Clinical trial NCT02350634
Conditions: Alzheimer's Disease
Sponsor: Avid Radiopharmaceuticals
Start date: 2016-11-26; Completion date: 2017-06-16
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is designed to examine the relationship between imaging results detected on a 18F-AV-1451 PET scan and pathology found at autopsy within six months of imaging.

Detailed description:

Arms: arm 1: End-of-life subjects (life expectancy \< 6 months) consenting to brain donation at autopsy. Subjects will receive a single IV bolus injection of 370 MBq(10 mCi) of flortaucipir F18.
Interventions: intervention 1: Flortaucipir F18
Intervention descriptions: intervention 1: Subjects will receive a single IV bolus injection of 370 megabecquerel (MBq) (10 millicurie \[mCi\]) of flortaucipir.

Protocol documents:
Prot_000.pdf: 
 
ClinicalTrials.gov Cover Page 
Study Protocol: 18F-AV-1451-A13 
Official Title: A High Resolution Autopsy Study Evaluating the Relationship of 
18F-AV-1451 PET Imaging and Tau Pathology 
NCT Number: NCT02350634 
Document Date: 14 November 2016 
 
 


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Sponsor: 
Avid 
Radiopharmaceuticals, Inc. 
Name of Compound: 
18F-AV-1451 
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-
b] indole 
Title of Study:  
18F-AV-1451-A13: A High Resolution Autopsy Study Evaluating the Relationship of 18F-
AV-1451 PET Imaging and Tau Pathology  
Test Product: 18F-AV-1451 
Dose: 370 MBq (10mCi) 
Route of Administration:  Intravenous (IV) bolus 
Study Phase: I 
Study Centers: 1 – 4 centers in the United States 
Trial Objectives: 
To explore the relationship between 18F-AV-1451 PET scan results and brain pathology 
observed at autopsy.  
Planned number of subjects to be enrolled: 
Up to 10 subjects will be enrolled and imaged with 18F-AV-1451. All subjects will be 
followed to autopsy. A subset of approximately 5 brains will be selected for high resolution 
analysis.  
Eligibility: 
Subjects may be enrolled if they: 
1. Are males or females between 60 and 89 years of age; 
2. Have a projected life expectancy of ≤ 6 months as determined by the site principal 
investigator;  
3. Can tolerate an MRI and 20 minute PET scan. The site principal investigator will 
carefully assess each patient and use sound medical judgment to determine whether 
the patient can tolerate both scan procedures; and 
4. Give informed consent or have a legally authorized representative (LAR) to consent 
for study procedures and brain donation consistent with the legal requirements of the 
state where the study is conducted. 
 
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Sponsor: 
Avid 
Radiopharmaceuticals, Inc. 
Name of Compound: 
18F-AV-1451 
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-
b] indole 
Subjects may not be enrolled if they:    
1. Have primary brain tumor, known metastases to the brain, central nervous system 
(CNS) lymphoma; 
2. Have any major, focal structural brain lesion that would interfere with interpretation 
of PET images; 
3. Are aggressively being treated with life sustaining measures (e.g. currently on 
respirator; receiving high dose chemotherapy – subjects on low maintenance dose or 
between dose cycles may be enrolled after consultation with Avid); 
4. Have a clinically significant infectious disease, including Human Immunodeficiency 
Virus (HIV) infection, hepatitis or prion disease; 
5. Are receiving any investigational medications, or have participated in a trial with 
investigational medications within the last 30 days; 
6. Are females of childbearing potential who are pregnant or are not using adequate 
contraception; 
7. A history of additional risk factors for Torsades de Pointes (TdP) or are taking drugs 
that are known to cause QT-prolongation (a list of prohibited and discouraged 
medications is provided by the Sponsor). 
 
Study Design: 
The study is designed to examine the relationship between imaging results detected on a 18F-
AV-1451 PET scan and pathology found at autopsy within six months of imaging. The 
participating clinical centers will make an effort to enroll subjects with various levels of 
cognitive status, ranging from cognitively normal through dementia. 
Screening assessments may take place over several days and will include collection of 
demographic information, diagnostic interview, brain MRI, and safety assessments.  At the 
time of screening, subjects and/or next-of-kin will be asked to provide consent for brain 
donation in addition to providing informed consent for the screening and imaging procedures 
in the study.   
 
Subjects who qualify for the study will receive a single I.V. bolus of 18F-AV-1451 
followed by brain PET imaging for 20 minutes duration, beginning approximately 80 
minutes post-injection.  Vital signs will be obtained prior to the administration of 18F-
AV-1451 and at the completion of the imaging session.  Adverse events will be 
continuously monitored during the imaging session.  Subjects who experience an adverse 
event will not be released until the event has been resolved or stabilized. After the 48 
hour safety follow-up is completed subject participation in the study will end.  
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Sponsor: 
Avid 
Radiopharmaceuticals, Inc. 
Name of Compound: 
18F-AV-1451 
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-
b] indole 
 
Study Analysis:   
An exploratory analysis will be performed to compare the relationship of 18F-AV-1451 PET 
scan results and tau accumulation at autopsy within six months of imaging on a regional and 
global basis. 
 
The 18F-AV-1451 PET imaging results of the 10 subjects will be analyzed on a subject by 
subject basis.  The tau levels seen on the 18F-AV-1451 PET scan will determine which 
subjects will get high resolution brain analysis at autopsy to ensure recruited subjects have a 
full range of tau distribution. 
Assessments and Endpoints: 
Screening may take place over several days. Some screening assessments may be performed 
on imaging day. Assessments will include: 
 
• Informed consent (for clinical, imaging and autopsy procedures); 
• Demographics (age, gender, race, ethnicity, education); 
• Brief cognitive / dementia evaluation including:  
 Medical history and concomitant medications; 
 Alzheimer’s disease history (if relevant: date/months since symptom onset, 
date/months since diagnosis, family history of neurological disease); 
 Mini-Mental Status Examination (MMSE) may be obtained if the subject is able to 
cooperate with the test; 
 IQCODE will be administered to the subject’s caregiver/informant to include 
information about clinically meaningful decline in cognitive status during the ten 
years prior to the subject’s most recent illness;  
Note: If an informant is not available to provide information for the IQCODE this 
will not necessarily result in exclusion for the subject.  
• Safety (vital signs); 
• Most recent height and weight will be obtained from medical records; 
• Urine pregnancy test (for females of childbearing potential); 
• Brain MRI (MRI should be performed within 2 weeks of the 18F-AV-1451 PET scan); 
and 
• A physician evaluation and summary of current medical status. 
   
18F-AV-1451 Imaging Day:  
 
The following assessments will be performed for all subjects on the imaging day: 
• Any procedure not completed during the screening visit;  
• The subject will be seen by a physician who will assess their ability to safely tolerate the 
imaging procedure;  
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Sponsor: 
Avid 
Radiopharmaceuticals, Inc. 
Name of Compound: 
18F-AV-1451 
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-
b] indole 
• Females of childbearing potential will have a urine (or serum if required by local IRB) 
pregnancy test prior to injection (the result must be negative for the subject to be 
administered 18F-AV-1451); 
• Following an I.V. bolus injection of 18F-AV-1451, 20 minutes of continuous brain PET 
imaging will begin 80 minutes post-injection;   
• Vital signs will be taken immediately prior to administration of  18F-AV-1451 and after 
completion of imaging, prior to discharge; 
• Subjects will be observed continuously for signs of adverse events (AE) or serious 
adverse events (SAE). All AEs and SAEs will be followed until resolution or 
stabilization;  
• The injection site will be observed for excessive inflammation or damage to the 
surrounding tissue where the dose was injected; and  
• A physician will see the subject prior to release from the PET center to evaluate any 
adverse events. 
 
