Clinical trial NCT02795780
Conditions: Alzheimer's Disease
Sponsor: Avid Radiopharmaceuticals
Start date: 2016-08-01; Completion date: 2017-08-28
Enrollment: 79 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate longitudinal change of tau deposition as measured by flortaucipir F 18 uptake over time.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Flortaucipir F18 intervention 2: PET Scan
Intervention descriptions: intervention 1: 370 megabecquerel (MBq) IV single-dose intervention 2: positron emission tomography (PET) scan

Protocol documents:
Prot_000.pdf: 
18F-AV-1451-A18 Protocol 
 
An Open Label, Multicenter Study Evaluating the Imaging Characteristics of a Follow up 18F-
AV-1451 Scan in Subjects That Participated in the Confirmatory Cohort of 18F-AV-1451-A05 
 
NCT02795780 
Approval date: 22 Mar 2016


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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-A18 
An open label, multicenter study evaluating the imaging characteristics of a follow up 18F-AV-
1451 scan in subjects that participated in the confirmatory cohort of 18F-AV-1451-A05 
Planned number of subjects (Enrolled): Approximately 160  
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 25 centers in the United States 
Trial Objectives:  
The primary objective of this protocol is to assess longitudinal change of tau deposition as 
measured by 18F-AV-1451 uptake over time. 
Eligibility: 
See Section 5.3, Selection of Subjects. 
Study Design: 
This is a phase 2 study that will evaluate longitudinal change of tau deposition as measured by 
18F-AV-1451 uptake over time. As subjects from the 18F-AV-1451-A05 confirmatory cohort 
complete the 18F-AV-1451-A05 study, they will be presented with the opportunity to participate 
in this longitudinal study. 
All subjects will provide informed consent before starting any study procedures.  
Screening assessments should take place at the time of the subject’s final 18F-AV-1451-A05 
study visit and will include safety labs (may be collected any time prior to 18F-AV-1451 
Injection), ECG, and collection of updated medical history and concomitant medications if not 
collected within last 30 days. An MRI, including both volumetric and standard clinical 
sequences will be conducted prior to the subject’s 18F-AV-1451 PET imaging session. Subjects 
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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 
who qualify for the study will return to the clinic within 30 days of the screening visit for an 18F-
AV-1451 PET imaging session. 
Assessments and Endpoints: 
Each subject will have a screening visit(s), an MRI visit, an 18F-AV-1451 PET imaging visit, 
and a follow-up phone call after the imaging visit.  
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, a 
continuous 20-minute brain scan (4 acquisitions of 5-minute duration) will be obtained. 
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 
to 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. Additional 
assessments that will be performed at each visit are detailed in Section 7.1.   
Statistical Methods:   
Descriptive statistics will be used to summarize the change in AV-1451 from A05 baseline 
(Change From Baseline; CFB) for the AV-1451 SUVR from the combination region and 
individual sub-regions.   Analysis of covariance (ANCOVA) adjusting for baseline AV-1451 
SUVR level and age will be applied to compare the least square (LS) mean tau CFB by clinical 
diagnosis groups (MCI vs. AD), amyloid status (AB+ vs. AB-) and the interaction of these two 
factors. The relationship between AV-1451 SUVR CFB and cognitive function assessments 
CFB will also be explored using ANCOVA models. 
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TABLE OF CONTENTS 
1. 
INTRODUCTION .............................................................................. 8 
2. 
TRIAL OBJECTIVES ...................................................................... 11 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 11 
4. 
TEST DRUG AND CONTROL AGENTS ...................................... 12 
4.1. 
Descriptive Name:  18F AV-1451 ..................................................... 12 
4.2. 
Radioactive Labeling ........................................................................ 12 
4.3. 
Decay Characteristics ....................................................................... 12 
4.4. 
Formulation and Dose 18F-AV-1451 Injection ................................. 12 
4.5. 
Packaging 18F-AV-1451 Injection .................................................... 13 
4.6. 
Storage and Handling 18F-AV-1451 Injection .................................. 13 
5. 
INVESTIGATIONAL PLAN ........................................................... 13 
5.1. 
Overall Design and Plan of Trial ...................................................... 13 
5.2. 
Planned Dosage and Duration of Treatment ..................................... 14 
5.2.1. 
Dosage and Administration .............................................................. 14 
5.2.2. 
Rationale for Dosages ....................................................................... 14 
5.3. 
Selection of Subjects ......................................................................... 14 
5.3.1. 
Inclusion Criteria .............................................................................. 14 
5.3.2. 
Exclusion Criteria ............................................................................. 15 
5.4. 
Prior and Concomitant Therapy ........................................................ 15 
5.5. 
Removal of Subjects from Trial ....................................................... 15 
5.6. 
Premature Termination of Trial/Closure of Center .......................... 16 
6. 
WARNINGS/PRECAUTIONS ........................................................ 16 
7. 
PROCEDURES AND METHODS .................................................. 16 
7.1. 
Assessment Periods .......................................................................... 16 
7.1.1. 
Screening Visit: ................................................................................ 17 
7.1.2. 
MRI Visit: ......................................................................................... 17 
7.1.3. 
PET Imaging Visit: ........................................................................... 17 
7.2. 
Observations and Measurements ...................................................... 18 
7.3. 
Protocol for Image Collection .......................................................... 19 
7.4. 
Good Clinical Practice and Monitoring ............................................ 19 
7.5. 
Informed Consent and Subject Information ..................................... 19 
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7.6. 
Documentation .................................................................................. 20 
7.7. 
Adverse Events (AE) ........................................................................ 20 
7.7.1. 
Adverse Event Monitoring ............................................................... 21 
7.7.2. 
Adverse Event Definitions ................................................................ 21 
7.7.3. 
Adverse Event Documentation ......................................................... 23 
7.7.4. 
Reporting of Serious Adverse Events ............................................... 23 
8. 
STATISTICAL ANALYSIS ............................................................ 23 
8.1. 
General Statistical Considerations .................................................... 23 
8.1.1. 
Sample Size Estimation .................................................................... 24 
8.2. 
Efficacy Analysis .............................................................................. 24 
8.3. 
Safety Analysis ................................................................................. 24 
8.4. 
18F-AV-1451 Image Analysis ........................................................... 25 
9. 
USE OF DATA AND PUBLICATION ........................................... 25 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................. 26 
10.1. 
Institutional Review Board (IRB) ..................................................... 26 
10.2. 
Informed Consent ............................................................................. 26 
10.3. 
Protocol Adherence .......................................................................... 26 
10.4. 
Documents Necessary for Initiation of the Trial .............................. 26 
10.5. 
Investigational Product Control ........................................................ 27 
10.6. 
Data Collection ................................................................................. 27 
10.7. 
Adverse Events ................................................................................. 27 
10.8. 
Records Retention ............................................................................. 28 
11. 
APPENDICES .................................................................................. 29 
11.1. 
References ......................................................................................... 29 
11.2. 
Trial Flow Chart ............................................................................... 31 
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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AD 
Alzheimer’s disease 
Adverse Event 
(AE) 
Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. 
Audit 
A systematic and independent examination of the trial-related activities 
and documents to determine whether the evaluated trial-related activities 
were conducted, and the data were recorded, analyzed, and accurately 
reported according to the protocol, applicable standard operating 
procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s). 
Case Report Form 
(CRF) and 
electronic Case 
Report Form 
(eCRF) 
A printed or electronic form for recording study participants’ data during 
a clinical study, as required by the protocol. 
CNS 
Central Nervous System 
CRO 
Contract Research Organization: A person or organization (commercial, 
academic, or other) contracted by the sponsor to perform one or more of 
the sponsor’s trial-related duties and functions.  
CT 
 
