Conditions: Alzheimer's Disease Traumatic Brain Injury Depression
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 179
Healthy volunteers: yes

Brief summary:
This study is designed to expand the database of flortaucipir F 18 safety and tau binding as measured by PET imaging and to provide standardized conditions for flortaucipir PET use, data collection and analysis to facilitate companion studies including, but not limited to, longitudinal studies of aging, depression, and traumatic brain injury.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Flortaucipir F18 intervention 2: Brain PET scan
Intervention descriptions: intervention 1: IV injection, 370 MBq (10 mCi), up to two doses intervention 2: positron emission tomography (PET) scan of the brain

Protocol document:
Prot_000.pdf: 


Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451([F-18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Title of Study: 18F-AV-1451-A14 
“Clinical Evaluation of 18F-AV-1451” 
Planned number of subjects (Enrolled):  
Approximately 250 subjects including healthy controls and subjects at risk for tau accumulation as 
defined by the site’s companion protocol.  
Name of compound: 18F-AV-1451([F-18]T807) 
Dose: Up to a target dose 370 MBq (10 mCi) 
Route of Administration: Intravenous (IV) bolus 
Study Phase: II 
Study Centers: Approximately 10 centers in the United States and Canada 
Trial Objectives:  
The primary objectives of this study are: 
• Provide standardized conditions for 18F-AV-1451 use, data collection, and analysis to 
facilitate evaluation of subject’s tau burden.  
• To expand the 18F-AV-1451 safety database. 
Eligibility: 
Subjects should meet inclusion and exclusion criteria for the companion protocol, and in 
addition: 
Subjects who meet all of the following criteria are eligible to enroll in this study:  
1. Male or female subjects at least 18 years of age; 
2. Subjects who sign an IRB approved informed consent prior to any study procedures.  Where 
subjects are deemed incapable of informed consent, a legally authorized representative may 
provide consent, with the subject’s documented assent;  
3. Subjects who have historical volumetric brain MRI images obtained as part of the site’s 
companion protocol available for submission to Avid; and  
4. Subjects who in the opinion of the investigator can tolerate the PET scan procedures. 
 
05Sep2014 Amendment 1 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451([F-18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Subjects will be excluded from enrollment if they: 
1. Have clinically significant cardiac, hepatic, renal, pulmonary, metabolic, or endocrine 
disturbances as indicated by history, which in the opinion of the investigator might pose a 
potential safety risk to the subject; 
2. Have either:  1) Screening ECG with QTc > 450 msec if male or QTc > 470 msec if female; or 
2) A history of additional risk factors for Torsades de Pointes (TdP) (e.g.,  hypokalemia, 
family history of Long QT syndrome) or are taking drugs that are known to cause QT-
prolongation (a list of prohibited and discouraged medications is provided by the Sponsor); 
Patients with a prolonged QTc interval in the setting of intraventricular conduction block 
(examples RBBB or LBBB), may be enrolled with sponsor approval; 
3. Have a history of drug or alcohol dependence within the last year, or prior prolonged history 
of dependence unless approved by the sponsor;  
4. Are females of childbearing potential who are not surgically sterile, not refraining from 
sexual activity or not using reliable methods of contraception. Females of childbearing 
potential must not be pregnant (negative serum or urine β-HCG at the time of screening and 
negative serum or urine β-HCG on imaging day) or breastfeeding at screening. Females 
must agree to avoid becoming pregnant, and both females and males must agree to refrain 
from sexual activity or to use reliable contraceptive methods for 90 days following 
administration of 18F-AV-1451 Injection; 
5. Have a history of relevant severe drug allergy or hypersensitivity (Relevant severe drug 
allergies should be determined by the PI, and any questions about a subject’s eligibility can 
be directed to Avid. If a subject has a history of severe drug allergies, it may be dangerous 
for them to participate in a study); 
6. Are patients who have received an investigational medication under an FDA IND protocol 
within 30 days prior to the planned imaging session for this study, with the exception of 
medications allowed in the companion study and approval from sponsor. Additionally, the 
time between the last dose of the previous experimental medication and imaging must be at 
least equal to 5 times the terminal half-life of the previous experimental medication;  
7. Are patients with current clinically significant unstable medical comorbidities, as indicated 
by history or physical exam that pose a potential safety risk to the subject; 
8. Are patients who have received a radiopharmaceutical for imaging or therapy within the past 
24 hours prior to the imaging session for this study.  If another radiotracer is required in the 
companion protocol, patients may be able to receive a radiopharmaceutical for imaging or 
therapy within the 24 hours prior to the imaging session with prior sponsor approval;  
9. Are patients who, in the opinion of the investigator, are otherwise unsuitable for a study of 
this type. 
 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451([F-18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Study Design: 
Study 18F-AV-1451-A14 is designed to expand the database of 18F-AV-1451 safety and tau binding 
as measured by PET imaging, and to provide standardized conditions for tau use, data collection 
and analysis to facilitate companion studies including, but not limited to, longitudinal studies of 
aging, depression, and traumatic brain injury.  Approximately 250 subjects will be studied under 
this protocol. 
Assessments and Endpoints: 
Screening:  
Screening assessments may take place over several days and will include collection of demographic 
information, a medical assessment for eligibility, ECG, a brief cognitive assessment (e.g. MMSE), 
and a traumatic brain injury questionnaire.  
18F-AV-1451 PET Imaging Visit:  
Subjects who qualify for the study will come to the imaging center at a later date and will have a 
catheter(s) placed for i.v. administration of 18F-AV-1451. Vital signs will be taken in a supine 
position immediately prior to administration of 18F-AV-1451 (within 30 minutes prior to injection) 
and at the completion of imaging prior to subject discharge. Subjects will receive up to a target dose 
of 370 mBq as a single i.v. bolus of 18F-AV-1451.  A 20 minute dynamic image starting 
approximately 80 minutes post injection will be obtained. With sponsor approval sites may elect an 
alternative imaging protocol (i.e. different duration or start time) with additional time points.  All 
datasets will be submitted to the sponsor for analysis. 
Adverse events will be continuously monitored during the imaging session.  Subjects who 
experience any adverse event will not be discharged until the event has resolved or stabilized. 
Repeat Imaging: 
Longitudinal imaging studies may be conducted under protocol 18F-AV-1451-A14, with prior 
sponsor approval.  In these studies, subjects may have up to two imaging sessions within a 12 
month time-frame. If the second scan is obtained more than 3 months after the previous scan, then 
the MMSE should be repeated and updates to the OSU-TBI, medical history, and concomitant 
medications will be collected. Procedures for each imaging day will be identical to those described 
above. 
Follow-Up Phone Call:  
A follow-up phone call to the subject, or designated decision maker, will be conducted between 2 or 
3 business days after imaging day, but not before 48 hours post-injection, to confirm subject well-
being and to collect information about any new adverse events.  If both of these days are not 
business days, the follow-up phone call can occur the following business day. 
Details of additional assessments that will be performed at each visit are detailed in Section 7.1.   
05Sep2014 Amendment 1 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451([F-18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Statistical Methods:   
Descriptive statistics will be applied to describe the distribution of tau deposition as measured by 
18F-AV-1451 across clinical diagnosis groups. Safety data will be summarized for patients who 
received at least one injection of 18F-AV-1451. 
 