Safety Follow-up/Phone Call: 
Each study subject (or caregiver/informant if applicable) will be contacted 2 or 3 business 
days after 18F-AV-1451 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 18F-AV-1451 administration. 
 
Evaluation of Imaging: 
18F-AV-1451 PET images will have quantitative and qualitative analysis performed for 
regional and global distribution.  
Neuropathology Evaluation: 
All neuropathology methods and analysis will be detailed in a separate neuropathology 
manual, which will be written prior to the first subject autopsy in this study.  
Statistical Methods: Descriptive statistics will be applied to summarize the autopsy findings 
and tau deposition as measured by 18F-AV-1451 uptake. A correlation analysis will be 
applied to explore the relationship of tau at 18F-AV-1451 PET scan and at autopsy on a 
regional and global basis. 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ......................................................................................................11 
2. 
TRIAL OBJECTIVES ................................................................................................12 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS .........................13 
4. 
TEST DRUG AND CONTROL AGENTS ................................................................13 
4.1. 
Descriptive Name:  18F AV-1451 ...............................................................................13 
4.2. 
Radioactive Labeling ..................................................................................................13 
4.3. 
Decay Characteristics .................................................................................................14 
4.4. 
Formulation and Dose 18F-AV-1451 Injection ...........................................................14 
4.5. 
Packaging 18F-AV-1451 Injection ..............................................................................14 
4.6. 
Storage and Handling 18F-AV-1451 Injection ............................................................14 
5. 
INVESTIGATIONAL PLAN .....................................................................................15 
5.1. 
Overall Design and Plan of Trial ................................................................................15 
5.2. 
Planned Dosage and Duration of Treatment ...............................................................15 
5.2.1. 
Dosage and Administration ........................................................................................15 
5.2.2. 
Rationale for Dosages .................................................................................................15 
5.3. 
Selection of Subjects ...................................................................................................16 
5.3.1. 
Inclusion Criteria ........................................................................................................16 
5.3.2. 
Exclusion Criteria .......................................................................................................16 
5.4. 
Prior and Concomitant Therapy ..................................................................................16 
5.5. 
Removal of Subjects from Trial .................................................................................17 
5.6. 
Premature Termination of Trial/Closure of Center ....................................................17 
6. 
WARNINGS/PRECAUTIONS ..................................................................................17 
7. 
PROCEDURES AND METHODS ............................................................................17 
7.1. 
Assessment Periods ....................................................................................................17 
7.1.1. 
Screening Visit ............................................................................................................18 
7.1.2. 
18F-AV-1451 PET Imaging Day .................................................................................18 
7.1.3. 
Safety Follow-up/Phone Call: .....................................................................................19 
7.2. 
Observations and Measurements ................................................................................19 
7.3. 
Protocol for Image Collection ....................................................................................20 
7.4. 
Good Clinical Practice and Monitoring ......................................................................20 
7.5. 
Informed Consent and Subject Information ...............................................................21 
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7.6. 
Documentation ............................................................................................................21 
7.7. 
Adverse Events ...........................................................................................................22 
7.7.1. 
Adverse Even Monitoring ...........................................................................................22 
7.7.2. 
Adverse Event Definitions ..........................................................................................22 
7.7.3. 
Adverse Event Documentation ...................................................................................24 
7.7.4. 
Reporting of Serious Adverse Events .........................................................................24 
8. 
STATISTICAL ANALYSIS ......................................................................................24 
8.1. 
General Statistical Considerations ..............................................................................24 
8.2. 
Safety Analysis ...........................................................................................................25 
8.3. 
Image Analysis ...........................................................................................................25 
8.4. 
Primary Objective Analysis ........................................................................................25 
8.5. 
Sample Size ................................................................................................................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) 
 
AIDS 
amu 
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. 
Acquired Immune Deficiency Syndrome 
Atomic mass unit 
Audit 
 
 
 
 
CFR 
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). 
Code of Federal Regulations 
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 
ECG 
EDC 
Computed Tomography 
Electrocardiogram 
Electronic Data Capture 
Efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
FDA 
US Food and Drug Administration  
FDG 
FTD 
18F – Fluorodeoxyglucose 
frontotemporal dementia 
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GCP 
hERG 
 
HIV 
ICF 
ICH/IEC 
IQCODE 
IRB 
Kd 
 
 
 
keV 
Good Clinical Practice 
human Ether-à-go-go-Related Gene is a gene that codes for a protein 
known as Kv11.1, the alpha subunit of a potassium ion channel. 
Human Immunodeficiency Virus 
Informed Consent Form 
International Conference on Harmonization/Independent Ethics 
Committee 
Informant Questionnaire on Cognitive Decline in the Elderly 
Institutional Review Board 
a specific type of equilibrium constant that measures the propensity of a 
larger object to separate (dissociate) reversibly into smaller components, 
as when a complex falls apart into its component molecules, or when 
a salt splits up into its component ions. 
kiloelectron volt  
ICH 
IND 
International Conference on Harmonization 
Investigational New Drug 
Institutional 
Review Board 
/Independent 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
the safety, welfare and human rights of the subjects participating in a 
clinical study are protected. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
IV 
Intravenous 
MBq 
Megabecquerel 
mCi 
MedDRA 
Millicurie 
Medical Dictionary for Regulatory Activities 
MHD 
µg 
mM 
Maximum Human Dose 
microgram 
millimeter  
MMSE 
Mini Mental State Examination 
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MRI 
mSv 
 
MW 
N 
NDA 
nM 
Magnetic Resonance Imaging 
The Sievert is a derived unit of ionizing radiation dose in the International 
System of Units (SI) 
Molecular Weight 
Number of subjects 
New Drug Application 
nanometer 
NOAEL 
PET 
PHF 
 
PhRMA 
No Observable Adverse Effect Level 
Positron emission tomography 
Paired helical filament is a major component of the neurofibrillary tangles 
involved in the pathology of Alzheimer’s disease 
Pharmaceutical Research and Manufacturers of America 
SAP 
SD 
Serious Adverse 
Event (SAE) 
 
 
 
 
SOC 
Statistics Analysis Plan 
Standard deviation 
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. 
System Organ Class 
SUVR 
Standard Uptake Value Ratio 
 
 
TBI 
TDP 
 
USP 
v/v 
Traumatic Brain Injury 
Traumatic Brain Injury 
Torsades de Pointes 
Ultraspiracle protein, a part of the ecdysone receptor 
Volume concentration 
 
 
 