Computed Tomography 
 
Efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
FDA 
US Food and Drug Administration  
FDG 
18F - Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
Institutional 
Review Board 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
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/Independent 
Ethics Committee 
the safety, welfare and human rights of the subjects participating in a 
clinical study are protected. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
IV 
Intravenous 
Kd 
Dissociation Constant 
MBq 
Megabecquerel 
mCi 
Millicurie 
MCI 
Mild Cognitive Impairment 
MHD 
Maximum Human Dose 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No Observable Adverse 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 0.54 
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 
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doses up to 50x the intended maximum human dose (MHD).  Nonetheless, until 
sufficient human cardiovascular safety data are available, initial clinical studies will 
exclude subjects with a history of risk factors for Torsades de Pointes and subjects taking 
drugs known to prolong the QT interval. 
In vivo safety pharmacology studies were also conducted in rats to determine potential 
effects on the CNS and respiratory systems. In these studies no clinically relevant effects 
were reported at doses exceeding 100x the intended MHD. Additionally, non-radioactive 
AV-1451 has been tested in single and repeat-dose toxicology studies in rat and dog.  In 
each of these studies the no observable adverse effect levels (NOAELs) were the highest 
doses tested (150x MHD for single, 50x MHD for repeat).   
Potential genotoxicity of non-radioactive AV-1451 was tested in both in vitro and in vivo 
assays.  In the in vitro assays, AV-1451 tested positive for potential genotoxicity.   
However, in the in vivo rat micronucleus assay at doses up to 750x MHD (scaled 
allometrically), AV-1451 showed no evidence of genotoxicity. The different results in the 
in vitro genotoxicity assays and the in vivo micronucleus study are likely related to 
differences in the exposure conditions encountered by the target cells in the different test 
systems. In vivo, AV-1451 is cleared rapidly; however, the in vitro experiments employ 
static, prolonged exposure of cells to high concentrations of the test article. While the in 
vitro data show the potential for genotoxicity, the in vivo data provide assurance that 
genotoxicity is unlikely to occur at clinically-relevant doses for human diagnostic studies. 
Three human clinical studies have been completed with 18F-AV-1451. A total of 59 
subjects have been exposed to 18F-AV-1451 in these studies. The following side effects 
have been reported in clinical studies: diarrhea, headache, and altered taste. All reported 
events were mild in intensity and all subjects recovered from these events. 
Evaluation of the PET images from completed studies demonstrates little focal cortical 
retention of 18F-AV-1451 in either young cognitively normal (YCN) or older cognitively 
normal (OCN) subjects known to be amyloid negative (florbetapir PET SUVR <1.10; 
Figure 1 Panels A and B). However, OCN subjects frequently demonstrated retention in 
the mesial temporal lobes and some OCN subjects also demonstrated retention in the 
brainstem or striatum (Figure 1 Panel B). In MCI and AD subjects, retention appeared to 
spread from mesial temporal lobes to isocortical areas (Figure 1 Panels C-F). The pattern 
of 18F-AV-1451 distribution seen on PET imaging, across subjects with various levels of 
impairment, paralleled the pattern reported in the classic autopsy series of older persons 
and subsequently used to define the Braak stage (Braak and Braak, 1991). Two clinically 
diagnosed AD subjects that were found to be amyloid negative on a florbetapir PET scan 
were the exception to this pattern, as their scans were similar to clinically normal elder 
controls and showed no cortical 18F-AV-1451 retention (Figure 1 Panel G).  
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Figure 1: 
Representative 18F-AV-1451 PET Scans 
 
 
 
B) Typical Aβ- Older Control
A) Typical young control subject
D) Aβ+ MCI subject (MMSE = 26)
C) Aβ+ MCI subject (MMSE = 26)
G) Aβ- AD subject (MMSE = 23)
E) Aβ+ AD subject (MMSE = 21)
F) Aβ+ AD subject (MMSE = 18)
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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 
upper large intestinal wall (0.0955 ± 0.0134 mSv/MBq), the small intestine 
(0.0845±0.0118 mSv/MBq)   and the liver (0.0572±0.00803 mSv/MBq).  The Effective 
Dose was 0.0235 ± 0.0016 mSv/MBq. This results in an estimated Effective Dose of 
8.70 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.  To accomplish this 
goal, the protocol will investigate longitudinal 18F-AV-1451 results in patients with 
cognitive complaints ranging from mild cognitive impairment (MCI) to mild and 
moderate Alzheimer’s disease (AD).  
2. 
TRIAL OBJECTIVES 
The primary objective of this protocol is to assess longitudinal change of tau deposition 
as measured by 18F-AV-1451 uptake over time. 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER 
PARTICIPANTS 
The trial is sponsored by: 
 
Avid Radiopharmaceuticals, Inc. 
 
The medical contact is: 
 
 
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Approximately 25 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. 
Radioactive Labeling 
The compound is labeled with [18F] fluorine that decays by positron (β+) emission and 
has a half-life of 109.77 min.  The principal photons useful for diagnostic imaging are the 
511 keV gamma photons, resulting from the interaction of the emitted positron with an 
electron. 
4.3. 
Decay Characteristics 
The time course of radioactive decay for Fluorine [18F] is shown below 
Min. 
Fraction Remaining 
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
Physical decay chart for Fluorine [18F].  Half-life = 109.77 min. 
4.4. 
Formulation and Dose 18F-AV-1451 Injection 
 18F-AV-1451 Injection is a sterile, apyrogenic clear solution for intravenous bolus 
administration. 18F-AV-1451 Injection contains 18F-AV-1451 (drug substance) 
formulated in 10% (v/v) ethanol, USP in 0.9% sodium chloride injection, USP. 
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The shelf-life of 18F-AV-1451 Injection is dependent on the strength or specific activity 
calculated at End-of-Synthesis (EOS) but is not more than 10 hours post EOS. The 18F-
AV-1451 Injection expiration time and date will be provided on the label on the 
secondary packaging of each vial or syringe.  
4.5. 
Packaging 18F-AV-1451 Injection 
Each package of 18F-AV-1451 Injection includes a sterile apyrogenic sealed glass vial or 
sterile apyrogenic syringe containing 18F-AV-1451 Injection, a surrounding protective 
lead shield canister, and an outside delivery case. 
4.6. 
Storage and Handling 18F-AV-1451 Injection 
18F-AV-1451 Injection is stored at room temperature. 18F-AV-1451 Injection should be 
stored within the original container or equivalent radiation shielding.   
5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Design and Plan of Trial 
This is a phase 2 study that will evaluate longitudinal change of tau deposition as 
measured by 18F-AV-1451 uptake over time. As subjects from the 18F-AV-1451-A05 
confirmatory cohort complete the 18F-AV-1451-A05 study, they will be presented with 
the opportunity to participate in this longitudinal study. 
All subjects will provide informed consent before starting any study procedures.  
Screening assessments should take place at the time of the subject’s final 18F-AV-1451-
A05 study visit and will include safety labs (may be collected any time prior to 18F-AV-
1451 Injection), ECG, and collection of updated medical history and concomitant 
medications if not collected within last 30 days. An MRI, including both volumetric and 
standard clinical sequences will be conducted prior to the subject’s 18F-AV-1451 PET 
imaging session. Subjects who qualify for the study will return to the clinic within 30 
days of the screening visit for an 18F-AV-1451 PET imaging session.  
Avid personnel will be blinded to the MRI and 18F-AV-1451 PET scans performed on 
subjects with the exception of the following: 
 Medical Director safety review, as necessary 
 Periodic quality assurance (QA) assessments of a random subset of PET 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. 
 Avid personnel will remain blinded to the MRI and 18F-AV-1451 PET scans until the 
18F-AV-1451-A05 database lock. 
 