 
 
05Sep2014 Amendment 1 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................ 10 
2. 
TRIAL OBJECTIVES ...................................................................... 11 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 11 
4. 
TEST DRUG AND CONTROL AGENTS ...................................... 12 
4.1. 
Descriptive Name:  18F AV-1451 ..................................................... 12 
4.2. 
Radioactive Labeling ........................................................................ 12 
4.3. 
Decay Characteristics ....................................................................... 12 
4.4. 
Formulation and Dose 18F-AV-1451 Injection ................................. 13 
4.5. 
Packaging 18F-AV-1451 Injection .................................................... 13 
4.6. 
Storage and Handling 18F-AV-1451 Injection .................................. 14 
5. 
INVESTIGATIONAL PLAN ........................................................... 14 
5.1. 
Overall Design and Plan of Trial ...................................................... 14 
5.1.1. 
Dosage and Administration .............................................................. 14 
5.1.2. 
Rationale for Dosages ....................................................................... 15 
5.2. 
Selection of Subjects ......................................................................... 15 
5.2.1. 
Inclusion Criteria .............................................................................. 15 
5.2.2. 
Exclusion Criteria ............................................................................. 15 
5.3. 
Prior and Concomitant Therapy ........................................................ 16 
5.4. 
Removal of Subjects from Trial ....................................................... 17 
5.5. 
Premature Termination of Trial/Closure of Center .......................... 17 
6. 
WARNINGS/PRECAUTIONS ........................................................ 17 
7. 
PROCEDURES AND METHODS .................................................. 18 
7.1. 
Assessment Periods (See Section 11.2, Trial Flow Chart) ............... 18 
7.1.1. 
Screening: ......................................................................................... 18 
7.1.2. 
Imaging Visit .................................................................................... 19 
7.1.3. 
Follow-Up: ........................................................................................ 19 
7.1.4. 
Repeat Imaging: ................................................................................ 19 
7.2. 
Observations and Measurements ...................................................... 19 
7.3. 
Protocol for Image Collection .......................................................... 21 
7.4. 
Good Clinical Practice and Monitoring ............................................ 21 
7.5. 
Informed Consent and Subject Information ..................................... 22 
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7.6. 
Documentation .................................................................................. 22 
7.7. 
Adverse Events (AE) ........................................................................ 22 
7.7.1. 
Adverse Event Monitoring ............................................................... 23 
7.7.2. 
Adverse Event Definitions ................................................................ 23 
7.7.3. 
Adverse Event Documentation ......................................................... 24 
7.7.4. 
Reporting of Serious Adverse Events ............................................... 25 
8. 
STATISTICAL ANALYSIS ............................................................ 25 
8.1. 
General Statistical Considerations .................................................... 25 
8.1.1. 
Populations for Analysis ................................................................... 25 
8.2. 
Analyses ............................................................................................ 26 
8.2.1. 
Efficacy Analyses ............................................................................. 26 
8.2.2. 
Safety Analyses ................................................................................ 26 
9. 
USE OF DATA AND PUBLICATION ........................................... 26 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................. 27 
10.1. 
Institutional Review Board (IRB) ..................................................... 27 
10.2. 
Informed Consent ............................................................................. 27 
10.3. 
Protocol Adherence .......................................................................... 27 
10.4. 
Documents Necessary for Initiation of the Trial .............................. 27 
10.5. 
Study Drug Control........................................................................... 28 
10.6. 
Data Collection ................................................................................. 28 
10.7. 
Adverse Events ................................................................................. 28 
10.8. 
Records Retention ............................................................................. 29 
11. 
APPENDICES .................................................................................. 30 
11.1. 
References ......................................................................................... 30 
11.2. 
Trial Flow Chart ............................................................................... 31 
11.3. 
Guidelines for diagnostic classification ............................................ 32 
 
 
 
05Sep2014 Amendment 1 
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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AD 
 
Alzheimer’s disease 
Adverse Event 
(AE) 
Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. 
Audit 
A systematic and independent examination of the trial-related activities 
and documents to determine whether the evaluated trial-related activities 
were conducted, and the data were recorded, analyzed, and accurately 
reported according to the protocol, applicable standard operating 
procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s). 
Case Report Form 
(CRF) and 
electronic Case 
Report Form 
(eCRF) 
A printed or electronic form for recording study participants’ data during 
a clinical study, as required by the protocol. 
CNS 
Central Nervous System 
CRO 
Contract Research Organization: A person or organization (commercial, 
academic, or other) contracted by the sponsor to perform one or more of 
the sponsor’s trial-related duties and functions.  
CT 
ECG 
Computed Tomography 
Electrocardiogram 
Efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
FDA 
US Food and Drug Administration  
FDG 
18F - Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
05Sep2014 Amendment 1 
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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 
Millicurie 
MHD 
Maximum Human Dose 
MMSE 
Mini Mental State Examination 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No Observable Adverse Effect Level 
OSU TBI-ID 
Ohio State University Traumatic Brain Injury Identification Method 
(OSU TBI-ID) 
PET 
Positron Emission Tomography 
RBT 
Repetitive Brain Trauma 
SUVR 
Standard Uptake Value Ratio 
TBI 
Traumatic Brain Injury 
Traumatic Brain Injury 
 
 
 
 
 
 
 
 
 
 
 
 
05Sep2014 Amendment 1 
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1. 
INTRODUCTION  
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 
Paired Helical Fragment-Tau isolated brains of AD patients yielded a Kd value of 0.7 nM. 
AV-1451 was assessed in competitive binding assays against a panel of 72 of the most 
common central nervous system (CNS) targets and no clinically relevant inhibition was 
seen.   AV-1451 was positive in the in vitro hERG assay, albeit at a concentration more 
than 40-fold the maximum theoretical AV-1451 plasma concentration. Additionally, in 
vivo cardiovascular safety pharmacology assessments in dogs showed no evidence of QT 
prolongation at doses up to 50x the intended maximum human dose (MHD).  
Nonetheless, until sufficient human cardiovascular safety data are available, initial 
clinical studies will exclude subjects with a history of risk factors for Torsades de Pointes 
and subjects taking drugs known to prolong the QT interval. 
In vivo safety pharmacology studies were also conducted in rats to determine potential 
effects on the CNS and respiratory systems. In these studies no clinically relevant effects 
were reported at doses exceeding 100x the intended MHD. Additionally, non-radioactive 
AV-1451 has been tested in single and repeat dose toxicology studies in rat and dog 
species.  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. 
05Sep2014 Amendment 1 
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18F-AV-1451 may be useful as a marker of tau pathology in patients with AD and other 
neurodegenerative disorders (Figures 1 and 2).  Several preliminary studies using 18F-
AV-1451 have been completed (e.g., Chien et al., 2013).  
 The present study is designed to expand the database of 18F-AV-1451 safety and tau 
binding as measured by PET imaging, and to provide standardized conditions for tau use, 
data collection, and analysis to facilitate companion studies including, but not limited to, 
longitudinal studies of aging, depression, and traumatic brain injury. 
 
 
Figure 1: 
control subject (MMSE = 29) 
 
Figure 2: 
AD subject (MMSE = 18) 
2. 
TRIAL OBJECTIVES 
The primary objectives of this study are: 
• Provide standardized conditions for 18F-AV-1451 use, data collection and 
analysis to facilitate evaluation of subject’s tau burden.  
• To expand the 18F-AV-1451 safety database. 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER 
PARTICIPANTS 
 
 
 
05Sep2014 Amendment 1 
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The trial is sponsored by: 
Avid Radiopharmaceuticals 
3711 Market Street, 7th Floor 
Philadelphia, PA 19104 
Phone: +1 215-298-0700 
 
The medical contact is: 
 
Approximately 10 centers in the United States and Canada will participate. 
4. 
TEST DRUG AND CONTROL AGENTS  
4.1. 
Descriptive Name:  18F AV-1451  
 7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole  
 
MW = 262.27 amu 
4.2. 
Radioactive Labeling 
      The compound is labeled with [18F] fluorine that decays by positron (β+) emission and 
has a half-life of 109.77 min.  The principal photons useful for diagnostic imaging are the 
511 keV gamma photons, resulting from the interaction of the emitted positron with an 
electron. 
4.3. 
Decay Characteristics 
 
The time course of radioactive decay for Fluorine [18F] is shown below 
 
05Sep2014 Amendment 1 
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Min. 
Fraction 
Remaining 
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
 
       
Physical decay chart for Fluorine [18F].  Half-life = 109.77 min. 
4.4. 
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. 
05Sep2014 Amendment 1 
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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. 
5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Design and Plan of Trial 
Protocol 18F-AV-1451-A14 is designed to expand the database of 18F-AV-1451 safety 
and tau binding as measured by PET imaging, and to provide standardized conditions for 
18F-AV-1451 use, data collection and analysis to facilitate companion studies looking at 
tauopathies. Approximately 250 subjects will be studied under this protocol.   
Screening assessments may take place over several days and will include the collection of 
demographic information, a medical assessment for eligibility, ECG, a brief cognitive 
interview, including an MMSE, and a brain injury questionnaire.   
Subjects who qualify for the study will come to the imaging center at a later date and will 
have catheter(s) placed for i.v. administration of 18F-AV-1451. Vital signs will be taken 
in a supine position immediately prior to administration of 18F-AV-1451 (within 30 
minutes prior to injection) and at the completion of imaging prior to discharge. Subjects 
will receive a single i.v. bolus of 18F-AV-1451, a 20 minute dynamic scan will be 
obtained starting approximately 80 minutes post injection. With sponsor approval sites 
may elect an alternative imaging protocol with additional time points. All datasets will be 
submitted to the sponsor for analysis.  
Adverse events will be continuously monitored during the imaging session.  Subjects 
who experience any adverse event will not be discharged until the event has resolved or 
stabilized.  
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days after imaging day, but not before 48 hours post-injection, to 
confirm subject well-being and to collect information about any new adverse events.  If 
both of these days are not business days, the follow-up phone call can occur the following 
business day.  
Longitudinal imaging studies may be conducted under protocol 18F-AV-1451-A14, with 
prior sponsor approval.  In these studies subjects may have up to two imaging sessions 
within a 12 month time-frame. If the second scan is obtained more than 3 months after 
the previous scan then the MMSE should be repeated and updates to the OSU-TBI, 
medical history, and concomitant medications will be collected. Procedures for each 
imaging day will be identical to those described above.  Adverse events will not be 
collected during the time between the first follow-up phone call and the second imaging 
session, but will be added to the medical history if clinically relevant. 
5.1.1. 
Dosage and Administration 
 