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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 change (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 shown to predict rate of future 
deterioration and has not been established as a tool to predict or monitor response to therapy.   
Deposited tau is one of the defining neuropathological lesions of AD, but is also one of the 
hallmark pathologic features of other dementias, including frontotemporal dementia (FTD) 
[Bigio 2008; Cairns 2007; Piguet 2011].  In contrast to Aβ neuritic plaques, the density and 
distribution of phosphorylated tau, aggregated in neurofibrillary tangles, increases with AD 
related cognitive impairment and correlates with neurodegeneration (Duyckaerts et al., 1987; 
Braak et al., 2011; Nelson et al., 2012).  Thus a PET imaging agent that binds to phosphorylated 
tau has potential application as 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 Aβ negative tissue.  Scatchard 
analysis based on this heterogeneous autoradiography assay yielded an estimated Kd of 15nM. A 
saturation binding experiment using purified PHF tau isolated brains of AD patients yielded a Kd 
value of 0.7 nM. 
AV-1451 was assessed in competitive binding assays against a panel of 72 of the most common 
central nervous system (CNS) targets and no clinically relevant inhibition was seen.   AV-1451 
was positive in the in vitro hERG assay; however, in vivo cardiovascular safety pharmacology 
assessments in dogs showed no evidence of QT prolongation at doses up to 50x the intended 
maximum human dose (MHD).  Nonetheless, until sufficient human cardiovascular safety data 
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are available, initial clinical studies will exclude subjects with a history of risk factors for 
Torsades de Pointes and subjects taking drugs known to prolong the QT interval. 
In vivo safety pharmacology studies were also conducted in rats to determine potential effects on 
the CNS and respiratory systems. In these studies no clinically relevant effects were reported at 
doses exceeding 100x the intended MHD. Additionally, non-radioactive AV-1451 has been 
tested in single and repeat-dose toxicology studies in rat and dog.  In each of these studies the no 
observable adverse effect levels (NOAELs) were the highest doses tested (150x MHD for single, 
50x MHD for repeat).   
Potential genotoxicity of non-radioactive AV-1451 was tested in both in vitro and in vivo assays.  
In the in vitro assays, AV-1451 tested positive for potential genotoxicity.   However, in the in 
vivo rat micronucleus assay at doses up to 750x MHD (scaled allometrically), AV-1451 showed 
no evidence of genotoxicity. The different results in the in vitro genotoxicity assays and the in 
vivo micronucleus study are likely related to differences in the exposure conditions encountered 
by the target cells in the different test systems. In vivo, AV-1451 is cleared rapidly; however, the 
in vitro experiments employ static, prolonged exposure of cells to high concentrations of the test 
article. While the in vitro data show the potential for genotoxicity, the in vivo data provide 
assurance that genotoxicity is unlikely to occur at clinically-relevant doses for human diagnostic 
studies. 
Human dosimetry has been obtained in nine subjects.  Generally, the radiotracer distribution was 
consistent among the subjects and showed rapid hepatobiliary clearance.  There were three 
organs that received estimated doses higher than 0.05 mSv/MBq. The organ that received the 
largest estimated dose was the upper large intestinal wall (0.0962 ± 0.0134 mSv/MBq), followed 
by the small intestine and the liver.  The Effective Dose was 0.0241 ± 0.0016 mSv/MBq. This 
results in an estimated Effective Dose of 8.92 mSv for an anticipated 370 MBq (10 mCi) 
injection and is comparable to the effective dose of approved 18F-labeled compounds such as 
fluorodeoxyglucose (FDG) and florbetapir F 18 injection. 
Preliminary analyses of human 18F-AV-1451 PET images from human subjects have shown little 
accumulation of tracer in young subject, accumulation largely limited to medial temporal lobe in 
older subjects with clinically normal cognition, and increased accumulation in cortical areas of 
amyloid positive MCI and AD subjects.  Although these preliminary results are consistent with 
the pattern of tau pathology previously reported in autopsy studies (Braak, 1991) and suggest 
18F-AV-1451 may be useful as a marker of tau pathology in patients with AD and other 
neurodegenerative disorders, additional studies are needed to confirm that the in vivo 18F-AV-
1451 PET signal specifically reflects brain tau accumulation.  Thus, the present study is intended 
to explore the relationship between 18F-AV-1451 PET scan signal and brain tau pathology as 
seen at autopsy. 
2. 
TRIAL OBJECTIVES 
 To explore the relationship between 18F-AV-1451 PET scan results and brain pathology 
observed at autopsy. 
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3.
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS
The trial is sponsored by: 
Avid Radiopharmaceuticals, Inc. 
3711 Market Street, 7th Floor 
Philadelphia, PA 19104 
Phone: +1 215-298-0700 
The medical contact is: 
 M.D. 
  
Office: 
 
Fax: 
 
E-mail: 
 
This study will be conducted at 1 to 4 centers in the United States. 
4.
TEST DRUG AND CONTROL AGENTS
4.1. 
Descriptive Name:  18F AV-1451
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole 
MW = 262.27 amu 
4.2. 
Radioactive Labeling 
The compound is labeled with [18F] fluorine that decays by positron (β+) emission and has a half-
life of 109.77 min.  The principal photons useful for diagnostic imaging are the 511 keV gamma 
photons, resulting from the interaction of the emitted positron with an electron. 
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4.3. 
Decay Characteristics 
The time course of radioactive decay for Fluorine [18F] is shown below 
Min. 
Fraction Remaining 
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
Physical decay chart for Fluorine [18F].  Half-life = 109.77 min. 
4.4. 
Formulation and Dose 18F-AV-1451 Injection 
18F-AV-1451 Injection is a clear solution containing 18F-AV-1451 (drug substance) formulated 
for intravenous bolus administration. Depending on the manufacturer, 18F-AV-1451 Injection 
will be formulated in either: 
• aqueous 21 mM sodium phosphate solution containing up to 10% (v/v) ethanol, or  
• a solution containing 10% (v/v) ethanol, USP in 0.9% sodium chloride injection, 
USP. 
Drug product of either formulation is manufactured to meet one common set of specifications. 
The expiration time and date of 18F-AV-1451 Injection are provided on the outer label of each 
dose based on specific activity or strength. 18F-AV-1451 Injection should be stored at room 
temperature. 
4.5. 
Packaging 18F-AV-1451 Injection 
Each package of 18F-AV-1451 Injection includes a sterile apyrogenic sealed glass vial or sterile 
apyrogenic syringe containing 18F-AV-1451 Injection, a surrounding protective lead shield 
canister, and an outside delivery case. 
4.6. 
Storage and Handling 18F-AV-1451 Injection 
18F-AV-1451 Injection is stored at room temperature. 18F-AV-1451 Injection should be stored 
within the original container or equivalent radiation shielding.  18F-AV-1451 Injection must not 
be diluted. 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Design and Plan of Trial 
The study is designed to examine the relationship between imaging results detected on a 18F-AV-
1451 PET scan and pathology found at autopsy within six months of imaging. Up to 10 subjects 
will be enrolled and imaged with 18F-AV-1451. All subjects will be followed to autopsy. 
Approximately 5 brains will be selected for high resolution analysis. 
All subjects and/or their LAR/next-of-kin will provide informed consent before starting any 
study procedures. 
Screening assessments may take place over several days and will include collection of 
demographic information, diagnostic interview, brain MRI, and safety assessments.  At the time 
of screening, subjects and/or their LAR/next-of-kin will be asked to provide consent for brain 
donation in addition to providing informed consent for the screening and imaging procedures in 
the study. 
Subjects who qualify for the study will receive a single I.V. bolus of 18F-AV-1451 followed 
by brain PET imaging for 20 minutes duration, beginning approximately 80 minutes post-
injection.  Vital signs will be obtained prior to the administration of 18F-AV-1451 and at the 
completion of the imaging session.  Adverse events will be continuously monitored during 
the imaging session.  Subjects who experience an adverse event will not be released from the 
PET center until the event has been resolved or stabilized. After the 48 hour safety visit or 
follow-up phone call is completed subject participation in the study will end.  
5.2. 
Planned Dosage and Duration of Treatment 
5.2.1. 
Dosage and Administration  
18F-AV-1451: 
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) of 
18F-AV-1451 Injection. 
5.2.2. 
Rationale for Dosages 
18F-AV-1451 will be administered IV in a radioactive dose of 370 MBq with a maximum human 
dose (MHD) limited to 20 µg of compound by weight.  This dose is 150 fold lower than the 
NOAEL observed in the rat single dose toxicity study and is 50 fold lower than the NOAEL 
observed in the rat and dog repeat dose toxicity studies. 
Human dosimetry has been obtained in nine subjects. The results estimated an Effective Dose of 
8.92 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable to the effective dose 
of approved 18F-labeled compounds such as FDG and florbetapir F 18 injection. 
The proposed dose has been shown to have acceptable image quality in preliminary human 
studies. No treatment related adverse events have been reported using this regimen.   
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5.3. 
Selection of Subjects 
5.3.1. 
Inclusion Criteria 
Subjects who meet the following criteria are eligible to enroll in this trial: 
1. Are males or females between 60 and 89 years of age; 
2. Have a projected life expectancy of ≤ 6 months as determined by the site  principal 
investigator;  
3. Can tolerate an MRI and 20 minute PET scan. The site principal investigator will 
carefully assess each patient and use sound medical judgment to determine whether the 
patient can tolerate both scan procedures; and 
4. Give informed consent or have a legally authorized representative to consent for study 
procedures and brain donation consistent with the legal requirements of the state where 
the study is conducted. 
5.3.2. 
Exclusion Criteria 
Subjects may not be enrolled if they:    
1. Have primary brain tumor, known metastases to the brain, central nervous system (CNS) 
lymphoma; 
2. Have any major, focal structural brain lesion that would interfere with interpretation of 
PET images; 
3. Are aggressively being treated with life sustaining measures (e.g. currently on respirator; 
receiving high dose chemotherapy – subjects on low maintenance dose or between dose 
cycles may be enrolled after consultation with Avid); 
4. Have a clinically significant infectious disease, including Human Immunodeficiency 
Virus (HIV) infection, hepatitis or prion disease; 
5. Are receiving any investigational medications, or have participated in a trial with 
investigational medications within the last 30 days; 
6. Are females of childbearing potential who are pregnant or are not using adequate 
contraception; 
7. A history of additional risk factors for Torsades de Pointes (TdP) or are taking drugs that 
are known to cause QT-prolongation (a list of prohibited and discouraged medications is 
provided by the Sponsor). 
 
