 
tau deposition change over time. The details of these statistical analyses will be provided 
in SAP.    
8.1.4. 
Confirmatory Phase 
Longitudinal data from the exploratory study phase will be assessed periodically to 
determine the relationships between various 18F-AV-1451 imaging parameters (e.g., 
composite and regional SUVr, voxel based statistics and visual interpretation) and the 
change from baseline in the various cognitive and functional assessments.  These data 
will be used to generate hypotheses regarding the relationship between 18F-AV-1451 PET 
tau imaging and cognitive/functional change that will be formally incorporated into an 
analysis plan and tested in the confirmatory stage of the study.     
Based on discoveries using data from Exploratory Phase, a disease progression 
measurement will be chosen as truth standard (TS), and the accuracy of 18F-AV-1451 
PET scans to detect this TS within 18 months of scan will be evaluated.  Hypothesis 
testing and detailed analyses will be described in a statistical analysis plan (SAP), which 
will be finalized prior to database lock. Possible analyses include calculation of accuracy 
measures such as sensitivity, specificity, and two sided 95% confidence intervals (CI) 
around these rates. Other analyses may include Mixed-Effect Model Repeated Measures 
(MMRM) analysis, risk ratio analysis, and time to event analysis.   
8.2. 
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 treatment and seriousness.  All subjects who experience SAEs or 
who discontinue due to AEs will be summarized. 
Discontinuation  
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All subjects who discontinued participation prior to completing the study will be listed 
and their discontinuation reasons will be tabulated. 
Laboratory Data 
Changes in laboratory data from Baseline will be summarized.  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 
Mean changes in ECG parameters will be summarized.  The average of the two ECG 
collected prior to administration of 18F-AV-1451 on imaging day (-10 and -5 min prior to 
the administration of 18F-AV-1451), will be used for the baseline estimate.  Any subjects 
showing QTc > 500 or change from baseline of more than 60 msec will be highlighted. 
8.3. 
18F-AV-1451 Image Analysis 
All 18F-AV-1451 PET images obtained at baseline and follow-up starting at 80 minutes 
post injection will be analyzed. 18F-AV-1451 PET images starting at 110 minutes post 
injection, for those subjects in which they were acquired, will also 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 to accomplish the study objectives.  
Exploratory analysis will include co-registration of MRI to the 18F-AV-1451 PET images 
for ROI creation and/or partial volume correction of 18F-AV-1451 PET images using 
anatomical information from MRI data. 
Additional analyses may explore various voxel and threshold based approaches.   
The final primary method image analysis for the confirmatory phase will be chosen based 
on results from the exploratory phase before any of the confirmatory phase images are 
analyzed. 
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
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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. The primary analysis will include data from all centers.  A 
multicenter publication, reporting the primary analysis data set, with authorship from all 
contributing centers, 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, EMA 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/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. 
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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 florbetapir F 18 or 
18F-AV-1451. 
10.5. 
Investigational Product 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 and Florbetapir F18 Injection 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.  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. 
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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 
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 3 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 3 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 
Albert, M. S., DeKosky, S. T., Dickson, D., et al. “The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging and Alzheimer’s Association workgroup.”  The Alzheimer’s Association. 
Alzheimer’s and Dementia, 1-10, 2011. 
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. 
Dickson, T.C., Saunder, H.L., Vickers, J.C.  “Relationship between apolipoprotein E and 
the amyloid deposits and dystrophic neuritis of Alzheimer’s disease.”  Neuropathol Appl 
Neurobiol.  1997; (23):483-491.  
Dubois, B., Feldman, H.H., Jacova, C., et al.  “Research criteria for the diagnosis of 
Alzheimer’s disease: revising the NINCDS-ADRDA criteria.”  Lancet Neurol. 6:734-46 
Review, 2007. 
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.  
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. 
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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.    
Price, J.L., Morris, J.C. ”Tangles and plaques in nondemented aging and “preclinical”  
Alzheimer’s disease.” Ann Neurol 45:358–368, 1999. 
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, 
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 Adult Intelligence ScaleFRevised. 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 
Exploratory Phase and Confirmatory Phase Cohorts 
 
a. 
Screening may take place over several days.  All assessments must be performed within 30 days of the first 18F-AV-1451 
imaging session (with the exception of the MRI if previously performed). 
b. 
The 18F-AV-1451 and florbetapir F 18 imaging sessions must be performed at least 48 hours apart, but the order of the scans is 
interchangeable. 
c. 
Two ECGs will be taken approximately 5 minutes apart immediately prior to (within approximately 10 minutes) 18F-AV-1451 
Injection administration.  One will be taken within 5 minutes after completion of injection.   
d. 
Screening vital signs include pulse rate, respiratory rate, supine blood pressure, height and weight  
e. 
Vital signs (pulse rate, respiratory rate, supine blood pressure, weight) will be taken immediately prior to injection of florbetapir 
F 18.  
f. 
Pulse, respiratory rate, supine blood pressure, temperature and weight  will be taken immediately prior to administration of 18F-
AV-1451.  Pulse, respiratory rate, and supine blood pressure within 5 minutes after completion of injection of 18F-AV-1451 
Injection.  
g. 
Pulse, respiratory rate, supine blood pressure, temperature 
h. 
Blood and urine samples will be collected prior to administration of 18F-AV-1451 Injection.  
i. 
Serum beta-hCG pregnancy test at screening (for females of childbearing potential defined as pre-menopausal or less than 2 
years post-menopausal and not surgically sterile. 
j. 
For women of childbearing potential, a negative urine pregnancy test must be obtained within 24 hours prior to florbetapir F 18 
injection and within 24 hours prior to 18F-AV-1451 injection. 
k. 
Including CDR for subjects tin the Confirmatory Cohort. 
l. 
CSF collection may occur after the subject has passed screening procedures for subjects in the Exploratory Cohort only 
m. 
A physician or physician designee  
 