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All subjects will receive a single IV bolus administration of up to a target dose of 370 
MBq (10 mCi) of 18F-AV-1451 Injection. Where necessary to minimize trial-wise 
radiation exposure or to comply with local regulations, lower dose may be planned with 
sponsor approval. 
5.1.2. 
Rationale for Dosages  
18F-AV-1451 will be administered IV up to a radioactive target dose of 370 MBq with a 
maximum human mass dose (MHD) limited to 20 µg of compound by weight.  This dose 
is 150 fold lower than the NOAEL observed in the rat single dose toxicity study and is 50 
fold lower than the NOAEL observed in the rat and dog repeat dose toxicity studies. 
Human dosimetry has been obtained in nine subjects. The results estimated an Effective 
Dose of 8.92 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable to 
the effective dose of approved 18F-labeled compounds such as FDG and florbetapir F 18 
injection. 
The proposed dose has been shown to be well tolerated and to have acceptable image 
quality in preliminary human studies.  
5.2. 
Selection of Subjects 
Subjects should meet inclusion and exclusion criteria for the companion protocol, and 
in addition: 
 
5.2.1. 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible to enroll in this study:  
1. Male or female subjects at least 18 years of age; 
2. Subjects who sign an IRB approved informed consent prior to any study 
procedures.  Where subjects are deemed incapable of informed consent, a legally 
authorized representative may provide consent, with the subject’s documented 
assent;  
3. Subjects who have historical volumetric brain MRI images obtained as part of the 
site’s companion protocol available for submission to Avid; and 
4. Subjects who in the opinion of the investigator can tolerate the PET scan 
procedures. 
5.2.2. 
Exclusion Criteria 
Subjects will be excluded from enrollment if they: 
1. Have clinically significant cardiac, hepatic, renal, pulmonary, metabolic, or 
endocrine disturbances as indicated by history, which in the opinion of the 
investigator might pose a potential safety risk to the subject;  
2. Have either:  1) Screening ECG with QTc > 450 msec if male or QTc > 470 msec if 
female; or 2) A history of additional risk factors for Torsades de Pointes (TdP) 
(e.g.,  hypokalemia, family history of Long QT syndrome) or are taking drugs that 
05Sep2014 Amendment 1 
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are known to cause QT-prolongation (a list of prohibited and discouraged 
medications is provided by the Sponsor);  Patients with a prolonged QTc interval 
in the setting of intraventricular conduction block (examples RBBB or LBBB), 
may be enrolled with sponsor approval; 
3. Have a history of drug or alcohol dependence within the last year, or prior 
prolonged history of dependence unless approved by the sponsor;  
4. Are females of childbearing potential who are not surgically sterile, not refraining 
from sexual activity or not using reliable methods of contraception. Females of 
childbearing potential must not be pregnant (negative serum or urine β-HCG at 
the time of screening and negative serum or urine β-HCG on imaging day) or 
breastfeeding at screening. Females must agree to avoid becoming pregnant, and 
both females and males must agree to refrain from sexual activity or to use 
reliable contraceptive methods for 90 days following administration of 18F-AV-
1451 Injection; 
5. Have a history of relevant severe drug allergy or hypersensitivity (Relevant severe 
drug allergies should be determined by the PI, and any questions about a subject’s 
eligibility can be directed to Avid. If a subject has a history of severe drug 
allergies, it may be dangerous for them to participate in a study); 
6. Are patients who have received an investigational medication under an FDA IND 
protocol within 30 days prior to the planned imaging session for this study, with 
the exception of medications allowed in the companion study and approval from 
sponsor. Additionally, the time between the last dose of the previous experimental 
medication and imaging must be at least equal to 5 times the terminal half-life of 
the previous experimental medication.  
7. Are patients with current clinically significant unstable medical comorbidities, as 
indicated by history or physical exam that pose a potential safety risk to the 
subject. 
8. Are patients who have received a radiopharmaceutical for imaging or therapy 
within the past 24 hours prior to the imaging session for this study.  If another 
radiotracer is required in the companion protocol, patients may be able to receive 
a radiopharmaceutical for imaging or therapy within the 24 hours prior to the 
imaging session with prior sponsor approval;  
9. Are patients who, in the opinion of the investigator, are otherwise unsuitable for a 
study of this type. 
5.3. 
Prior and Concomitant Therapy 
Except as noted below, all medications (prescription or OTC) that have been started prior 
to screening may be continued during the course of the trial.  Attempts should be made to 
keep the dosage and administration stable throughout the trial (from screening through 
the end of the imaging session).  Stable is generally defined as 2 weeks on therapy.  All 
medications that are continued from the start of the trial, or that are started during the trial 
05Sep2014 Amendment 1 
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(other than the study medication), must be documented on the Concomitant Medication 
Page of the Electronic Case Report Form (eCRF).  
• Patients with AD may be on a stable dose of an anticholinesterase and/or 
Namenda, and may be taking vitamin E at the time of imaging.  
• Investigators should carefully consider whether subjects requiring 
psychotropic medications for behavioral control will be able to complete the 
imaging session and necessary procedures such as cognitive testing. 
• 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). 
5.4. 
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. 
3. Subjects who are being considered for a follow up AV-1451 scan within this 
protocol must meet all inclusion/exclusion criteria at the time of the second 
imaging session.   
Subjects may be withdrawn from the trial if a SAE occurs. The date and reason for 
discontinuation should be noted on the eCRF. Subjects who discontinue prematurely 
should be seen for a final evaluation.  
5.5. 
 Premature Termination of Trial/Closure of Center 
The sponsor may discontinue the trial at any time.  Reasons for discontinuation of the 
trial may include, but are not limited to, new information on safety or efficacy, requests 
from regulatory authorities, or changes in business priorities.  Additional reasons for 
center closure may include, but are not limited to, excessive protocol violations, 
inadequate regard for subject safety, failure to follow recommended procedures (e.g., 
documentation), failure or inability to accommodate Avid/Contract Research 
Organization (CRO) monitors or to provide required access to data and source 
documents, staff turnover or inadequate staffing, and inadequate enrollment.  Except in 
cases affecting subject safety, the investigator may complete final study evaluations for 
ongoing subjects. In all cases of center or study termination, appropriate steps will be 
taken to ensure the safety of study subjects. 
6. 
WARNINGS/PRECAUTIONS 
The most up-to-date and complete information regarding the use of 18F-AV-1451 
Injection can be found in the investigator's brochure.  
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In brief, 18F-AV-1451 Injection is an experimental imaging agent that will be used at 
relatively low (tracer) doses.  However, because 18F-AV-1451 Injection is in the early 
stages of clinical investigation, it is recommended that subjects receiving 18F-AV-1451 
Injection be followed closely by means of adverse event reporting and vital signs. 
There are no data on the effects of 18F-AV-1451 Injection in human perinatal 
development.  For this reason, females must avoid becoming pregnant.  Both females and 
males must use adequate contraceptive methods for 90 days after administration of 18F-
AV-1451 Injection.  18F-AV-1451 Injection must not be administered to females who are 
pregnant, or lactating. 
7. 
PROCEDURES AND METHODS 
7.1. 
 Assessment Periods (See Section 11.2, Trial Flow Chart) 
       