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18F-AV-1451 PET Imaging Session(s):  
For the 18F-AV-1451 PET imaging session, 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. Pregnancy test will be obtained prior to 
injection. 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 to 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 
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 8.70 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:  
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1. Subjects who participated as a confirmatory subject in the 18F-AV-1451-A05 
study; 
2. Subjects who completed the 18F-AV-1451-A05 study; 
3. Subjects who signed an IRB approved informed consent prior to any study 
procedures. 
5.3.2. 
Exclusion Criteria 
Subjects will be excluded from enrollment if they: 
1. Have current clinically significant cardiovascular disease or clinically significant 
abnormalities on screening ECG; 
2. 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); 
3. 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; 
4. 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 urine β-HCG within 24 
hours prior to injection) or breastfeeding at screening. Females must agree to 
avoid becoming pregnant, and  agree to refrain from sexual activity or to use 
reliable contraceptive methods for 24 hoursfollowing administration of 18F-AV-
1451 Injection. Males with female partners who are pregnant or of childbearing 
potential must agree to refrain from sexual activity for 24 hours following 
administration of 18F-AV-1451 Injection.  Additionally, males must agree not to 
donate sperm for 24 hours following administration of 18F-AV-1451 Injection; 
5. Have had a non-study related radiopharmaceutical imaging or treatment 
procedure within 7 days prior to the 18F-AV-1451 imaging session; 
6. Are receiving any investigational medications within the last 30 days; 
7. In the opinion of the investigator, are otherwise unsuitable for this study. 
5.4. 
Prior and Concomitant Therapy 
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 on the Concomitant Medication Page in the electronic 
data capture (EDC) system.   
5.5. 
Removal of Subjects from Trial 
Subjects must be removed from the trial if: 
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1. Informed consent is withdrawn; or  
2. The investigator or the sponsor believes it is in the best interest of the subject to 
be removed from the trial. 
Subjects may be withdrawn from the trial if a 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 
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.  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, and ECGs 
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 24 hours after administration of 18F-
AV-1451 Injection.  18F-AV-1451 Injection must not be administered to females who are 
pregnant or lactating. Males with female partners who are pregnant or of childbearing 
potential must agree to refrain from sexual activity for 24 hours following administration 
of 18F-AV-1451 Injection.  Additionally, males must agree not to donate sperm for 24 
hours following administration of 18F-AV-1451 Injection. 
7. 
PROCEDURES AND METHODS 
7.1. 
Assessment Periods  
See Section 11.2, Trial Flow Chart. 
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7.1.1. 
Screening Visit: 
Screening assessments should take place at the time of the subject’s final 18F-AV-1451-
A05 study visit.  All screening assessments should be performed within 30 days of the 
initial 18F-AV-1451 PET imaging session.  
Screening assessments will include: 
 Informed consent; 
 Blood and urine samples will be collected for safety labs (may be collected 
any time prior to 18F-AV-1451 Injection) 
 ECG; 
 Updated medical history and concomitant medications. 
7.1.2. 
MRI Visit: 
MRI should be acquired after subject consent is obtained, prior to the time of 18F-AV-
1451 Imaging Visit. 
 MRI imaging including standard clinical sequences and volumetric MRI. 
7.1.3. 
PET Imaging Visit: 
It is preferable that the 18F-AV-1451 PET Imaging Visit is performed within 30 days of 
the subject’s final 18F-AV-1451-A05 study visit, but no later than 3 months from the final 
18F-AV-1451-A05 study visit. 
18F-AV-1451 PET Imaging Session:  
 A physician or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by the 
site principal investigator must assess or evaluate the subject prior to 
administration of 18F-AV-1451 Injection to determine if they are still suitable 
to undergo the scan. If a designee performs this activity, a physician must be 
available to provide medical consultation; 
 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 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 
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; 
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 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 or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by the 
site principal investigator must assess or evaluate the subject prior to 
discharge from the imaging center to evaluate the subject’s readiness for 
discharge. If a designee performs this activity, a physician must be available 
to provide medical consultation; and a follow-up phone call to the subject, or 
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. 
7.2. 
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.  
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB) prior to use. 
Medical History  
The investigator or designee will obtain a case history at the screening visit. 
 Updated medical and surgical history 
 Updated concurrent medications 
Whenever possible, the medical history will be confirmed by medical records. 
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.   
Electronic copies of MRI scans will be submitted to designated imaging core lab. 
Vital Signs  
Vital signs (pulse rate, respiratory rate, and supine blood pressure) will be taken at the 
18F-AV-1451 imaging visit. 
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Electrocardiogram 
 A resting 12-lead electrocardiogram will be recorded at Screening Visit.   
Pregnancy Testing  
 Urine beta hCG performed at the 18F-AV-1451 imaging visit prior to injection 
for females of childbearing potential (defined as pre-menopausal, less than 2 
years post-menopausal or not surgically sterile). 
Physician Visit 
A physician or a licensed/credentialed medical professional (i.e., a PET technologist, 
imaging center nurse or a regional equivalent) designated by the site principal 
investigator must see the subject prior to drug administration and at study end, prior to 
discharge from the 18F-AV-1451 imaging session.  At this time, the physician should 
review all safety data and briefly examine/query the subject regarding potential adverse 
events or other treatment issues.   
7.3. 
Protocol for Image Collection 
Imaging manuals for both PET and MRI will be prepared by the respective core 
laboratories to include image acquisition parameters and transmission procedures.   
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 
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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 
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 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 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 
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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, 
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 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. Adverse events associated with the use of 18F-AV-1451 injection will be 
recorded as treatment emergent.  Adverse experiences that occur after administration of 
18F-AV-1451 but outside the 48 hour reporting window will not be reported unless the 
investigator believes they are attributable to the drug. 
In order to capture possible adverse effects of trial participation, trial-emergent adverse 
events will also be reported as any untoward medical occurrences occurring between the 
time of consent and the time of imaging, but not during the 48 hour window following 
the administration of 18F-AV-1451 injection.   
The end of study for the purpose of adverse event reporting is defined as 48 hours after 
the administration of 18F-AV-1451. 
Serious Adverse Event (SAE) 
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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. 
Severe:   
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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 
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. 
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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 
This study is estimated to enroll about 100 subjects from A05 confirmatory arm.  Current 
analyses with A05 exploratory arm data showed that for subjects met A05 confirmatory 
arm enrollment criteria (MCI or demented, MMSE between 20 and 27), AV1451 SUVR 
on average changed 0.0527 (SD=0.0970) for amyloid positive subjects at 9 months 
follow up. Assume a similar amyloid positivity to A05 exploratory arm (~60%), and 
assume the change of AV1451 SUVR is linear, this study is expected to have 
approximately 60 amyloid positive subjects and the mean change of AV1451 SUVR is 
expected to be 0.105, with a 95% confidence interval (0.0635, 0.1473).      
8.2. 
Efficacy Analysis 
The tau deposition measured as AV1451 SUVR values change from baseline (CFB) will 
be summarized by enrolling clinical diagnosis and amyloid status.  
Analysis of covariance (ANCOVA) adjusting for baseline AV1451 SUVR and age will 
be applied to compare the least square (LS) mean SUVR CFB by clinical diagnosis 
groups, amyloid status and the interaction of two, through proper contrasts set up. The 
relationship between SUVR CFB and cognitive function assessments CFB will also be 
explored with ANCOVA models.  The analysis details will be provided in statistical 
analysis plan (SAP).    
Clinical and imaging data from the 18F-AV-1451-A05 study will be made available to the 
18F-AV-1451-A18 study for these analyses once the database lock and unblinding has 
occurred for 18F-AV-1451-A05 study.  
8.3. 
Safety Analysis 
Safety laboratory test results and vital signs measurements will be summarized by subject 
and by evaluation time point.  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  
All subjects who discontinue participation prior to completing the study will be listed and 
their discontinuation reasons will be tabulated. 
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Laboratory Data 
Subjects whose laboratory values are outside threshold values will be identified and 
tabulated. 
Vital Signs 
Vital signs measurements will be summarized by subject and by evaluation time point. 
ECG 
Any subjects showing QTc > 500 will be highlighted. 
8.4.
18F-AV-1451 Image Analysis 
All 18F-AV-1451 PET images obtained starting at approximately 80 minutes post 
injection will be analyzed. The 18F-AV-1451 PET images will be spatially normalized to 
standard stereotactic atlas space using MNI brain atlas. The uptake in tau protein rich 
brain regions will be assessed with regions of interest (ROI, designed in MNI brain atlas) 
in terms for standard uptake value ratio (SUVr, normalized by cerebellar uptake). The 
spatially normalized images and the measured SUVr values will be used to accordingly 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.  
9.
USE OF DATA AND PUBLICATION
Avid adheres to the Pharmaceutical Research and Manufacturers of America (PhRMA) 
Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results. A 
complete copy of these principles is available from Avid and can also be found at the 
PhRMA website (http://www.phrma.org).  Our policy is briefly summarized below: 