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 of the eCRF. 
 
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Subjects who are taking drugs that are known to cause QT-prolongation may not be enrolled in 
the study (a list of prohibited and discouraged medications is provided by the Sponsor). 
5.5. 
Removal of Subjects from Trial 
Subjects must be removed from the trial if: 
1. Informed consent is withdrawn; or  
2. The investigator or the sponsor believes it is in the best interest of the subject to be 
removed from the trial. 
Subjects may be withdrawn from the trial if a serious adverse event occurs.   The date and reason 
for discontinuation should be noted on the eCRF. 
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.  However, because relatively little toxicological evaluation has been 
completed, and because  18F-AV-1451 Injection is in the early stages of clinical investigation, it 
is recommended that subjects receiving  18F-AV-1451 Injection be followed closely by means of 
adverse event reporting and vital signs. 
There are no data on the effects of 18F-AV-1451 Injection in human perinatal development. Both 
females and males must use adequate contraceptive methods for 90 days after administration of 
18F-AV-1451 Injection.  18F-AV-1451 Injection must not be administered to females who are 
pregnant or lactating. 
7. 
PROCEDURES AND METHODS 
7.1. 
Assessment Periods  
See Section 11.2, Trial Flow Chart. 
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7.1.1. 
Screening Visit 
Screening may take place over several days. Some screening assessments may be performed on 
imaging day.  
Assessments will include: 
• Informed consent (for clinical, imaging and autopsy procedures); 
• Demographics (age, gender, race, ethnicity, education); 
• Brief cognitive / dementia evaluation including:  
 Medical history and concomitant medications; 
 Alzheimer’s disease history (if relevant: date/months since symptom onset, date/months 
since diagnosis, family history of neurological disease); 
 Mini-Mental Status Examination (MMSE) may be obtained if the subject is able to 
cooperate with the test; 
  IQCODE will be administered to the subject’s caregiver/informant to include 
information about clinically meaningful decline in cognitive status during the ten years 
prior to the subject’s most recent illness;; Note: If an informant is not available to 
provide information for the IQCODE this will not necessarily result in exclusion for the 
subject. 
• Safety (vital signs); 
• Most recent height and weight will be obtained from medical records; 
• Urine pregnancy test (for females of childbearing potential); 
• Brain MRI (MRI should be performed within 2 weeks of the 18F-AV-1451 PET scan); 
• A physician evaluation and summary of current medical status. 
7.1.2. 
  18F-AV-1451 PET Imaging Day 
 
The following assessments will be performed for subjects on imaging day: 
 
• Any procedure not completed during the screening visit;  
• The subject will be seen by a physician who will assess their ability to safely tolerate the 
imaging procedure;  
• Females of childbearing potential will have a urine (or serum if required by local IRB) 
pregnancy test prior to injection (the result must be negative for the subject to be 
administered 18F-AV-1451); 
• Following an I.V. bolus injection of 18F-AV-1451, 20 minutes of continuous brain PET 
imaging will begin 80 minutes post-injection;   
• Vital signs will be taken immediately prior to administration of 18F-AV-1451 and after 
completion of imaging, prior to discharge; 
• Subjects will be observed continuously for signs of adverse events (AE) or serious adverse 
events (SAE). All AEs and SAEs will be followed until resolution or stabilization;  
• The injection site will be observed for excessive inflammation or damage to the surrounding 
tissue where the dose was injected; and  
• A physician will see the subject prior to release from the PET center to evaluate any adverse 
events. 
 
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7.1.3. 
Safety Follow-up/Phone Call: 
Each study subject (or caregiver/informant if applicable) will be contacted 2 or 3 business days 
after 18F-AV-1451 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 18F-AV-1451 administration. 
7.2. 
Observations and Measurements 
Autopsy: 
For those subjects who come to autopsy within six months of imaging, neuropathological 
examination will be conducted according to a separate neuropathology manual, which will be 
written prior to the first subject autopsy in this study. Cases not included in the high-resolution 
autopsy study will be banked until the time of study conclusion. At this time, a clinical autopsy 
may be conducted and a clinical autopsy report provided to the subject’s physician. 
Brain tissue will be maintained at the Grinberg Lab/UCSF until 2 years after the study is 
completed for study purposes. After that period of time, brain tissue will be placed in a 
biospecimen repository located at the Grinsberg Lab/UCSF for future research studies. Approved 
research studies may be conducted at the VA, other Federal health agencies, academic 
institutions, or for-profit organizations.  Brain tissue will only be provided to researchers in a 
coded manner so that they will not be able to identify participants. If participant does not consent 
to allow his/her brain tissue to be placed into this biospecimen repository, he/she cannot 
participate in this study. 
Informed Consent 
Potential subjects and legally authorized representatives, if applicable, will be allowed to read a 
written informed consent form.  The site 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. 
 
IQCODE – Short Version (Jorm, 1994) 
Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) is a tool used to assess 
cognitive impairment in older people. IQCODE will be administered to subject’s 
caregiver/informant during screening. 
 
Medical History, Neurologic Disease History  
The investigator or designee will obtain a case history at the screening visit. 
• 
Relevant demographic information  
• 
Medical and surgical history 
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• 
Concurrent medications 
• 
Alzheimer’s disease history (month and year of symptom onset, month and year of diagnosis, 
family history of neurologic disease) 
Whenever possible, the medical history will be confirmed by medical records. 
Documentation of the events leading up to death will be collected. 
 