The study will consist of the following sequence of activities:  
7.1.1. 
Screening: 
Screening may take place over several days. All screening assessments will preferably be 
performed within 30 days prior to the PET imaging session. Some screening assessments 
may be performed on the imaging day prior to injection with sponsor approval.  
Screening assessments will include: 
• Informed consent; 
• Demographics (age, gender, education, race, ethnicity); 
• Medical history, concomitant medications; 
• Disease history (date/months since symptom onset, date/months since 
diagnosis, family history of relevant neurologic disease); 
• An ECG will be performed to assess the subject’s cardiac status. If an ECG 
was performed within the last 6 months and is available for review, the ECG 
does not need to be repeated;  
• Cognitive status interview, including MMSE and OSU TBI-ID; 
• Where appropriate, informant interview with family member or close friend 
who is familiar with subject’s everyday functioning abilities; 
• Urine or serum pregnancy test (women of childbearing potential);  
• A physician will see the patient during the screening visit. 
Demographic information, cognitive status assessment, MMSE, and OSU TBI-ID 
collected within the last 60 days as part of a companion protocol or clinic visit need 
not be repeated. 
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7.1.2. 
Imaging Visit  
18F-AV-1451 PET Imaging Visit 
The following assessments will be performed for all subjects: 
• Females of childbearing potential will have a urine or serum pregnancy test 
prior to injection (the result must be negative for the subject to be 
administered 18F-AV-1451);  
• Vital signs will be taken in a supine position immediately prior to 
administration of 18F-AV-1451 (within 30 minutes prior to injection) and at 
the completion of imaging at discharge.  
• Body weight and height will be measured prior to injection. 
• 
18F-AV-1451 will be administered, a 20 minute dynamic image will begin 
approximately 80 minutes post-injection. The images will be reconstructed 
immediately after the scan. With sponsor approval, sites may elect an 
alternative imaging protocol with additional time points.  All datasets will be 
submitted to the sponsor for analysis.  
• Subjects will be observed continuously for signs of adverse events, or serious 
adverse events;  
• A physician will see the patient prior to dosing and prior to discharge. 
7.1.3. 
Follow-Up: 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days after imaging day, but not before 48 hours post-injection, to 
confirm subject well-being and to collect information about any new adverse events.  If 
both of these days are not business days, the follow-up phone call can occur the following 
business day. 
7.1.4. 
Repeat Imaging: 
Longitudinal imaging studies may be conducted under protocol 18F-AV-1451-A14, with 
prior sponsor approval.  In these studies subjects may have up to two imaging sessions 
within a 12 month timeframe. If the second scan is obtained more than 3 months after the 
previous scan then the MMSE should be repeated and updates to the medical history, 
OSU-TBI and concomitant medications will be collected. Procedures for each imaging 
day will be identical to those described above. 
7.2. 
 Observations and Measurements 
Informed Consent 
 
Potential subjects will be allowed to read a written informed consent form.  The principal 
investigator, or designee, will explain all study procedures, risks, and alternative 
therapies to 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 
05Sep2014 Amendment 1 
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their willingness to participate in the study (see Section 7.5). A copy of the signed 
informed consent will be given to the subject.  
All informed consent forms must be approved by Avid, or designee, and by the 
appropriate Institutional Review Board (IRB) prior to use. 
Medical History  
The investigator, or designee, will obtain an updated history at the screening visit. 
• Relevant demographic information  
• Review of body systems 
• Social history 
• Medical and surgical history, including medical care for head trauma 
• Concurrent medications 
Whenever possible, the medical history will be confirmed by medical records. 
 
Electrocardiogram 
A resting ECG will be recorded at screening if a previous ECG performed within the last 
6 months is not available for review.  
 
MRI 
Electronic copies of historical volumetric brain MRI scans obtained as part of the site’s 
companion protocol will be submitted to Avid, or designated imaging core lab. 
 
Vital Signs  
Vital signs (pulse rate, respiratory rate, blood pressure) will be taken as part of the 
imaging day procedures in the supine position prior to injection and at the completion of 
imaging at discharge. 
 
Height and Weight 
At the imaging visit (prior to 18F-AV-1451 dose administration) body weight and height 
will be measured, lightly clothed.   
 
Mini-Mental State Examination (MMSE)  
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive function 
in elderly patients.  The instrument is divided into 2 sections.  The first section measures 
orientation, memory, and attention.  The maximum score for the first section is 21.  The 
second section tests the ability of the patient to name objects, follow verbal and written 
05Sep2014 Amendment 1 
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commands, write a sentence, and copy figures.  The maximum score for the second 
section is 9.  The range for the total MMSE score is 0 to 30. 
 
Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-ID) 
The OSU TBI-ID (Corrigan and Bogner, 2007) short version will be used to screen for a 
history of traumatic brain injury. It is the briefest version that still provides several 
summary indices on which the original version was validated. To shorten the instrument, 
TBIs resulting in loss of consciousness are emphasized over less severe injuries. 
 
Physician Visit 
A physician must see the subject at screening, prior to drug administration and at study 
end, prior to discharge from the 18F-AV-1451 imaging session.  At discharge, the 
physician should review all safety data and briefly examine/query the subject regarding 
potential adverse events, or other treatment issues.   
 
Pregnancy Testing  
Serum beta hCG or Urine beta hCG: performed at screening and imaging day prior to 
injection for females of childbearing potential (defined as pre-menopausal or less than 2 
years post-menopausal or not surgically sterile).  
7.3. 
 Protocol for Image Collection 
The sponsor will prepare and distribute imaging manuals for 18F-AV-1451 image 
acquisition parameters and transmission procedures prior to site initiation.   
7.4. 
 Good Clinical Practice and Monitoring 
All clinical studies performed under the direction of Avid/CRO will be conducted in 
accordance with applicable regulatory requirements and International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) and Avid/CRO Standard Operating 
Procedures (SOP).  
This includes: 
1. IRB approval:  An investigation will be initiated at a study site only after the IRB 
for that study site has given their written approval of the protocol and informed 
consent;    
2. Informed Consent:  Study procedures will not be initiated until the subject signs 
the informed consent form;   
3. Recording and monitoring of adverse events as outlined in Section 7.7.3 including 
the notification of study site clinical investigators, local IRBs and the FDA 
regarding serious adverse event; 
4. Avid RP’s obligation to monitor the participating center on a regular basis; and 
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5. The termination of a center, or the trial, if conditions apply, as outlined in Section 
5.6. 
7.5. 
 Informed Consent and Subject Information 
Potential subjects, or their legally authorized representative (as appropriate), will be 
allowed to read a written informed consent form.  The principal investigator, or designee, 
will explain all study procedures, risks, and alternative therapies.  The subject, and 
legally authorized representative, will have an opportunity to have all questions answered 
by a physician.  The subject will then sign and date the informed consent form, indicating 
willingness to participate in the study. 
 All informed consent forms must be approved by Avid, or designee, and by the 
appropriate Institutional Review Board (IRB).  No study related procedures shall be 
performed prior to completion of the informed consent process, and signing of the 
consent form.  A copy of the signed informed consent should be given to the patient for 
their records. 
7.6. 
 Documentation 
18F-AV-1451 scans will be saved in an appropriate electronic format as specified in the 
imaging manuals.  All other data required by the protocol will be recorded in the eCRFs.  
All data in the eCRFs will be substantiated by “source documents,” which consist of the 
subject’s medical files, laboratory result sheets, ECG tracings, etc.  All source 
documentation must be available to Avid, and designees.  Completed source documents 
and eCRFs may need to be made available and complete for an audit by the FDA, other 
international regulatory authorities, or Avid at any time.  eCRFs and all other records 
must be filed in accordance with applicable laws and regulations (see Section 10.6) 
7.7. 
 Adverse Events (AE) 
Avid’s standards for recording and reporting adverse events (AEs) are to be followed 
regardless of applicable regulatory requirements that may be less stringent.  All AEs must 
be fully recorded on the adverse event eCRFs. Investigators will be instructed to report to 
Avid or its designee their assessment of the potential relatedness of each AE to study 
drug or protocol procedure via electronic data entry.  If a patient’s treatment is 
discontinued as a result of an AE, study site personnel must clearly report to Avid or its 
designee via electronic data entry the circumstances and data leading to any such 
discontinuation of treatment. In cases where the investigator notices an unanticipated 
benefit to the patient, study site personnel should report “unexpected benefit” with the 
actual event term to Avid or its designee (for example, the complete actual term would be 
“unexpected benefit- sleeping longer”). 
Laboratory test abnormalities considered by the Investigator to be clinically relevant 
should be reported on the adverse event eCRFs.  Signs and symptoms of each AE should 
be described in detail (e.g., start and stop dates/time, severity/intensity, relationship to 
study drug, action taken, and 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.  
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7.7.1. 
 Adverse Event Monitoring 
Each patient must be carefully monitored for adverse events.  This includes clinical 
laboratory test variables.  An assessment must be made of the severity/intensity and 
relationship to the administration of the study drug. 
7.7.2. 
 Adverse Event Definitions 
 