We commit to timely communication of meaningful results of controlled
clinical trials, regardless of outcome.

As a sponsor, we may recommend that the Investigator(s) delay or decline
publication in cases where the study design, conduct, or data are insufficient
to allow meaningful interpretation.  Avid and the Investigator(s) will discuss
the study design and data in advance of the study, and again after completion,
and will strive, through appropriate scientific debate, to reach a consensus
regarding the potential merits of publication.

Avid retains the right to review any manuscripts, presentations, or abstracts
before they are submitted for publication. Where differences of opinion or
interpretation exist regarding data planned for publication, the parties (Avid
and the Investigator) should try to resolve them through appropriate scientific
debate.  Avid retains the right to delay publication for up to 60 days to protect
intellectual property.
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 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. 
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;  
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 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 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 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  or a designated Imaging Core Lab as specified in the Imaging Manual.   
Each patient’s source file should include an original signed informed consent form.  
When the trial is completed, the informed consent form should be kept on file with other 
trial related records. 
All original laboratory reports must be available for review in each patient’s file.  It is 
important that the original reports be available for review because of the possibility of 
inaccuracies or errors in transcribing data from original records to the eCRF. 
The eCRFs must be kept in order and up-to-date so that they always reflect the latest 
observations on the subjects that are enrolled in the trial.  The eCRFs must be completed 
for each patient enrolled in the trial and signed by the investigator.  This should be done 
as soon as possible after completion of the patient’s participation in the trial.  A monitor 
will verify the source data for all information on the eCRF. 
10.7. 
Adverse Events 
All adverse events encountered during the clinical trial must be documented on the eCRF, 
whether or not considered drug-related. 
Eli Lilly must be notified immediately (as soon as possible, and in all cases within 24 
hours) of a drug experience, condition, development, or event, which is considered 
serious. Eli Lilly must be notified immediately of any findings with the use of the drug 
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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. 
Braak, H. and Braak, E. “Demonstration of Amyloid Deposits and Neurofibrillary 
Changes in Whole Brain Section.” Brain Pathology. 1991; 1(3):213-216.  
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.  
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Hyman, B.T., Phelps, C.H., Beach, T.G., et al. “National Institute on Aging-Alzheimer's 
Association guidelines for the neuropathologic assessment of Alzheimer's disease”. 
Alzheimers Dement. 2012;8(1):1-13. 
Jack, C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., 
Petersen, R.C., Trojanowski, J.Q.  “Hypothetical model of dynamic biomarkers of the 
Alzheimer’s pathological cascade.”  Lancet Neurol 9:119-128, 2010. 
Kantarci, K., Lowe, V.J., Boeve, B.F., Weigand, S.D., Senjem, M.L., Przybelski, S.A., et 
al. “Multimodality imaging characteristics of dementia with Lewy bodies”. Neurobiol 
Aging 2011: Oct 20. [Epub ahead of print]. 
Leinonen, V., Alafuzoff, I., Aalto S., Suotunen, T., Savolainen, S., Nagren, K., et al. 
“Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron 
emission tomography with carbon 11-labeled Pittsburgh Compound B”. Arch Neurol 
2008; 65(10):1304–1309. 
McKhann, G.M., Knopman, D.S., Chertkow, H., et al. “The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease”. Alzheimers 
Dement. May 2011;7(3):263-269.    
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 
 
 
aSafety labs to be collected any time between consent and 18F-AV-1451 Injection at Imaging Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluations 
Screening 
Visit 
 
MRI Visit 
18F-AV-1451 
Imaging Visit 
Follow-Up Phone 
Call 
Updated Medical History 
X 
 
X 
 
Updated Concomitant Meds 
X 
 
X 
 
ECG  
X 
 
 
 
Vital Signs    
 
 
X 
 
Safety Labsa  
X 
 
 
 
Urine Pregnancy Test 
 
 
X 
 
MRI of the Brain 
 
X  
 
 
PET Brain Scan 
 
 
X 
 
Follow-up Phone Call 
 
 
 
X 
Evaluation by Physician/Designee   
X 
 
X 
 
Adverse Events  
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
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INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol:  An open label, multicenter study evaluating the imaging characteristics of a 
follow up 18F-AV-1451 scan in subjects that participated in the confirmatory cohort of 
18F-AV-1451-A05 
 
 
 
Date and Version: 22 March 2016, Final 
 
 
I agree to conduct the study according to this protocol and to comply with its obligations, 
subject to ethical and safety considerations and all applicable regulations (ICH, CFR). 
 