MRI 
The screening brain MRI should be obtained within 2 weeks of the 18F-AV-1451 PET scan. A 
second brain MRI will be taken post-mortem to help correct for brain deformations when co-
registering histology and PET scan data. The post-mortem MRI can be done in vivo or in a 3D 
printed skull. The MRI sequences and acquisition parameters will be described in a separate 
document. Electronic copies of MRI scans will be submitted to Avid.  
Pregnancy Testing  
A urine beta-hCG test will be performed at screening and at the 18F-AV-1451 imaging visit(s) 
prior to injection for females of childbearing potential (defined as pre-menopausal, less than 2 
years post-menopausal or not surgically sterile). A serum pregnancy test may also be obtained 
prior to injection at the 18F-AV-1451 imaging visit(s) if required by the local site. 
 
Vital Signs  
Vital signs (pulse rate, respiratory rate, and supine blood pressure) will be taken at the following 
time points: 
• Screening Visit; 
• Immediately prior to the administration of 18F-AV-1451 Injection; 
• After the completion of imaging prior to discharge;   
 
The most recent height and weight recorded in the subject’s medical records will be collected at 
screening. 
7.3. 
Protocol for Image Collection 
The sponsor will prepare and distribute a PET Imaging Manual for 18F-AV-1451 as well as an 
MRI Manual.   
7.4. 
Good Clinical Practice and Monitoring 
All clinical studies performed under the direction of Avid/CRO will be conducted in accordance 
with applicable regulatory requirements and International Conference on Harmonization (ICH) 
Good Clinical Practice (GCP) and Avid/CRO Standard Operating Procedures (SOP).  
This includes: 
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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 including the 
notification of study site clinical investigators, local IRBs and the FDA regarding serious 
adverse events; 
4. Avid’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 site principal investigator or designee will explain all 
study procedures, risks, and alternative therapies.  The subject and legally authorized 
representative will have an opportunity to have all questions answered by a physician.  The 
subject will then sign and date the informed consent form, indicating willingness to participate in 
the study. 
Subjects with AD are potentially a vulnerable population with compromised mental capacity.  
Investigators should take extra care to evaluate a patient’s ability to give consent.  If the subject 
is capable of giving informed consent then the subject should sign on the consent line of the 
informed consent form.  When applicable the legally authorized 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.   
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 and MRI scans, will be saved in an appropriate electronic format as 
specified in the imaging manuals.  A copy of all scans will be saved at the site/imaging center 
and a copy of each will be forwarded to the sponsor or to the designated imaging core lab as 
described in the imaging manuals.  All other data required by the protocol will be recorded in the 
eCRF.  All data in the eCRF will be substantiated by “source documents,” which consist of the 
subject’s medical files, laboratory result sheets, ECG tracings, etc.  All source documentation 
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must be available to Avid and designees.  Completed source documents and eCRFs may need to 
be made available and complete for an audit by the FDA or other international regulatory 
authorities or Avid at any time.  A ballpoint pen should be used to ensure that all copies are 
legible.  eCRFs and all other records must be filed in accordance with applicable laws and 
regulations (see Section 10.6) 
7.7. 
Adverse Events 
Avid’s standards for recording and reporting adverse events (AEs) are to be followed regardless 
of applicable regulatory requirements that may be less stringent.  All AEs must be fully recorded 
on the Adverse Event Page of the eCRF. Investigators will be instructed to report to Avid or its 
designee their assessment of the potential relatedness of each AE to investigational product or 
protocol procedure via electronic data entry.  If a patient’s treatment is discontinued as a result of 
an AE, study site personnel must clearly report to Avid or its designee via electronic data entry 
the circumstances and data leading to any such discontinuation of treatment. In cases where the 
investigator notices an unanticipated benefit to the patient, study site personnel should report 
“unexpected benefit” with the actual event term to Avid or its designee (for example, the 
complete actual term would be “unexpected benefit- sleeping longer”). 
Laboratory test abnormalities considered by the Investigator to be clinically relevant should be 
reported on the Adverse Event Page of the eCRF.  Signs and symptoms of each AE should be 
described in detail (e.g., start and stop dates/time, severity/intensity, 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 Even 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.  
In order to capture possible adverse effects of trial participation, any untoward medical 
occurrences occurring after the informed consent until the administration of 18F-AV-1451 will be 
recorded in the CRF for reporting as trial-emergent adverse events. 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Untoward medical occurrences will be 
considered associated with the use of 18F-AV-1451, and thus be reported as adverse events, if 
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they occur within 48 hours after 18F-AV-1451 administration. 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. 
The end of study for the purpose of adverse event reporting is defined as 48 hours after the last 
administration of 18F-AV-1451. 
Serious Adverse Event (SAE) 
An SAE is an AE that results in one of the following outcomes or constitutes one of the 
following events: 
• Death; 
• Initial or prolonged inpatient hospitalization (other than that required by protocol; 
“social hospitalization” or any hospitalization for non-medical reasons does not 
constitute an SAE); 
• A life-threatening experience (that is, immediate risk of dying); 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect; 
• Considered significant by the investigator for any other reason. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
In the context of this study, death occurring after the 48 hour safety follow-up is expected and 
will not be considered a reportable SAE in the clinical or Global Patient Safety databases unless 
the investigator believes the death is caused by the investigational product or protocol procedure. 
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:   
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A mild adverse event is an adverse event, usually transient in nature and generally not interfering 
with normal activities. 
Moderate:   
A moderate adverse event is an adverse event that is sufficiently discomforting to interfere with 
normal activities. 
Severe:   
A severe adverse event is an adverse event that incapacitates the subject and prevents normal 
activities.   Note that a severe event is not necessarily a serious event.  Nor must a serious event 
necessarily be severe. 
7.7.3. 
Adverse Event Documentation 
All adverse events must be fully recorded on the Adverse Event Page via the eCRFs.  
Documentation must be supported by an entry in the subject file.  Vital signs 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 receives 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 in the clinical or Global 
Patient Safety databases 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 be reported on the eCRF and to Eli Lilly or its designee.  
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 
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characteristics data will be summarized for all subjects in the safety population.  Safety data will 
be summarized for all patients. 
Subject listings of all data from the electronic case report forms (eCRFs) as well as any derived 
variables will be presented.  
Additional details concerning statistical analyses will be included in the Statistical Analysis Plan 
(SAP). 
8.2. 
Safety Analysis 
Vital signs measurements will be summarized by subject.  Change from baseline (pre-dose time 
point) values will be determined and summarized. 
Adverse events including injection site reactions will be summarized in terms of number and 
percentage of subjects experiencing an AE.  The summary will be further broken down by 
system organ class (SOC) and preferred term using Medical Dictionary for Regulatory Activities 
(MedDRA) terms.  Adverse events will also be presented by severity, relationship to treatment 
and seriousness.  All subjects who experience SAEs or who discontinue due to AEs will be 
summarized. 
Discontinuation  
All subjects who discontinued participation prior to completing the study will be listed and their 
discontinuation reasons will be tabulated. 
8.3. 
Image Analysis 
All 18F-AV-1451 PET images will be analyzed and include co-registration of the MRI to the PET 
images. The exploratory analysis will be detailed in the Image Analysis Plan. 
8.4. 
Primary Objective Analysis 
The relationship of tau at 18F-AV-1451 PET scan and at autopsy will be graphically displayed on 
a regional and global basis.  Pearson product correlation analysis will be applied to quantify this 
relationship, if there are no obvious outliers. If there are obvious outliers, a Spearman’s rank 
correlation analysis will be applied instead. 
8.5. 
Sample Size  
Due to the exploration nature of this study, the sample size was determined outside of statistical 
considerations. 
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.  
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• As a sponsor, we may recommend that the Investigator(s) delay or decline publication 
in cases where the study design, conduct, or data are insufficient to allow meaningful 
interpretation.  Avid and the Investigator(s) will discuss the study design and data in 
advance of the study, and again after completion, and will strive, through appropriate 
scientific debate, to reach a consensus regarding the potential merits of publication. 
• Avid retains the right to review any manuscripts, presentations, or abstracts before 
they are submitted for publication. Where differences of opinion or interpretation 
exist regarding data planned for publication, the parties (Avid and the Investigator) 
should try to resolve them through appropriate scientific debate.  Avid retains the 
right to delay publication for up to 60 days to protect intellectual property.  
• Anyone who provides substantial contributions should receive appropriate 
recognition as an author or contributor when the manuscript is published.  
 