Adverse Events 
An adverse event is any undesirable experience occurring to a subject during a clinical 
trial, whether or not considered related to the study drug. 
For reporting purposes, Avid will distinguish among pre-existing conditions, trial-
emergent adverse events and treatment-emergent adverse events.   
Pre-existing conditions (i.e., undesirable experiences, signs or symptoms that begin prior 
to the Screening Visit) will be recorded on the medical history eCRF pages. During the 
study, site personnel will record any change in the condition(s) and occurrence and nature 
of any AEs.  Signs and symptoms that are believed to be due to the pre-existing condition 
under study (started prior to dose of study medication) do not have to be recorded in the 
AEs section of the eCRF, unless there is an increasing in frequency and severity. 
Trial-emergent adverse events are undesirable experiences, signs or symptoms that begin, 
or worsen in intensity or frequency, after the informed consent, and prior to 
administration of study drug (18F-AV-1451) at the imaging visit.  These will be recorded 
on the adverse event eCRFs.  
Treatment-emergent adverse events are undesirable experiences, signs, or symptoms 
associated with the use of a study drugs.  For the purposes of this study an adverse event 
will be considered associated with the use of 18F-AV-1451 if it begins or worsens in 
intensity or frequency within 48 hours after the administration of 18F-AV-1451. Adverse 
experiences that occur after administration of study drug but outside the 48 hour 
reporting window will not be reported unless the investigator believes they are 
attributable to the drug. 
The end of study for the purpose of adverse event reporting is defined as 48 hours after 
the administration of 18F-AV-1451 Injection.  
Serious Adverse Event (SAE) 
A SAE is an AE that results in one of the following outcomes or constitutes one of the 
following events: 
• Death; 
• Initial or prolonged inpatient hospitalization (other than that required by 
protocol; “social hospitalization” or any hospitalization for non-medical 
reasons does not constitute a SAE); 
• A life-threatening experience (that is, immediate risk of dying); 
• Persistent or significant disability/incapacity; 
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• Congenital anomaly/birth defect; 
• Considered significant by the investigator for any other reason. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical, 
or surgical, intervention to prevent one of the outcomes listed in this definition. 
Unexpected Adverse Event 
An unexpected adverse event is an adverse event not previously reported or an adverse 
event that occurs with specificity, severity, or frequency that is not consistent with the 
current investigator’s brochure. 
Relationship to Study Drug 
Investigators will be instructed to report their assessment of the potential relatedness of 
each adverse event to protocol procedure or study drug.  The assessment of the 
relationship of an adverse event to the administration of the study drug is a clinical 
decision based on all available information at the time of the completion of the eCRF. 
Intensity/Severity of an Adverse Event 
In addition to assessing the relationship of the administration of the study drug to adverse 
events, an assessment is required of the intensity (severity) of the event.  
The following classifications should be used: 
 
Mild:   
A mild adverse event is an adverse event, usually transient in nature and generally not 
interfering with normal activities. 
 
Moderate:   
A moderate adverse event is an adverse event that is sufficiently discomforting to 
interfere with normal activities. 
 
Severe:   
A severe adverse event is an adverse event that incapacitates the subject and prevents 
normal activities.   Note that a severe event is not necessarily a serious event.  Nor must a 
serious event necessarily be severe. 
7.7.3. 
 Adverse Event Documentation 
All adverse events must be fully recorded on the adverse event eCRFs.  Documentation 
must be supported by an entry in the subject file.  Laboratory tests, vital signs and ECG 
abnormalities considered by the Investigator to be clinically relevant should be reported 
on the adverse event eCRFs.  Signs and symptoms of each AE should be described in 
detail (e.g., start and stop dates, severity/intensity, relationship to study drug, action 
taken, and outcome). 
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Adverse events and laboratory test abnormalities fulfilling the definition of a serious 
adverse event should, in addition, be reported on the Serious Adverse Event Reporting 
Form. 
7.7.4. 
 Reporting of Serious Adverse Events  
Study site personnel must alert Eli Lilly or its designee of any SAE within 24 hours of 
their awareness of the event via a sponsor-approved method.  Alerts issued via telephone 
are to be immediately followed with official notification on study-specific SAE forms.  
Serious adverse events occurring after a subject receive a dose of study drug will be 
collected until 48 hours after the  dosing of the study drug, regardless of the investigator’s 
opinion of causation.  Therefore, SAEs that occur later than 48 hours after the dosing of 
the study drug are not required to be reported unless the investigator feels the events were 
related to either study drug or a protocol procedure. 
If a patient experiences a SAE after signing informed consent, but prior to receiving 
study drug, the event will NOT be reported unless the investigator feels the event may 
have been caused by a protocol procedure.  Previously planned (prior to signing the ICF) 
surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study. 
8. 
STATISTICAL ANALYSIS 
8.1. 
General Statistical Considerations 
All statistical analyses will be performed using SAS® version 8.2 or higher. 
All values will be summarized by diagnostic group:  cognitively normal volunteers, 
patients with AD, patients with MCI and where relevant, other disorders as determined 
by the companion protocol.  Guidelines for diagnostic classification of cognitively 
normal volunteers, subjects with MCI and subjects with AD can be found in Appendix 
11.3.  
Frequency distributions including counts and percentages will be included for all 
categorical outcome variables.  All continuous outcome variables will be summarized 
with statistics including mean, standard deviation, median, minimum and maximum 
values.  
All data from the electronic case report forms (eCRFs) as well as any derived variables 
will be presented by listings.  
Additional details concerning statistical analyses will be included in the Statistical 
Analysis Plan (SAP) to be completed prior to the end of enrollment into the study. 
8.1.1. 
Populations for Analysis 
The efficacy population will include all patients for whom image data are available.   All 
analyses involving tau imaging outcomes will be based on the efficacy population. Safety 
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population will include all patients that received at least one dose of 18F-AV-1451 
compound. Safety evaluation will be based on safety population.  
8.2. 
Analyses 
8.2.1. 
Efficacy Analyses 
18F-AV-1451 images will be evaluated to determine if the tracer shows favorable 
characteristics for further development as a tau protein imaging agent. Descriptive 
statistics will be applied to describe the distribution of tau deposition as measured by 18F-
AV-1451 across clinical diagnosis groups. Mean, standard deviation, median, minimum, 
and maximum values will be provided for continuous variables and counts and 
percentages will be provided for categorical variables  
8.2.2. 
Safety Analyses 
Adverse events including injection site reactions will be summarized in terms of number 
and percentage of patients experiencing an AE. The AEs will be summarized 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 patients who experience SAEs, or who discontinue due to 
AEs, will be summarized.  
9. 
USE OF DATA AND PUBLICATION 
Avid adheres to the Pharmaceutical Research and Manufacturers of America (PhRMA)     
Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results.  A      
complete copy of these principles is available from Avid and can also be found at the 
PhRMA website (http://www.phrma.org).  Our policy is briefly summarized below: 
 
• We commit to timely communication of meaningful results of controlled 
clinical trials, regardless of outcome.  
• As a sponsor, we may recommend that the Investigator(s) delay or decline 
publication in cases where the study design, conduct, or data are insufficient 
to allow meaningful interpretation.  Avid and the Investigator(s) will discuss 
the study design and data in advance of the study, and again after completion, 
and will strive, through appropriate scientific debate, to reach a consensus 
regarding the potential merits of publication. 
• Avid retains the right to review any manuscripts, presentations, or abstracts 
before they are submitted for publication. Where differences of opinion or 
interpretation exist regarding data planned for publication, the parties (Avid 
and the Investigator) should try to resolve them through appropriate scientific 
debate.  Avid retains the right to delay publication for up to 60 days to protect 
intellectual property.  
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• Anyone who provides substantial contributions should receive appropriate 
recognition as an author or contributor when the manuscript is published.  
This is a multi-center study. A multi-center publication, reporting the primary analysis 
data set, should precede any other publications. 
10. 
  INVESTIGATOR’S REGULATORY OBLIGATIONS 
All clinical work conducted under this protocol is subject to Good Clinical Practice 
regulations; this may include an inspection by Avid and/or Health Authority 
representatives (FDA or international regulatory authorities) at any time. 
10.1. 
 Institutional Review Board (IRB) 
 