Evaluations 
 
Screening 
Visita 
Florbetapir 
F 18 
Imaging 
Visitb 
End of 
Florbetapi
r F 18 
Imaging 
(prior to 
discharge) 
Follow-up 
Phone Call 
18F-AV- 
1451 
Imaging 
Visitb 
End of 18F-AV- 
1451 Imaging 
(prior to 
discharge) 
Follow-up 
Phone Call 
Signed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical 
History/Neurologic 
Disease History 
X 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
 
 
X 
 
 
Physical Exam/ 
Neurological Exam 
X 
 
 
 
 
 
 
ECG  
X 
 
  
 
Xc 
X 
 
Vital Signs    
Xd 
Xe 
 
 
X f 
Xg 
 
Safety Labs  
X 
 
  
 
Xh 
X 
 
Serum beta-hCG i 
X 
 
 
 
 
 
 
Urine Pregnancy testj 
 
X 
 
 
X 
 
 
OSU TBI-ID 
X 
 
 
 
 
 
 
MMSE 
X 
 
 
 
  
 
 
ADAS-Cog 11 
X 
 
 
 
 
 
 
Neuropsych batteryk 
X 
 
 
 
 
 
 
MRI of the brain 
X 
 
 
 
  
 
 
PET Brain Scan 
 
X 
 
 
X 
 
 
ApoE 
 
 
 
 
X 
 
 
Genetic sample 
 
 
 
 
X 
 
 
Optional CSF 
Xl 
 
 
 
 
 
 
Evaluation by a physician   
X 
Xm 
Xm 
 
X  
X 
 
Adverse Events  
X  
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
 X 
X 
X 
X 
X 
X 
X 
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Longitudinal Component 
 
Exploratory Phase Cohorts ONLY 
 
 
 
 
 
 
The First and Second Longitudinal Follow-up Visits will be performed over several days.  
n. 
Two ECGs will be taken approximately 5 minutes apart immediately prior to (within approximately 10 minutes) 18F-AV-1451 
Injection administration. One will be taken within 5 minutes after completion of injection. One will be obtained at the end of 
imaging day 
o. 
Vital signs include pulse rate, respiratory rate, supine blood pressure, temperature and weight 
p. 
Blood and urine samples will be collected prior to administration of 18F-AV-1451 Injection and at the end of the imaging day.  
q. 
For women of childbearing potential, a negative urine pregnancy test must be obtained within 24 hours prior to 18F-AV-1451 
injection. 
r. 
ADAS-Cog 11, Neuropsych battery, and MRI can be performed +/- 30 days of the 18F-AV-1451 scan and within 30 days of each 
other. Assessments should be performed within the specified window of 9 (+/-2) months or 18 (+/-2) months.  
s. 
Between 2 or 3 business days of the imaging day 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluations 
5 Month 
Follow-up 
Phone Call 
9 (+/-2) Months 
First 
Longitudinal 
Follow-up Visit 
14 Month Follow-up 
Phone Call 
18 (+/-2) Months, 
Second Longitudinal 
Follow-up Visit 
Updated Medical History 
X 
X 
X 
X 
Updated Concomitant Meds 
X 
X 
X 
X 
ECG  
 
Xn 
 
Xn 
Vital Signs    
 
Xo 
 
Xo 
Safety Labs  
 
Xp 
 
Xp 
Urine Pregnancy testq 
 
X 
 
X 
MMSE 
 
X 
 
X 
ADAS-Cog 11r 
 
X 
 
X 
Neuropsych battery, including 
CDRr 
 
X 
 
X 
MRI of the brainr 
 
 X 
 
 X 
PET Brain Scan 
 
X 
 
X 
Follow-up Phone Calls  
 
X 
 
X 
Evaluation by a physician   
 
X  
 
X  
Adverse Events  
 
X 
 
X 
Serious Adverse Events 
 
X 
 
X 
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Confirmatory Phase Cohort ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluations 
5 Month 
Follow-up 
Phone Call 
9 (+/-2) Months, 
First 
Longitudinal 
Follow-up Visit 
14 Month Follow-up 
Phone Call 
18 (+/-2) Months, 
Second Longitudinal 
Follow-up Visit 
Updated Medical History 
X 
X 
X 
X 
Updated Concomitant Meds 
X 
X 
X 
X 
MMSE 
 
X 
 
X 
ADAS-Cog 11 
 
X 
 
X 
Neuropsych battery, including 
CDR 
 
X 
 
X 
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INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol:  An open label, multicenter study, evaluating the safety and imaging 
characteristics of 18F-AV-1451 in cognitively healthy volunteers, subjects with mild 
cognitive impairment, and subjects with Alzheimer’s disease 
 
 
 
 
Date and Version: 07 August 2015, Amendment 2 
 
 
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. 
 
 
 
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Printed Name                                                                    Date 
 
 
 
______________________________________ 
Signature 
 
 
LY3191748