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); 
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• Copy of the IRB/IEC stamped approved consent form; 
• Name and location of the laboratory utilized for laboratory assays, and other facilities 
conducting tests, including laboratory certification number and date of certification if 
available.  Avid may be responsible for supplying these to the investigator if a central 
laboratory is used;  
• List of reference range laboratory values.  Avid may be responsible for this if a 
central laboratory is used; and 
• Any additional licenses required in order to order to use 18F-AV-1451. 
10.5. 
Investigational Product Control 
The receipt of clinical supplies 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.  
The files should include information such as visit dates, records of medical history, examinations 
administered, vital signs, concomitant treatment, any adverse event encountered and other notes 
as appropriate.  These constitute “source data”.  All entries on the eCRFs must be backed up by 
source data.  Original electronic versions of imaging studies are also considered source data and 
should be kept on file by the site/imaging center, and appropriate copies should be forwarded to 
Avid or a designated Imaging Core Lab as specified in the Imaging Manual.   
Each patient’s source file should include an original signed informed consent form.  When the 
trial is completed, the informed consent form should be kept on file with other trial related 
records. 
The eCRFs must be kept in order and up-to-date so that they always reflect the latest 
observations on the subjects that are enrolled in the trial.  The eCRFs must be completed for each 
patient enrolled in the trial and signed by the investigator.  This should be done as soon as 
possible after completion of the patient’s participation in the trial.  A monitor will verify the 
source data for all information on the eCRF. 
10.7. 
Adverse Events 
All adverse events encountered during the clinical trial must be documented on the eCRF, 
whether or not considered drug-related. 
Eli Lilly must be notified immediately (as soon as possible, and in all cases within 24 hours) of a 
drug experience, condition, development, or event, which is considered serious. Eli Lilly must be 
notified immediately of any findings with the use of the drug that may suggest significant 
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hazards, contraindications, adverse drug reactions (ADRs) and precautions pertinent to the safety 
of the drug.  The investigator will be requested to complete a separate report form in addition to 
the information on the eCRF.  See section 7.7.4 for reporting serious adverse events 
If 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 
Bigio EH. Update on recent molecular and genetic advances in frontotemporal lobar 
degeneration. J Neuropathol Exp Neurol. 2008;67(7):635-48. 
Braak H, Thal DR, Ghebremedhin E, Del Tredici K. “Stages of the Pathologic Process in 
Alzheimer Disease: Age Categories from 1 to 100 Years.” J Neuropathol Exp Nerol, J 
Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. 
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. 
Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for 
frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar 
Degeneration. Acta Neuropathol. 2007;114(1):5-22. 
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. 
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. 
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. 
Jorm, A. F. (1994). A short form of the Informant Questionnaire on Cognitive Decline in the 
Elderly (IQCODE): Development and cross-validation. Psychological Medicine, 24, 145-153.  
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]. 
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14Nov2016 – Amendment 3                                 Page 30 of 32                                                      
 
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. 
Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic 
changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012 
May;71(5):362-81. 
Piguet O, Hornberger M, Mioshi E, et al. Behavioural-variant frontotemporal dementia: 
diagnosis, clinical staging, and management. Lancet Neurol. 2011;10(2):162-72. 
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.  
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  
 
Evaluations 
Screen 
 
Pre-dose 
 
Dose 
Continuous PET 
Imaging 20 
minutes 
End of 
Imaging 
48 Hour Safety 
Follow-Up   
Death 
Signed Informed Consent1 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical / Disease History 
X 
 
 
 
 
 
Concomitant Meds 
X 
X 
 
 
 
 
Cognitive Impairment Interview with 
Informant (IQCODE) 
X 
 
 
 
 
 
Brain MRI 
X 
 
 
 
 
X 
Physician Visit 
X 
X 
 
X 
 
 
Vital Signs2 
X 
X 
 
X 
 
 
18F-AV-1451 Administration 
 
 
X 
 
 
 
PET Imaging 
 
 
 
Continuous 20 
minute scan - 80 
minutes after dose 
injection 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
 
Brain Harvesting 
 
 
 
 
 
 
X 
1 Subjects should consent for clinical, imaging, and autopsy procedures at screening. 
2 Vital signs: pulse rate, respiratory rate, and supine blood pressure
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INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
Protocol 18F-AV-1451-A13:  “A High Resolution Autopsy Study Evaluating the 
Relationship of 18F-AV-1451 PET Imaging and Tau Pathology” 
 
 
Date and Version: 14Nov2016– Amendment 3 
 
 
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. 
 
 
Principal Investigator: 
 
 
 
Printed Name   
 
 
 
 
 
 
 
 
 
 
__________________________________  
___________________________________ 
Signature  
 
 
 
 
 
 
 
 
 
Date 
 
 
LY3191748

SAP_001.pdf: 
 
ClinicalTrials.gov Cover Page 
Study Statistical Analysis Plan: 18F-AV-1451-A13 
Official Title: A High Resolution Autopsy Study Evaluating the Relationship of 
18F-AV-1451 PET Imaging and Tau Pathology 
NCT Number: NCT02350634 
Document Date: 22 November 2024 
 
 


18F-AV-1451-A13 CSR Addendum Appendix Statistical Methods 
Page 1 
 
 LY3191748  
 
Documentation of Statistical Methods  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document ID: VV-CLIN-171797 
 
 
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CONFIDENTIAL 
18F-AV-1451-A13 Study Efficacy Statistical Analysis Plan version 1.0 
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Title Page   
18F-AV-1451-A13 Study Efficacy Statistical Analysis Plan 
Protocol Title: A High-Resolution Autopsy Study Evaluating the Relationship of 18F-AV-
1451 PET Imaging and Tau Pathology 
Protocol Number: 18F-AV-1451-A13 
Compound Number: LY3191748 
Short Title: AV1451 A13 Efficacy SAP 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
Enter 
Registry 
Name 
 
 
 
Confidential Information  
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries 
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.  
 
 
 
Document ID: VV-CLIN-077445 
Version: 1.0 
 
 
 
 
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Table of Contents  
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................2 
Version history ...............................................................................................................................3 
1. 
Introduction .....................................................................................................................4 
1.1. 
Objectives, Endpoints, and Estimands ..............................................................................5 
1.2. 
Study Design .....................................................................................................................7 
2. 
Statistical Hypotheses .....................................................................................................8 
2.1. 
Multiplicity Adjustment ....................................................................................................8 
3. 
Analysis Sets ....................................................................................................................9 
4. 
Statistical Analyses .......................................................................................................10 
4.1. 
General Considerations ...................................................................................................10 
4.2. 
Participant Dispositions ..................................................................................................10 
4.3. 
Primary Endpoint Analysis .............................................................................................10 
4.4. 
Secondary Endpoint(s)/Estimands(s)] Analysis .............................................................10 
4.5. 
Tertiary/Exploratory Endpoint Analysis .........................................................................10 
4.6. 
(Other) Safety Analyses ..................................................................................................10 
4.7. 
Other Analyses ................................................................................................................11 
4.8. 
Interim Analyses .............................................................................................................11 
4.9. 
Changes to Protocol-Planned Analyses ..........................................................................11 
5. 
Sample Size Determination ..........................................................................................12 
6. 
Supporting Documentation ..........................................................................................13 
7. 
References ......................................................................................................................14 
 
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Version history  
This Statistical Analysis Plan (SAP) for study 18F-AV-1451-A13 is based on the protocol dated 
14NOV2016.  
Table 1 SAP Version History Summary  
SAP 
Version 
Approval 
Date 
Change 
Rationale 
1.0 
 
Not Applicable 
Initial version 
 
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1. 
Introduction  
Molecular imaging biomarkers hold great potential in aiding the diagnosis of individuals 
undergoing evaluation for cognitive impairment and Alzheimer’s disease (AD) (Dubois et. al., 
2010; McKhann et. al., 2011). One such biomarker is 18F-Flortaucipir (commonly referred to as 
flortaucipir or 18F-AV-1451, or initially known as [F-18]T807 by Siemens Molecular Imaging 
Biomarker Research group), which has been developed as a positron emitting 
radiopharmaceutical for in vivo imaging of tau protein aggregates (Xia et al., 2013).  
 