The intent of the research program, the trial protocol, the patient information/informed 
consent form and any advertising material used to recruit subjects must be submitted to 
the clinical investigator’s local IRB and its approval must be obtained prior to its use.  A 
copy of the approval must be forwarded to Avid.  When necessary, an extension or 
renewal of IRB approval must be obtained and also forwarded to Avid. 
10.2. 
 Informed Consent 
A signed, written informed consent must be obtained from each patient.  A copy of the 
signed informed consent should be given to the patient for their records.  A copy of the 
local IRB’s approved version of the informed consent form must be forwarded to Avid, 
or 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 and radiation safety committee approval (if applicable); 
• Copy of the IRB stamped approved consent form; 
• Name and location of the laboratory utilized for laboratory assays, and other 
facilities conducting tests, including laboratory certification number and date 
of certification if available.  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 
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• Any additional licenses required in order to order to use 18F-AV-1451. 
10.5. 
Study Drug 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.  All drug supplies must be accounted for.  After completion of the trial, all 
remaining clinical supplies must be returned to the sponsor or their representative.   
10.6. 
Data Collection 
Electronic case report forms (eCRFs) will be used for this trial.  Individual patient files 
should include appropriate source documents, including but not limited to patient’s 
medical records and laboratory test results.  The files should include information such as 
visit dates, records of medical history, examinations administered, laboratory, 
concomitant treatment, any adverse event encountered and other notes as appropriate.  
These constitute “source data”.  All entries on the eCRFs must be backed up by source 
data.  Original electronic versions of imaging studies are also considered source data and 
should be kept on file by the site/imaging center, and appropriate copies should be 
forwarded to Avid, or a designated Imaging Core Lab, as specified in the Imaging 
Manual.   
Each patient’s source file should include an original signed informed consent form.  
When the trial is completed, the informed consent form should be kept on file with other 
trial related records. 
All original laboratory reports must be available for review in each patient’s file.  It is 
important that the original reports be available for review because of the possibility of 
inaccuracies or errors in transcribing data from original records to the eCRF. 
The eCRFs must be kept in order and up-to-date so that they always reflect the latest 
observations on the subjects that are enrolled in the trial.  The eCRFs must be completed 
for each patient enrolled in the trial and signed by the investigator.  This should be done 
as soon as possible after completion of the patient’s participation in the trial.  A monitor 
will verify the source data for all information on the eCRF. 
10.7. 
Adverse Events 
All adverse events encountered during the clinical trial must be documented on the eCRF, 
whether or not considered drug-related. 
Eli Lilly must be notified immediately (as soon as possible, and in all cases within 24 
hours) of a drug experience, condition, development, or event, which is considered 
serious. Eli Lilly must be notified immediately of any findings with the use of the drug 
that may suggest significant hazards, contraindications, adverse drug reactions (ADRs) 
and precautions pertinent to the safety of the drug.  The investigator will be requested to 
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complete a separate report form in addition to the information on the eCRF.  See section 
7.7.4 for reporting serious adverse events. 
If a SAE is determined to be unexpected (not previously reported or described by Avid), 
and study drug-related, Eli Lilly will notify the investigator in writing.  The investigator 
should forward this notification to the IRB within 24 hours of receipt. 
10.8. 
Records Retention 
All correspondence (e.g., with Avid, IRB, etc.) relating to this clinical trial should be kept 
in appropriate file folders.  Records of subjects, source documents, and drug inventory 
sheets pertaining to the trial must be kept on file.  Records must be retained until the date 
a marketing application (NDA) is approved for the drug for the indication for which it is 
being investigated, or until 2 years following the date of clinical trial termination or 
completion, whichever is later.   If no application is to be filed or if the application is not 
approved for such indication, records should be kept until 2 years following the date of 
clinical trial termination, or completion. 
If an investigator moves, withdraws from an investigation, or retires, the responsibility 
for maintaining the records may be transferred to another person who will accept the 
responsibility.  Notice of transfer must be made to and agreed upon by Avid. 
 
 
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11. 
APPENDICES 
 
11.1. 
References 
 
 
Albert, M. S., DeKosky, S. T., Dickson, D., et al. “The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging and Alzheimer’s Association workgroup.”  The Alzheimer’s Association. 
Alzheimer’s and Dementia, 1-10, 2011. 
 
Chien, D.T., Bahri, S., Szardenings, A.K., Walsh, J.C., Mu, F., Su, M.Y., Shankle, W.R., 
Elizarov, A., Kolb, H.C., “Early clinical PET imaging results with the novel PHF-tau 
radioligand [18F]-T807.” J Alzheimers Dis, 2013 Jan 1l34(2):467-68.  
 
Corrigan, J.D., & Bogner, J. (2007). Initial reliability and validity of the Ohio State 
University TBI identification method. Journal of Head Trauma Rehabilitation, 22, 318 – 
329. 
 
Folstein, M.R., Folstein, S.E., and McHugh, P.R. “Mini Mental State: A practical method 
for grading the cognitive status of patients for the clinician.”  Journal of Psychiatric 
Research, 12: 189-198, 1975.  
 
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. 
 
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 
 PET Imaging  
End of Imaging 
2 – 3 days post 
injection   
Signed Consent 
X 
 
 
 
 
 
 
Medical / Disease History 
X 
 
 
 
 
Concomitant Meds 
X 
X 
 
 
 
ECG 
X 
 
 
 
 
MMSE 
X 
 
 
 
 
Physician Visit 
X 
X 
 
X 
 
OSU TBI-ID 
X 
 
 
 
 
Vital Signs2 
 
X 
 
X 
 
Pregnancy Test 
X 
X 
 
 
 
18F-AV-1451 
Administration 
 
 
X 
 
 
PET Imaging1 
 
 
 
Continuous 20 
minute scan  
 
 
Follow-up Phone Call 
 
 
 
 
 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
1Sites may elect to perform additional imaging time points with prior sponsor approval. 
2Height and weight will be measured prior to injection on imaging day.
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11.3. 
Guidelines for diagnostic classification 
Subjects meeting the NINCDS-ADRDA criteria (McKhann 2011) should be classified as 
possible or probable AD: 
1. Patients with dementia as evidenced by a MMSE score typically ranging from 10 
to 24, boundaries included, at screening; 
2. Patients whose history of cognitive decline has been gradual in onset and 
progressive over months to years. Evidence should be present indicating sustained 
memory deterioration in an otherwise cognitively normal patient, plus additional 
cognitive deficits in another cognitive function such as: learning, language 
presentation, visuospatial presentation, and executive dysfunction.  
Subjects who meet the following NIA-Alzheimer’s Association working group’s 
diagnostic guidelines for AD: Alzheimer’s Dementia 7:270-9, 2011 (Albert 2011),   
criteria should be classified as mild cognitive impairment: 
1. Have cognitive decline verified by the study physician.  
2.  Evidence of objective impairment in one or more cognitive domains, with 
supporting evidence from objective testing if available.  
3. Preservation of independence in functional abilities. 
4. Not demented.  
5. Patients typically with an MMSE score ≥ 24. 
Subjects who meet the following criteria should be classified as cognitively normal 
volunteers: 
1. Subjects with an MMSE score > 29, and are cognitively normal based on history 
(no evidence of significant recent cognitive decline) and psychometric test battery 
at screening;  
Note:  Subjects with dementia who do not meet criteria for probable AD, as described in 
point number 1, should be classified as ‘other dementing disorders’. 
 
 
05Sep2014 Amendment 1 
Page 32 of 33 
 
 


INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol 18F-AV-1451-A14: “Clinical Evaluation of 18F-AV-1451” 
 
Date and Version: 05Sep2014 Amendment 1 
 
I agree to conduct the study according to this protocol and to comply with its obligations, 
subject to ethical and safety considerations and all applicable regulations (ICH, CFR). 
 
I shall not disclose the confidential information contained in this protocol or any results 
obtained from the study, except for publication in accordance with Section 9 of this 
protocol, without written authorization from Avid. 
 