I shall not disclose the confidential information contained in this protocol or any results 
obtained from the study, except for publication in accordance with Section 9 of this 
protocol, without written authorization from Avid. 
 
 
 
________________________________________________________________________ 
Printed Name                                                                    Date 
 
 
 
______________________________________ 
Signature 
 
 
LY3191748

SAP_001.pdf: 
18F-AV-1451-A18 SAP v1.0 
 
An Open Label, Multicenter Study Evaluating the Imaging Characteristics of a Follow up 18F-
AV-1451 Scan in Subjects That Participated in the Confirmatory Cohort of 18F-AV-1451-A05 
 
NCT02795780 
Approval date: 11 Jan 2018


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STATISTICAL ANALYSIS PLAN 
 
 
DATE OF PLAN: 
11 January 2018 
 
BASED ON: 
18F-AV-1451-A18 Protocol, 22 March 2016 
 
STUDY DRUG: 
18F-AV-1451 ([F-18]T807) 
 
PROTOCOL NUMBER: 
18F-AV-1451-A18 
 
STUDY TITLE: 
An open label, multicenter study evaluating the imaging characteristics of a follow up 18F-AV-
1451 scan in subjects that participated in the confirmatory cohort of 18F-AV-1451-A05 
 
SPONSOR: 
Avid Radiopharmaceuticals 
Philadelphia, Pennsylvania USA 
215-298-0700 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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SIGNATURE PAGE 
This document has been prepared and/or reviewed by: 
 
 
 
 
 
This document has been reviewed and accepted by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objective .......................................................................................................10 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Study Design ...............................................................................................................11 
3.2. 
Study Treatments and Assessments ............................................................................11 
3.2.1. 
Trial Flow Chart .........................................................................................................11 
3.3. 
Randomization and Blinding ......................................................................................11 
3.4. 
Sample Size Justification ............................................................................................11 
3.5. 
Subject Selection Criteria ...........................................................................................12 
4. 
CLINICAL AND IMAGING ASSESSMENTS ........................................................13 
4.1. 
Screening and Baseline Clinical Assessments ............................................................13 
4.2. 
MRI Visit ....................................................................................................................13 
4.3. 
Flortaucipir PET Imaging Visit ..................................................................................13 
4.3.1. 
Safety Follow-up/Phone Call ......................................................................................14 
5. 
CHANGES FROM PROTOCOL ...............................................................................15 
6. 
DEFINITIONS AND CONVENTIONS ....................................................................16 
6.1. 
Data Conventions ........................................................................................................16 
6.2. 
Definition of Baseline .................................................................................................16 
7. 
ANALYSIS POPULATIONS ....................................................................................17 
7.1.1. 
Enrolled Population ....................................................................................................17 
7.1.2. 
Safety Analysis Population .........................................................................................17 
7.1.3. 
Efficacy Analysis Population .....................................................................................17 
8. 
DISPOSITION AND WITHDRAWALS ...................................................................18 
9. 
BASELINE ANALYSIS ............................................................................................19 
9.1. 
Baseline Characteristics and Demographics ...............................................................19 
9.1.1. 
Missing Baseline Data ................................................................................................19 
9.2. 
Electrocardiogram .......................................................................................................19 
9.3. 
Safety Labs .................................................................................................................19 
10. 
MRI DATA ANALYSIS ............................................................................................21 
11. 
MEDICAL AND SURGICAL HISTORY .................................................................22 


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12. 
CONCOMITANT MEDICATION ............................................................................23 
12.1.1. 
Missing and Partially Missing Start and Stop Dates ..................................................23 
13. 
FLORTAUCIPIR IMAGING DATA .........................................................................24 
13.1. 
Pregnancy Test ............................................................................................................24 
13.2. 
PET Scan ....................................................................................................................24 
14. 
EFFICACY ANALYSIS ............................................................................................25 
14.1. 
Efficacy Variable ........................................................................................................25 
14.2. 
Primary Analysis ........................................................................................................25 
14.2.1. 
Longitudinal Analysis .................................................................................................25 
14.2.2. 
Correlation Analysis ...................................................................................................26 
14.2.3. 
Statistical Considerations in Primary Analysis ...........................................................26 
15. 
SAFETY AND TOLERABILITY ANALYSIS .........................................................27 
15.1. 
Exposure to Flortaucipir .............................................................................................27 
15.1.1. 
Unit Conversion and Volume Calculation ..................................................................27 
15.2. 
Adverse Events ...........................................................................................................27 
15.2.1. 
All AEs .......................................................................................................................27 
15.2.2. 
All TEAEs ..................................................................................................................28 
15.2.3. 
Severity .......................................................................................................................28 
15.2.4. 
Relationship to Flortaucipir ........................................................................................28 
15.2.5. 
Relationship to Study Procedure ................................................................................28 
15.2.6. 
Serious Adverse Events ..............................................................................................29 
15.2.7. 
Adverse Events Leading to Death ..............................................................................29 
15.2.8. 
Missing and Partial AE Onset Dates ..........................................................................29 
15.3. 
Vital Signs ..................................................................................................................29 
15.3.1. 
Potentially Clinically Significant Vital Sign Changes ................................................29 
15.4. 
Follow-up Telephone Contact Data ............................................................................30 
16. 
INTERIM ANALYSES ..............................................................................................31 
APPENDIX I: ALGORITHMS TO HANDLE MISSING AND PARTIAL DATES ..................32 
1.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........32 
1.2. 
Missing and Partial AE Onset Dates ..........................................................................34 
 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: Visit Schedule .................................................................. Error! Bookmark not defined. 


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Table 3: Potentially Clinically Significant Criteria .......................................................................30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AD 
Alzheimer’s Disease 
ADAS-Cog11 
Alzheimer’s Disease Assessment Scale Cog-11 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomic Therapeutic Chemical 
bpm 
Beats per minute 
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CFB 
Change from Baseline 
cm 
centimeter 
ECG 
Electrocardiogram 
kg 
Kilogram 
max 
maximum 
MBq 
Megabecquerels 
MCI 
Mild Cognitive Impairment 
mCi 
Millicurie 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
mmHg 
Millimeters of Mercury 
MMSE 
Mini Mental State Exam 
MRI 
Magnetic Resonance Imaging 
MUBADA 
Multi-Block Barycentric Discriminant Analysis 
n 
Number of subjects 
PCS 
Potentially Clinically Significant 
PET 
Positron Emission Tomography 
PT 
Preferred Term 
ρ 
Pearson’s Correlation Coefficient 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 


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SUVr 
Standard Uptake Value Ratio 
TEAE 
Treatment Emergent Adverse Event 


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1. 
INTRODUCTION 
Flortaucipir 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.  
The overarching goal of this protocol is to further investigate the spectrum of PET imaging 
results with flortaucipir in patients with cognitive decline.  To accomplish this goal, the 
protocol will investigate longitudinal flortaucipir results in patients with cognitive complaints 
ranging from mild cognitive impairment (MCI) to mild and moderate Alzheimer’s disease 
(AD). 
The purpose of this statistical analysis plan (SAP) is to describe the statistical analyses for the 
analyses of the protocol.  The SAP should be read in conjunction with the protocol.  
  
 
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objectives of this protocol is to assess longitudinal change of tau deposition as 
measured by flortaucipir over time. 