Preliminary analyses of flortaucipir PET scans have shown minimal tracer accumulation in 
young subjects. In contrast, flortaucipir accumulation is predominately observed in the medial 
temporal lobe of amyloid-negative older adults with clinically normal cognition and is more 
pronounced in neocortical regions of amyloid-positive patients with mild cognitive impairment 
(MCI) and AD dementia (Johnson et. al., 2016, Scholl et. al., 2016, Schwarz et. al., 2016). These 
observations align with the tau pathology pattern previously documented in autopsy studies 
(Braak and Braak, 1991), suggesting that 18F-Flortaucipir may serve as a valuable marker for tau 
pathology in AD.  
 
Several studies have reported a correlation between in vivo 18F-Flortaucipir PET signal and the 
density of tau pathology observed at autopsy (Lowe et al., 2020; Pontecorvo et.al., 2020; Smith 
et al., 2019; Gatto et al., 2023; Martersteck et al., 2022, Freiburghaus et. al., 2024). The present 
study, 18F-AV-1451–A13, aims to investigate the relationship between the regional patterns 
observed in the 18F-Flortaucipir PET scan signal and the high-resolution 3D brain tau pathology 
as observed postmortem (Ushizima et. al., 2022).  
 
A statistical analysis plan (SAP) focused on safety analysis was approved on July 16, 2018, and 
can be found in the AVID Biostat shared folder under the title “18F-AV-1451-A13 SAP” (safety 
SAP).  Safety SAP did not include efficacy analyses as it was decided that efficacy analyses 
would be deferred until digitalized autopsy and imaging data became available. 
 
The current SAP, now addressing efficacy analyses per study protocol, is titled “8F-AV-1451-
A13 Efficacy SAP” (efficacy SAP) to differentiate it from the safety SAP. While the Efficacy 
SAP is comprehensive, it is recommended to review it alongside the protocol and the safety SAP 
to understand study fully. 
 
Throughout this document, as well as in the safety SAP and the study protocol, the terms 
“Flortaucipir”, 18F-Flortaucipir”, “18F-AV-1451”, and “AV1451” are used interchangeably. It is 
important to note that the analyses outlined in the protocol represent broad objectives, and the 
specifics detailed in this SAP align with those high-level objectives.  
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1.1. 
Objectives, Endpoints, and Estimands  
The primary objective of this study is to investigate the association at global, composite and regional levels between a flortaucipir 
PET scan and the corresponding global and regional signals derived from the high-resolution 3D histological maps of brain tau 
pathology observed at autopsy.  
 
Ideally, this relationship would be assessed at a finer resolution than FreeSurfer ROIs, e.g. voxel-wise. However, due to challenges in 
acquiring a complete set of pathology images from collaborators, as well as technical challenges related to image processing, we will 
conduct the analysis at the resolution of FreeSurfer ROIs. The availability of autopsy-based pathology data at the FreeSurfer ROIs 
level still is a unique advancement in PET-to-Autopsy analysis design, providing a rich dataset for efficacy analysis. 
An analysis dataset will include 82 FreeSurfer-defined regions of interest (ROIs), normalized to the brain stem for PET data. This 
dataset will incorporate average regional flortaucipir PET signal and the corresponding immunohistology results from three specific 
antibodies, AT8 (pSer202 + Thr205, Thermo), AT100 (pThr212 + Ser214, Thermo), and MC1 (MC1, gift of Peter Davies). The 
mapping of 3D histological immunohistology signals to FreeSurfer ROIs and the corresponding flortaucipir SUVR were estimated, 
quality-controlled and shared by a team at UCSF led by Duygu Tosun-Turgut.  
Available ROIs will be considered for global analysis, then focusing on macrolobar and/or composite brain regions deemed most 
relevant based on AD pathophysiology, also considering possible exclusions due to expected off-target flortaucipir PET binding 
(e.g. medial temporal regions). Composite regions of interest will include a combination of selected cortical and subcortical ROIs 
from the frontal, temporal, parietal, occipital regions. 
For each patient, separately and/or combined, with and without patient level data centering, Spearman’s rank correlation analysis 
will be applied to quantify the strength and direction of the relationship between tau levels measured by PET scan and tau pathology 
at autopsy based on the three different antibodies. The results of these correlation analyses will be presented graphically and in 
tabularly form, both at regional/composite and global levels.  
 
 
 
 
 
 
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Objectives 
Endpoints 
Primary 
 
The primary objective of this study is to 
investigate the relationship between 
flortaucipir PET scan signals and brain 
pathology observed at autopsy using tau 
antibody AT8. 
Correlation coefficients between flortaucipir 
PET quantitation and AT8 antibody staining in 
respective regions 
 Spearman correlation coefficients 
 Global and regional/composite levels 
Tertiary/Exploratory 
 
The exploratory objective is to evaluate the 
relationship among three antibodies (AT8, 
AT100, MC1) targeting different tau epitopes 
and evaluate differential correlative patterns 
between flortaucipir PET scan and these 
antibodies 
Pairwise correlation coefficients among AT8, 
AT100, MC1 antibody staining and flortaucipir 
PET quantitation 
 Spearman correlation coefficient 
 Global and regional/composite levels 
 
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1.2. 
Study Design  
The study was designed to investigate the correlation between imaging findings obtained through 
a flortaucipir PET scan and the pathological observations found at autopsy, using a high-
resolution approach, all of which occurred within a six-month window following the imaging 
procedure. Initially, multiple clinical centers were anticipated to enroll subjects of various levels 
of cognitive status, ranging from individuals with normal cognitive function to those with 
dementia. However, due to shifting priorities, only two clinical centres ultimately participated in 
this study. As a result, the study enrolled and completed just two participants, one cognitively 
normal and the other cognitively impaired. 
The inclusion of a cognitively normal participant in the study holds significance as it enables a 
comparison of the patterns of tracer distribution between normal and impaired. 
Participants who qualified for the study received a single intravenous (IV) bolus of flortaucipir 
followed by brain PET imaging for 20 minutes, beginning approximately 80 minutes post-
injection. Vital signs were obtained before the administration of flortaucipir and after the 
imaging session. Adverse events were continuously monitored during the imaging session. 
Participants who experienced an adverse event were released when the event was resolved or 
stabilized. After the 48-hour safety follow-up was completed, subject participation in the clinical 
portion of the study was considered to have ended. 
 