 
______________________________________              ___________________________ 
Printed Name                                                                    Date 
 
 
______________________________________ 
Signature 
 
05Sep2014 Amendment 1 
Page 33 of 33 
 
 

SAP_001.pdf: 
Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
Protocol No. 18F-AV-1451-A14 
Clinical Evaluation of 18F-AV-1451
Statistical Analysis Plan
Prepared by:
Avid Radiopharmaceuticals, Inc
06 December 2019
This document is the confidential information of Avid Radiopharmaceuticals. It may not 
be disclosed to parties not associated with the clinical investigation or used for any 
purpose without the prior written consent of Avid Radiopharmaceuticals.
Approval Date: 13-Dec-2019 GMT


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
Table of Contents
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.................................................. 4
2
INTRODUCTION........................................................................................................................... 6
3
STUDY OBJECTIVES................................................................................................................... 7
4
STUDY DESIGN............................................................................................................................. 7
4.1
GENERAL DESIGN ...................................................................................................................... 7
4.1.1
Screening Visit................................................................................................................... 7
4.1.2
Flortaucipir PET Imaging Visit.......................................................................................... 7
4.1.3
Follow-Up Phone Call....................................................................................................... 8
4.1.4
Repeat Imaging.................................................................................................................. 8
4.2
METHOD OF ASSIGNMENT OF SUBJECTS TO TREATMENT AND DIAGNOSIS GROUPS ....................... 8
4.3
BLINDING .................................................................................................................................. 8
4.4
DETERMINATION OF SAMPLE SIZE .............................................................................................. 9
5
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES...................... 10
5.1
CHANGES IN THE CONDUCT OF THE STUDY ............................................................................... 10
6
BASELINE, EFFICACY AND SAFETY EVALUATIONS......................................................... 11
6.1
SCHEDULE OF EVALUATIONS.................................................................................................... 11
6.2
TIME POINT ALGORITHMS ........................................................................................................ 12
6.2.5
Windows.......................................................................................................................... 12
6.3
SCREENING AND BASELINE ASSESSMENTS ................................................................................ 12
6.4
EFFICACY VARIABLES.............................................................................................................. 12
6.4.1
Primary Efficacy Variable................................................................................................ 12
6.4.1.1
Flortaucipir Quantitation ............................................................................................................ 12
6.4.2
Additional Variables........................................................................................................ 12
6.4.2.1
Mini-Mental State Examination (MMSE).................................................................................... 12
6.4.2.2
Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-ID)..................... 13
6.5
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETIC PARAMETERS...................... 13
6.5.1
Handling of Pharmacokinetic Parameter Outliers ............................................................ 13
6.6
SAFETY ASSESSMENTS............................................................................................................. 14
6.6.1
Extent of Exposure and Compliance to Study Treatment ................................................... 14
6.6.2
Adverse Events ................................................................................................................ 14
7
STATISTICAL METHODS......................................................................................................... 15
7.1
DEFINITIONS AND CONVENTIONS.............................................................................................. 15
7.1.1
Analysis Programming Platform ...................................................................................... 15
7.1.2
Reporting Conventions..................................................................................................... 15
7.1.3
Type I Error..................................................................................................................... 15
7.1.4
Definition of Baseline ...................................................................................................... 15
7.1.5
Age Calculation............................................................................................................... 15
7.2
HANDLING OF DROPOUTS OR MISSING DATA ............................................................................ 15
7.3
INTERIM ANALYSES AND DATA MONITORING ........................................................................... 16
7.4
MULTI-CENTER STUDIES AND POOLING OF CENTERS ................................................................. 16
7.5
MULTIPLE COMPARISONS/MULTIPLICITY.................................................................................. 16
7.6
EXAMINATION OF SUBGROUPS.................................................................................................. 16
8
STATISTICAL ANALYSIS ......................................................................................................... 17
8.1
ANALYSIS POPULATIONS.......................................................................................................... 17
8.1.1
Enrolled Population......................................................................................................... 17
8.1.2
Safety Population............................................................................................................. 17
8.1.3
Efficacy Population.......................................................................................................... 17


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
8.2
DISPOSITION AND WITHDRAWS ................................................................................................ 17
8.3
BASELINE SUBJECT DATA ........................................................................................................ 18
8.3.1
Demographic and Other Baseline Characteristics............................................................ 18
8.3.2
Medical and Surgical History........................................................................................... 18
8.3.3
Concomitant Therapy....................................................................................................... 18
8.3.4
Neurologic Disease History ............................................................................................. 18
8.3.5
Pregnancy Test................................................................................................................ 18
8.3.6
Family History................................................................................................................. 18
8.3.7
Electrocardiogram........................................................................................................... 18
8.3.8
MMSE & OSU TBI-ID..................................................................................................... 18
8.4
ANALYSIS OF EFFICACY PARAMETERS...................................................................................... 19
8.4.1
Analysis of Primary Efficacy Variable.............................................................................. 19
8.4.1.1
Quantitative Assessment of Images............................................................................................. 19
8.4.1.2
Correlation between MMSE and MUBADA SUVr...................................................................... 20
8.5
ANALYSIS OF SAFETY .............................................................................................................. 20
8.5.1
Exposure ......................................................................................................................... 20
8.5.1.1
Dose Unit Conversion ................................................................................................................ 20
8.5.2
Treatment Emergent Adverse Events ................................................................................ 20
8.5.2.1
Severity ..................................................................................................................................... 20
8.5.2.2
Relationship to Flortaucipir ........................................................................................................ 20
8.5.2.3
Relationship to Study Procedure ................................................................................................. 20
8.5.2.4
Serious Adverse Events.............................................................................................................. 21
8.5.2.5
Adverse Events Leading to Study Discontinuation....................................................................... 21
8.5.2.6
Adverse Events Leading to Death ............................................................................................... 21
8.5.2.7
Missing and Partial AE Onset Dates............................................................................................ 21
8.5.3
Vital Signs ....................................................................................................................... 22
8.5.3.1
Potentially Clinically Significant Vital Sign Changes .................................................................. 22
8.5.4
Follow-up Contact Data .................................................................................................. 22
9
APPENDICES............................................................................................................................... 23
9.1
REFERENCES............................................................................................................................ 23
Table 1: Abbreviations.............................................................................................................................. 4
Table 2: Consolidation of Diagnosis Groups for Presentation of Results .................................................... 8
Table 3: Schedule of Evaluations............................................................................................................ 11
Table 4: Imputation Algorithm for Missing AE Date/Time...................................................................... 21
Table 5: Potentially Clinically Significant Criteria................................................................................... 22


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table 1: Abbreviations
AAL
Automated anatomical labeling
Amyloid beta
Aβ
AD
Alzheimer’s disease
AE
adverse event
ANCOVA
Analysis of covariance
CFB
change from baseline
C.I.
Confidence interval
CI
cognitively impaired
CN
cognitively normal
CRF
Case report form
CSF
cerebrospinal fluid
CSR
clinical study report
DBP
diastolic blood pressure
ECG
electrocardiogram
IV
intravenous
LSM
Least squares mean
Max
maximum
MBq
Megabecquerel
mCi
Millicurie
MedDRA
Medical Dictionary for Regulatory Activities
Min
minimum
MMSE
Mini-Mental State Examination
MUBADA
Multiblock Barycentric Discriminant Analysis
N
Sample size
ODD
Other Dementing Disease
OND
Other Neurological Disorder
OSU-TBI
Ohio State University – Traumatic Brain Injury
PCS
Potential clinically significant
PD
Psychiatric Disorder
PERSI
parametric estimated signal reference intensity
PET
positron emission tomography
PLT
Posterolateral Temporal
PR
Pulse rate
PT
preferred term
RR
Respiratory rate
SAE
Serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis Software
SBP
Systolic blood pressure
SD
Standard deviation


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
SE
Standard error
SOC
system organ class
SUVr
standardized uptake value ratio
TEAE
treatment-emergent adverse event
WHO
World Health Organization


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
2
INTRODUCTION
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, amyloid-beta (Aβ)
positive, or tau and Aβ negative tissue
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, albeit at a concentration more
than 40-fold the maximum theoretical AV-1451 plasma concentration. Additionally, in
vivo cardiovascular safety pharmacology assessments in dogs showed no evidence of QT
prolongation at doses up to 50x the intended maximum human dose (MHD). Nonetheless, 
until sufficient human cardiovascular safety data are available, initial clinical studies will 
exclude subjects with a history of risk factors for Torsades de Pointes and subjects taking 
drugs known to prolong the QT interval.
In vivo safety pharmacology studies were also conducted in rats to determine potential
effects on the CNS and respiratory systems. In these studies no clinically relevant effects
were reported at doses exceeding 100x the intended MHD. Additionally, non-radioactive
AV-1451 has been tested in single and repeat dose toxicology studies in rat and dog
species. 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.