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3. 
STUDY DESIGN 
3.1. 
Study Design  
This is a phase 2 study, open label, multicenter study in subjects that participated in the 
confirmatory cohort of 18F-AV-1451-A05 evaluating longitudinal change of tau uptake as 
measured by flortaucipir Standard Uptake Value Ratio (SUVr). As subjects from the 18F-AV-
1451-A05 confirmatory cohort complete the 18F-AV-1451-A05 study, they will be presented 
with the opportunity to participate in this longitudinal study. 
All subjects will provide informed consent before starting any study procedures.  
3.2. 
Study Treatments and Assessments 
3.2.1. 
Trial Flow Chart 
 
3.3. 
Randomization and Blinding 
This is an open label, non-randomized study. All subjects who qualify for the study and sign 
informed consent will receive a single IV bolus of flortaucipir. 
3.4. 
Sample Size Justification 
This study is estimated to enroll about 100 subjects from A05 confirmatory arm.  Current 
analyses with A05 exploratory arm data showed that for subjects met A05 confirmatory arm 
enrollment criteria (MCI or demented, Mini Mental State Exam (MMSE) between 20 and 27), 
flortaucipir SUVr on average changed 0.0527 (SD=0.0970) for amyloid positive subjects at 9 
months follow up. Assume a similar amyloid positivity to A05 exploratory arm (~60%), and 
assume the change of flortaucipir SUVR is linear, this study is expected to have approximately 
60 amyloid positive subjects and the mean change of flortaucipir SUVR is expected to be 0.105, 
with a 95% confidence interval (0.0635, 0.1473). 
Evaluations 
Screening 
Visit 
 
MRI Visit 
Flortaucipir 
Imaging Visit 
Follow-Up Phone 
Call 
Updated Medical History 
X 
 
X 
 
Updated Concomitant Meds 
X 
 
X 
 
ECG  
X 
 
 
 
Vital Signs    
 
 
X 
 
Safety Labsa  
X 
 
 
 
Urine Pregnancy Test 
 
 
X 
 
MRI of the Brain 
 
X  
 
 
PET Brain Scan 
 
 
X 
 
Follow-up Phone Call 
 
 
 
X 
Evaluation by Physician/Designee   
X 
 
X 
 
Adverse Events  
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
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3.5. 
Subject Selection Criteria 
Refer to Protocol Section 5.3, Selection of Subjects, for the detail of inclusion/exclusion details. 


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4. 
CLINICAL AND IMAGING ASSESSMENTS 
4.1. Screening and Baseline Clinical Assessments 
Screening assessments should take place at the time of the subject’s final 18F-AV-1451-A05 
study visit.  All screening assessments should be performed within 30 days of the initial 
flortaucipir PET imaging session.  
Screening assessments will include: 
 Informed consent; 
 Blood and urine samples will be collected for safety labs (may be collected any time prior 
to flortaucipir injection) 
 Electrocardiogram (ECG); 
 Updated medical history and concomitant medications. 
4.2. 
MRI Visit 
MRI should be acquired after subject consent is obtained, prior to the time of Flortaucipir 
Imaging Visit. 
 MRI imaging including standard clinical sequences and volumetric MRI. 
4.3. 
Flortaucipir PET Imaging Visit 
It is preferable that the Flortaucipir PET imaging visit is performed within 30 days of the 
subject’s final 18F-AV-1451-A05 study visit, but no later than 3 months from the final 18F-AV-
1451-A05 study visit. 
Flortaucipir PET Imaging Session:  
 A physician or a licensed/credentialed medical professional (i.e., a PET technologist, 
imaging center nurse or a regional equivalent) designated by the site principal 
investigator must assess or evaluate the subject prior to administration of flortaucipir 
injection to determine if they are still suitable to undergo the scan. If a designee performs 
this activity, a physician must be available to provide medical consultation; 
 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 flortaucipir injection 
o 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 flortaucipir 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; 


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 The subject will be requested to void after completion of the PET scan; 
 Adverse events will be continuously monitored during the Flortaucipir Imaging Visit; 
Subjects who experience an adverse event will not be discharged from the imaging center 
until the event has resolved or stabilized;  
 A physician or a licensed/credentialed medical professional (i.e., a PET technologist, 
imaging center nurse or a regional equivalent) designated by the site principal 
investigator must assess or evaluate the subject prior to discharge from the imaging 
center to evaluate the subject’s readiness for discharge. If a designee performs this 
activity, a physician must be available to provide medical consultation. 
4.3.1. 
Safety Follow-up/Phone Call 
Each study subject (or caregiver/informant if applicable) will be contacted 2 or 3 business days 
after flortaucipir administration, but not prior to 48 hours post-injection, to collect any new 
adverse events.   End of study for the purpose of adverse event reporting and study participation 
is defined as 48 hours after flortaucipir administration. 
 
 
 


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5. 
CHANGES FROM PROTOCOL 
The following changes from the protocol are reflected in this SAP. 
 With continued development and accumulated knowledge, Multi-Block Barycentric 
Discriminant Analysis (MUBADA) SUVr instead of Combination ROI, will be used as 
the global measurement of tau deposition. 


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6. 
DEFINITIONS AND CONVENTIONS 
6.1. 
Data Conventions 
All analysis will be performed using SAS version 9.2 or higher. 
Data will be summarized using descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum (min), and maximum (max)) for continuous variables and 
using frequency count and percentage for discrete variables. Percentages will be rounded to one 
decimal place, except 100% will be displayed without any decimal places and percentages will 
not be displayed for zero counts. 
The tables and listings will be numbered using a decimal system to reflect main levels of unique 
tables and listings and sub-levels of replicate tables and the listings with maximum two digits per 
level (e.g., Table XX.YY.ZZ…). Tables will be presented in CSR section 14, and thus will be 
numbered as 14.YY.ZZ.  Baseline analysis will be reported in table series 14.1, efficacy analysis 
in series 14.2, and safety analysis in series 14.3.  Listings will be presented in in CSR section 16, 
and thus will be numbered as 16.YY.ZZ.  .  
6.2. 
Definitions of Baseline and Follow-up 
Baseline characteristics and demographics will be gathered from the AV-1451-A05 datasets for 
confirmatory cohort subjects who participated in AV-1451-A18. All other baseline data (i.e. 
electrocardiogram, and safety labs) will be reported from data collected from the AV-1451-A18 
CRFs. 
Efficacy analysis evaluating longitudinal change will require the use of the Baseline flortaucipir 
SUVr quantitation, and Baseline and 18 Month MMSE from the AV-1451-A05 datasets to 
calculate change. 
Safety analysis involving change from baseline (CFB) calculations for vital signs will consider 
AV-45-A18 Prior to Injection values as baseline and Prior to Discharge as follow-up. 


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7. 
ANALYSIS POPULATIONS 
7.1.1. 
Enrolled Population 
Subjects who participated in the 18F-AV-1451-A05 confirmatory cohort, meet the 
inclusion/exclusion criteria of 18F-AV-1451-A18, have consented to be enrolled in this study, 
and have baseline data captured in the AV-1451-A05 eCRF database will consist of the enrolled 
population.   
7.1.2. 
Safety Analysis Population 
The safety analysis population will consist of all enrolled subjects who received at least one 
injection of flortaucipir under the AV-1451-A18 protocol. 
7.1.3. 
Efficacy Analysis Population 
This population includes all subjects in safety population for whom valid image data are 
available for the AV-45-A18 flortaucipir scan. All primary analyses will be based on this 
population. 