Please refer to table 2 on page 11 of safety SAP for the visit schedule, safety data collection, and 
safety analysis.
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2. 
Statistical Hypotheses   
The primary objective of the study is to explore the relationship between signals detected on 
flortaucipir PET scan and tau pathology from immunohistochemistry observed postmortem. We 
aim to confirm a positive correlation between the in vivo flortaucipir PET signal and density of 
tau pathology at autopsy. We anticipate that the strength of this correlation will vary across 
different brain regions, either taken individually or as composite, while also depending on the 
antibodies used to target specific tau protein epitopes, as well as individual patient 
characteristics.  
 
In this study, we employed three antibodies that target different epitopes on tau protein. MC1 
identifies the earliest known structural conformational change in tau, primarily staining 
neurofibrillary tangles (NFT) pathology in its early maturity stages, including the pretangle 
phase, and to a lesser extent, more mature tangles. AT8, a widely used antibody, detects earlier 
stages NFT maturation, showing less affinity for pretangle compared to more mature tangles, and 
also reacts to neuritic pathology, contributing to the overall signal. AT100 shares a similar 
profile to AT8 but is more likely to detect later phosphorylation events. Given that AT8 and 
AT100 exhibit similar profiles and are more likely to capture mature tangles compared to MC1, 
and considering AT8’s widespread use as a tau pathology marker, we selected AT8 for the 
primary objective analysis to assess the relationship between flortaucipir PET signal and tau 
staining at autopsy.  
 
Based on the antibodies differences and similarities described above, we hypothesize that AT8 
vs. PET correlations will show relatively higher similarity to AT100 vs. PET correlations as 
compared to MC1 vs. PET correlations. To further understand these relationships, we will also 
explore the association between flortaucipir PET signal and both AT100 and MC1 in exploratory 
analyses. 
 
2.1. 
Multiplicity Adjustment  
Considering the exploratory nature of this study, no multiple testing adjustment is planned. 
 
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3. 
Analysis Sets  
Data Set 
Description 
Participant and analysis data set 
 
Participants 1181-0001 and 1183-0002 will be included in the 
analyses 
 
Flortaucipir and immunochemistry data from the two 
participants will be included in the analyses 
Data points include mean Flortaucipir-PET signal in each of 82 Freesurfer atlas ROI, normalized 
against the brainstem ROI, along with the mean immunochemistry signals for AT8, AT100, and 
MC1 in the same regions. These ROIs will be used for global correlation analyses. 
The selection of ROIs for regional/composite analysis will be based on well-established AD 
regions documented in the Study A16 and referenced publications. The objective is to fully 
capture the dynamic range of flortaucipir PET binding in AD, as highlighted in studies by 
Devous et. al. (2018), Pontecorvo et.al. (2020), and other relevant literature. Given the 
exploratory nature of this study, ROIs for regional/composite analyses will not be pre-
specified. 
 
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4. 
Statistical Analyses  
4.1. 
General Considerations  
All analysis will be performed using R Software, Version 4.3 or SAS 9.4. 
 
Participant demographics will be presented for the two participants individually and correlation 
analysis will be conducted for each participant individually and for the two participants 
combined, globally and regionally, with and without individual level data centering. Among the 
three antibodies AT8, AT100 and MC1, AT8 will be used to draw conclusion as primary 
outcome based on binding properties and frequent utilization in past Flortaucipir PET to Autopsy 
studies. Analyses on AT100 and MC1 will be included in the exploratory objective. 
 
4.2. 
Participant Dispositions  
Two participants enrolled and completed the study. 
 
4.3. 
Primary Endpoint Analysis  
Spearman correlation coefficients will be computed to quantify relationships between flortaucipir 
PET quantification and AT8 antibody staining quantification globally and regional/composite. 
 
Mean signals of antibody AT8 staining and flortaucipir PET signals from 82 ROIs will be used 
for the global correlation analyses, followed by regional/composite analyses based on selected 
ROIs based on AD pathophysiology and possibly expected off-target binding. Correlation 
analyses will be performed for each subject, and two subjects combined, with and without 
subject level data centering. 
 
4.4. 
Secondary Endpoint(s)/Estimands(s)] Analysis  
 
4.5. 
Tertiary/Exploratory Endpoint Analysis  
The same analysis as for the primary endpoint will be conducted, but with AT8, AT100 and 
MC1, focusing on exploring the differential patterns among the three antibodies. 
 
4.6. 
(Other) Safety Analyses  
Safety analyses were defined in a Safety SAP. 
 
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4.7. 
Other Analyses  
 
4.8. 
Interim Analyses  
4.9. 
Changes to Protocol-Planned Analyses   
 
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5. 
Sample Size Determination  
The sample size was determined outside of statistical consideration.  
 
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6. 
Supporting Documentation  
No supporting documentation.  
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7. 
References  
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 
(Berl). 1991;82:239–259 
Devours DM, Joshi, DA, Navistsky M, et. al. Retest Reproducibility for the Tau PET Imaging 
Agent Flortaucipir F 18, Journal of Nuclear Medicine. 2018; 59(6): 937-943 
Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer's disease: a new 
lexicon. Lancet Neurol. 2010;9(11):1118-1127. 
Gatto R, Carlos FA, Reichard RR, et al. Comparative assessment of regional tau distribution by 
Tau-PET and Post-mortem neuropathology in a representative set of Alzheimer’s & 
frontotemporal lobar degeneration patients. Plos One. 2023;18(5): e0284182 
Johnson KA, Schultz A, Betensky RA, et al. Tau positron emission tomographic imaging in 
aging and early Alzheimer disease. Ann Neurol. 2016;79:110–119. 
Lowe VJ, Lundt ES, Albertson SM, et al. Tau-positron emission tomography correlates with 
neuropathology findings. Alzheimers Dement. 2020;16(3):561-571. 
https://doi/10.1016/j.jalz.2019.09.079 
Martersteck A, Ayala I, Ohm DT, et al. Focal amyloid and asymmetric tau in an imaging-to-
autopsy case of clinical primary progressive aphasia with Alzheimer disease neuropathology. 
Acta Neuropathol Commun. 2022;10(1):111. https://doi.org/10.1186/s40478-022-01412-w 
McKhann GM, Knopman DS, 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. 
Pontecorvo MJ, Keene CD, Beach TG, et al. Comparison of regional flortaucipir PET with 
quantitative tau immunohistochemistry in three subjects with Alzheimer’s disease pathology: a 
clinicopathological study. EJNMMI Research. 2020;10(1). doi:10.1186/s13550-020-00653-x 
Scholl M, Lockhart SN, Schonhaut DR, et al. PET imaging of tau deposition in the aging human 
brain. Neuron. 2016;89:971–982. 
Schwarz AJ, Yu P, Miller BB, et al. Regional profiles of the candidate tau PET ligand 18F-AV-
1451 recapitulate key features of Braak histopathological stages. Brain. 2016;139:1539–1550. 
Smith R, Wibom M, Pawlik D, et al. Correlation of in vivo [18F]flortaucipir with postmortem 
Alzheimer disease tau pathology. JAMA Neurol. 2019;76(3):310-317. 
https://doi.org/10.1001/jamaneurol.2018.3692 
Freiburghaus T, Pawlik D, et. al. Association of in vivo retentions of [18F]flortaucipir PET with 
tau neuropathology in corresponding brain regions. Acta Neuropathol. 2024; 148(1):44 
 
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Ushizima D, Chen Y, Alegro M, et al. NeuroImage Deep learning for Alzheimer’ s disease : 
Mapping large-scale histological tau protein for neuroimaging biomarker validation. 
NeuroImage. 2022;248:118790. doi:10.1016/j.neuroimage.2021.118790 
Xia CF, Arteaga J, Chen G, et al. [18F]T807, a novel tau positron emission tomography imaging 
agent for Alzheimer’s disease. Alzheimers Dement. 2013;9(6):666-76 
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