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8. 
DISPOSITION AND WITHDRAWALS 
The entire screened population will be represented in the disposition table. The disposition table 
be broken down by diagnosis groups and include a summary of: 
 Total number of enrolled subjects 
 Total number of subjects in the safety population 
 Number of subjects in the efficacy population 
 Number of Completed Subjects 
 Number of Discontinued Subjects 
The disposition table will also include details on discontinuation reasons: 
 Protocol Violation 
 Adverse Event 
 Physician Decision 
 Pregnancy 
 Study Terminated by Sponsor 
 Lost to Follow-up 
 Technical Problems 
 Withdrawal by Subject 
 Death 
 Other 
Termination Status (i.e. ‘Completed’ and ‘Discontinued’) percentages will be based on the safety 
population. Percentages outlining discontinuation reasons will be based on the number of 
discontinued subjects. 
Subject disposition will be presented in a listing with the following information. 
 Date of Consent 
 Date Subject Ended Study 
 Did Subject Complete Study? (Yes/No); Reason for Discontinuation, if No 


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9. 
BASELINE ANALYSIS 
All baseline data will be summarized by diagnosis groups for the Safety Analysis Population.  
9.1. 
Baseline Characteristics and Demographics 
All baseline data will be gathered from the AV-1451-A05 datasets for confirmatory cohort 
subjects who participated in AV-1451-A18. 
The following data will be reported in the baseline characteristics and demographics table by 
diagnosis groups using descriptive statistics, and presented in a listing: 
 Age (years) 
 Gender 
 Race 
o Sub-race (if Asian): Japanese; Other 
 Ethnicity 
 Highest Level of Education 
 Alcohol History 
 Smoking History 
 Recreational Drug History 
 MMSE 
 Clinical Dementia Rating-Sum of Boxes (CDR-SB) 
 Flortaucipir SUVr (MUBADA) 
 Tau status according to visual interpretation (majority reading results from 5 independent 
readers) 
 Florbetapir SUVr 
9.1.1. 
Missing Baseline Data 
No imputation will be performed on missing baseline demographic data. 
9.2. 
Electrocardiogram 
ECG data will be presented in a listing including the following information 
 Was an ECG Collected at Screening? (Yes/No); Explanation, if No 
 Collection Date/time 
9.3. 
Safety Labs 
Safety Lab data will be presented in a listing including the following information 


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 Were Clinical Labs Collected? (Yes/No); Explanation, if No 
 Collection Date 


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10. 
MRI DATA ANALYSIS 
MRI volumes will be normalized to the intracranial volume, and summarized in a table by 
diagnosis groups at each visit and CFB using descriptive statistics for the following brain 
regions. 
 Total Brain Volume (excluding ventricle) 
 Left Hippocampal Volume 
 Right Hippocampal Volume 
 Ventricle Volume 
The MRI volumes will be presented in a listing with the following. 
 Was MRI Performed? (Yes/No) 
 Date of Screening MRI 
 Was SWI MRI Sequence Collected? (Yes/No) 
 
 


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11. 
MEDICAL AND SURGICAL HISTORY 
Medical and Surgical History will be coded using MedDRA Version 20.0. Medical and surgical 
history will be presented in a listing including: 
 Subject has Medical/Surgical History? (Yes/No) 
 System Organ Class (SOC) 
 Condition/Disease 
 Start Date 
 End Date 
 Condition Still Present (Yes/No) 


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12. 
CONCOMITANT MEDICATION 
Medications will be coded using the WHO-Drug Classic December 2016 dictionary.  
Concomitant medications are medications that started prior to, on or after the informed consent 
date and ended on or after the date of the flortaucipir injection or were ongoing at the end of the 
study. This will include any medication continuing from the AV-1451-A05 study. 
Medications will be presented in a listing including: 
 Medication Name/ Preferred term 
 Indication 
 Dose 
 Dose unit 
 Frequency 
 Route 
 Start date 
 End date 
 Ongoing  (Yes/No) 
 Used for Adverse Event? (AE) 
12.1.1. 
Missing and Partially Missing Start and Stop Dates 
See appendix 1.1 for specific algorithms to impute missing start and stop dates. 
 


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13. 
FLORTAUCIPIR IMAGING DATA 
All flortaucipir imaging data will be summarized by diagnosis groups for the Safety Analysis 
Population. 
13.1. 
Pregnancy Test 
Pregnancy testing information will be presented in a listing including: 
 Was a Pregnancy Test Performed? (Yes/No/ N/A) 
 Date of Collections 
 Result 
13.2. 
PET Scan 
The PET scan data will be presented in a listing including: 
 Date of PET Imaging 
 Scan Emission Start/Stop Time 
 Were There Any Deviations From the Standard PET Imaging Protocol? (Yes/No); 
Explanation, if Yes 
 Did the Subject Complete the Protocol-required Imaging Session? (Yes/No); 
Explanation, if No 
 
 
 
 


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14. 
EFFICACY ANALYSIS 
All efficacy analysis will be conducted using the Efficacy Analysis Population. 
14.1. 
Efficacy Variable 
Flortaucipir uptake CFB as measured by MUBADA SUVr will be the primary variable of 
interest. MUBADA CFB will be calculated as the difference between SUVr values from AV-
1451-A05 Baseline to the Flortaucipir Imaging Visit under the AV-1451-A18 protocol. 
MUBADA and all sub-regional SUVr will be presented in a listing. 
14.2. 
Primary Analysis 
14.2.1. 
Longitudinal Analysis 
The flortaucipir image data will be analyzed longitudinally for MUBADA  SUVr. 
The difference in MUBADA SUVr CFB between diagnosis groups will be tested using the 
following hypothesis: 
MCI
AD
LSM
LSM
H



:
0
 
MCI
AD
A
LSM
LSM
H



:
 
The difference in MUBADA SUVr CFB between Amyloid statuses will be tested using the 
following hypothesis: 







A
A
LSM
LSM
H :
0
 







A
A
A
LSM
LSM
H :
, 
where LSMΔ* is the respective  diagnosis or Amyloid group’s LS mean change at the follow-up 
flortaucipir imaging visit. 
An analysis of covariance (ANCOVA) model adjusted for baseline SUVr and age, including the 
interaction term of diagnosis group and Amyloid status. The appropriate contrasts will be set up 
to test both longitudinal hypotheses as well as look at the differences between amyloid statuses 
within each diagnosis group.  
A separate table summarizing MUBADA SUVr, and the MUBADA SUVr CFB will be created 
for each hypothesis, including: 
 Descriptive statistics by each group 
 LS Mean Changes (SE) by group 
 Differences between LS Mean Changes  (SE) from contrasts 
 95% Confidence Interval around differences between LS Mean Changes  
 P-value from respective contrast 


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14.2.2. 
Correlation Analysis 
A correlation analysis will be performed to investigate the relationship between MUBADA 
SUVr CFB and cognitive function CFB as measured by MMSE and CDR-SB. Partial’s 
correlation coefficient 
 adjusted for age, baseline MUBADA SUVr, and baseline cognitive 
score will be calculated to assess the association between changes in cognitive function and tau 
uptake. 
Scatter plots will be generated for MMSE change and SUVr change by Amyloid Beta status. 
Each plot will include: 
 Regression line with   
 p-value testing the hypothesis 
0


 
14.2.3. 
Statistical Considerations in Primary Analysis 
All hypothesis testing will be run at a two-sided 0.05 level of significance. No correction for 
multiplicity will be applied to control for alpha. 
ANCOVA models will be run separately for each amyloid status if the assumption of 
independent identically distributed normal variance is not met by a practical margin. Variances 
between groups separated by a factor of at least 2 will facilitate the need to run separate models. 
 


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15. 
SAFETY AND TOLERABILITY ANALYSIS 
The safety analysis population will be used for all safety outcomes. There will be no statistical 
comparisons between diagnosis or amyloid groups performed among the safety data. 
15.1. 
Exposure to Flortaucipir 
The net activity of flortaucipir injected (MBq) will be summarized using descriptive statistics in 
a table. 
All exposure data will be presented in listings by visit to include: 
 Date and time of the Injection 
 Injection site  
 Lot Number 
 Total Dose Administered (mCi and MBq) 
 Saline Flush Administered? (Yes/No) 
15.1.1. 
Unit Conversion and Volume Calculation 
Volume collected in mCi will be converted to MBq as follows: 
 
mCi
MBq

37
 
15.2. 
Adverse Events 
An AE is any undesirable experience occurring to a subject during a clinical trial, whether or not 
considered related to the study drug.  
Treatment-emergent adverse events (TEAE) are any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related.  For the purposes of 
this study, untoward medical occurrences will be considered associated with the use of 
flortaucipir, and thus be reported as AEs, if they occur within 48 hours after administration of the 
PET tracer. AE that occur after the administration of study drug but outside the 48 hour reporting 
window will not be reported unless the investigator believes they are attributable to the drug. 
The end of study for the purpose of AE reporting is defined as 48 hours after the administration 
of flortaucipir injection. 
15.2.1. 
All AEs 
All AEs will be coded using MedDRA Version 20.0. A summary of all AEs will be reported in a 
listing including: 
 SOC 
 PT 
 Start Date/time 
 End Date/time 


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 Severity 
 Relationship to Flortaucipir (Yes/No) 
 Relationship to Study Procedure (Yes/No) 
 Serious? (Yes/No) 
 Action Taken 
 Event Resolution 
 Lead to Death (Yes/No) 
15.2.2. 
All TEAEs 
A summary of TEAEs will be reported in the tables including: 
 Number of all TEAE 
 Number of subjects with at least one TEAE 
The summary of TEAEs will be broken down further in descending frequency by SOC and PT, 
and by PT only in separate tables. 
 A subject will be counted once if the subject reported one or more events in a given level of 
summarization. 
15.2.3. 
Severity 
Severity is classed as mild/moderate/severe (increasing severity).  TEAEs with a missing 
severity will be classified as severe.  If a subject reports a TEAE more than once within that 
SOC/PT, the TEAE with the worst case severity will be used in the corresponding severity 
summaries.  
TEAE severity will be reported in a table in the same manner as outlined in 15.2.2.  
15.2.4. 
Relationship to Flortaucipir 
Relationship, as indicated by the Investigator, is classed as related or unrelated to flortaucipir.  
TEAEs with a missing relationship to study medication will be regarded as related to flortaucipir.  
If a subject reports the same AE more than once within that SOC/PT, the AE with the worst case 
relationship to flortaucipir will be used in the corresponding relationship summaries.  
TEAE relationship to flortaucipir will be reported in a table in the same manner as outlined in 
15.2.2. 
15.2.5. 
Relationship to Study Procedure 
Relationship, as indicated by the investigator, is classed as related or unrelated to protocol 
procedure.  TEAEs with a missing relationship to study procedure will be regarded as related to 
study procedure.  If a subject reports the same AE more than once within that SOC/PT, the AE 
with the worst case relationship to study procedure will be used in the corresponding relationship 
summaries.  


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TEAE relationship to study procedure will be reported in a table in the same manner as outlined 
in 15.2.2. 
15.2.6. 
Serious Adverse Events 
Serious TEAEs will be summarized in a similar manner as described in Section 15.2.2.  If a 
subject reported more than one serious TEAE with the same SOC or PT, the TEAE will be 
counted only once in that SOC or PT. 
15.2.7. 
Adverse Events Leading to Death 
TEAEs leading to death will be summarized in a similar manner as described in Section 15.2.2. 
15.2.8. 
Missing and Partial AE Onset Dates 
See appendix 1.2 for specific algorithms to impute missing start and stop dates 
15.3. 
Vital Signs 
The following vital signs are collected at two time points – Immediately Prior to (within 5 
minutes) Flortaucipir Injection and Prior to Discharge - during the Flortaucipir Imaging Visit. 
Immediately Prior to Injection will be considered the baseline value for all vital sign change 
calculations 
 Supine Systolic Blood Pressure (mmHg) 
 Supine Diastolic Blood Pressure (mmHg) 
 Supine Pulse Rate (bpm) 
 Respiratory Rate (breaths/min) 
The data from each time point, along with calculated CFB, as defined as the difference from the 
Prior to Injection to Prior to Discharge values will be summarized by diagnosis groups in a table 
using descriptive statistics. A paired t-test will be performed on the aggregate data of each vital 
sign to assess if any significant changes occurred. 
Vital signs and changes (where applicable) will be presented in a listing along with the following 
information. 
 Time point 
 Were Vital Signs Collected 
 Collection Date/time 
15.3.1. 
Potentially Clinically Significant Vital Sign Changes 
Vital sign at visit and CFB will be monitored for potentially clinically significance (PCS). Below 
are the PCS criteria. 
 
 


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Table 2: Potentially Clinically Significant Criteria 
Parameter 
 
Potentially Clinically Significant Criteria 
Vital Sign 
 
Low 
High 
Systolic blood 
pressure 
mmHg 
 90 and  20 
decrease 
 180 and  20 
increase 
Diastolic blood 
pressure 
mmHg 
 50 and  15 
decrease 
105 and  15 
increase 
Pulse rate 
bpm 
 50 and  15 
decrease 
 120 and  15 
increase 
Respiration rate 
Breaths/min 
 10 
 
 
15.4. 
Follow-up Telephone Contact Data 
The follow-up safety data will be presented in a listing and include: 
 Was Contact Made? (Yes/No); Explanation, if No 
 Date/time of Follow-up Assessment 
 Any AE Reported? (Yes/No) 


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16. 
INTERIM ANALYSES 
There is no interim analysis planned for this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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


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


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AE ONSET 
DATE/TIME 
AE STOP 
DATE/TIME 
 
ACTION 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date/time < flortaucipir injection 
date/time, then not TEAE 
If stop date/time >= flortaucipir injection 
date/time, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. 59 
if minutes unknown or 23:59 if hours and 
minutes unknown; last day of month if day 
unknown or 31st December if day and month 
unknown), then: 
If stop date/time < flortaucipir injection 
date/time, then not TEAE 
If stop date/time >= flortaucipir injection 
date/time, then TEAE 
Missing 
Assumed TEAE