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
The present study is designed to expand the database of 18F-AV-1451 safety and tau
binding as measured by PET imaging, and to provide standardized conditions for tau use,
data collection, and analysis to facilitate companion studies including, but not limited to,
longitudinal studies of aging, depression, and traumatic brain injury.
The purpose of this statistical analysis plan (SAP) is to describe the statistical analyses 
for study 18F-AV-1451-A14. This SAP should be read in conjunction with the A14 
protocol.
3
STUDY OBJECTIVES
The primary objectives of this study are:

to provide standardized conditions for flortaucipir use, data collection, and 
analysis to facilitate evaluation of subjects’ tau burden.

To expand the flortaucipir safety database.
4
STUDY DESIGN
4.1
General Design
This is a phase II, multicenter study that will expand the flortaucipir safety database and
explore tau binding as measured by PET imaging, and will provide standardized 
conditions for the use, data collection and analysis of flortaucipir to facilitate companion 
studies looking at tauopathies.
4.1.1
Screening Visit
Screening assessment may have taken place over several days and included collection of 
demographic information, medical assessment for eligibility, electrocardiogram (ECG), a 
brief cognitive assessment (i.e. Mini-mental State Exam [MMSE]), and a traumatic brain 
injury questionnaire (i.e. Ohio State University Traumatic Brain Injury [OSU-TBI]).
4.1.2
Flortaucipir PET Imaging Visit
For the flortaucipir PET imaging session, an intravenous (IV) catheter was placed for 
administration of flortaucipir injection. Subjects received a single IV bolus injection 
target dose of 240 megabecquerel (MBq) (6.49 millicuries (mCi)) or 370 MBq (10 mCi) 
of flortaucipir injection. Vital signs were taken in a supine position immediately prior to 
(within 30 minutes of) flortaucipir injection and at the completion of imaging prior to 
subject discharge. At approximately 80 minutes post injection, a 20-minute dynamic 
brain scan was obtained. Sites may have elected to use an alternative imaging protocol 
(i.e. different scan duration or scan start time) with additional time points with sponsor 
approval. All datasets were submitted to the sponsor for analysis.
Adverse events (AE) were continuously monitored during the imaging visit (see section 
6.6.2). Any subject who experienced an adverse event was not discharged until the event 
had resolved or stabilized.


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
4.1.3
Follow-Up Phone Call
A follow-up phone call to the subject, or designated decision maker, was conducted 
between 2 and 3 business days after imaging day, but not before 48 hours post-injection, 
to confirm subject well-being and to collect information about any new adverse events. If 
both of these days were not business days, the follow-up phone call occurred the 
following business day.
4.1.4
Repeat Imaging
Longitudinal imaging studies may have been conducted under protocol 18F-AV-1451-A14
with prior sponsor approval. In these studies, subjects may have had up to two imaging 
sessions within a 12-month time-frame. If the second scan was obtained more than 3 
months after the previous scan, then the MMSE was repeated and updated OSU-TBI, 
medical history, and concomitant medications information was collected. Procedures for 
each the repeat imaging were identical to those described above.
4.2
Method of Assignment of Subjects to Treatment and Diagnosis Groups
Subjects who qualified for the study received a single IV bolus injection with a target 
dose of 240 (6.49 mCi) or 370 MBq (10 mCi) of flortaucipir (18F) injection.
Subjects will be classified into diagnosis groups (Alzheimer’s disease AD [AD], mild 
cognitive impairment [MCI], control subject [CN], other dementing disorder [ODD], 
other neurological disorder [OND], psychiatric disorder [PD]) as outlined by pre-
specified criteria (see protocol amendment 1, appendix 11.3 for details), however there 
was no design (adaptive or otherwise) to stratify an equal number of subjects in each 
diagnosis group. Diagnosis groups will be consolidated in the following way in the result 
summaries.
Table 2: Consolidation of Diagnosis Groups for Presentation of Results
Diagnosis Group
Presentation Group
AD
Cognitively Impaired (CI)
MCI
ODD
OND
PD
CN
Cognitively Normal (CN)
4.3
Blinding
This was a phase II open-label study of approximately 179 subjects including healthy 
controls and subjects at risk for tau accumulation as defined by the sites’ companion 
protocols. No blinding to flortaucipir treatment was required since all study participants 
received a single IV bolus injection of ~240 or 370 MBq (6.49 or 10 mCi) of flortaucipir 
(18F).


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
4.4
Determination of Sample Size
No power or sample size calculation was done for this study as there was no hypothesis 
for testing per study objectives. Approximately 179 subjects including healthy controls 
and subjects at risk for tau accumulation as defined by the sites’ companion protocols
were dosed with flortaucipir and underwent a PET scan.


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
5
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
5.1
Changes in the Conduct of the Study
There were no changes in the conduct of the study at the time of preparing this SAP.


Avid Radiopharmaceuticals
Study 18F-AV-1451-A14
                 Statistical Analysis Plan
6
BASELINE, EFFICACY AND SAFETY EVALUATIONS
6.1
Schedule of Evaluations
Table 3: Schedule of Evaluations


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
6.2
Time Point Algorithms
6.2.5
Windows
For all analyses, results will be summarized at the planned study visit they were obtained. 
6.3
Screening and Baseline Assessments
Screening assessments may take place over several days, preferably within 30 days prior to the 
flortaucipir PET scan, and will include collection of demographics, a medical assessment for 
eligibility, ECG, a brief cognitive assessment, and a traumatic brain injury questionnaire.
6.4
Efficacy Variables
6.4.1
Primary Efficacy Variable
6.4.1.1
Flortaucipir Quantitation
Standard uptake value ratios (SUVr) will be calculated to estimate tau load globally and in 
individual regions for the flortaucipir images. A target region derived statistically with a 
Multiblock Barycentric Discriminant Analysis (MUBADA) method will be used for the global 
measurement.
Voxels of interest determined in the automated anatomical labeling (AAL) atlas masked to 
exclude white matter and CSF for amygdala, anterior fusiform, posterior fusiform, anterior 
hippocampus, posterior hippocampus, anterior parahippocampus, posterior parahippocampus, 
caudate, frontal, parietal, precuneus, temporal, occipital, left frontal, right frontal, left occipital, 
right occipital, left parietal, right parietal, left putamen, right putamen, left temporal, right 
temporal will be applied at the individual region level. A selected white matter region derived 
using a parametric estimated signal reference intensity (PERSI) method will be used as reference 
region for all SUVr calculations.
MUBADA SUVr will be the variable used in in the primary efficacy analysis.
6.4.2
Additional Variables
6.4.2.1
Mini-Mental State Examination (MMSE)
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive function in 
elderly patients. The range for the total MMSE score is 0 to 30, the sum of each correct answer, 
with higher scores indicating better cognition. The score on a continuous scale will be used for 
primary objective analysis.


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
6.4.2.2
Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-ID)
The OSU TBI-ID (Corrigan and Bogner, 2007) short version was used to screen for a history of 
traumatic brain injury. It is the briefest version that still provides several
summary indices on which the original version was validated. To shorten the instrument,
TBIs resulting in loss of consciousness are emphasized over less severe injuries.
6.5
Drug Concentration Measurements and Pharmacokinetic Parameters
6.5.1
Handling of Pharmacokinetic Parameter Outliers
No pharmacokinetic parameters or drug concentration measurements will be collected during 
this study.


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
6.6
Safety Assessments
6.6.1
Extent of Exposure and Compliance to Study Treatment
During the flortaucipir imaging sessions, all subjects received a single IV bolus administration 
target dose of 240 (6.49 mCi) or 370 MBq (10 mCi) of flortaucipir injection.
6.6.2
Adverse Events
An AE is any undesirable experience occurring to a subject during a clinical trial, whether
considered related to the study drug or not. AEs are classed by severity and seriousness.
Treatment-emergent adverse events (TEAE) are any untoward medical occurrences associated 
with the use of a drug in humans.  For the purposes of this study, untoward medical occurrences 
will be considered associated with the use of flortaucipir, and thus be reported as TEAEs, if they 
occur within 48 hours after administration of the PET tracer. The end of study for the purpose of 
AE reporting is defined as 48 hours after the administration of flortaucipir injection.
The investigator’s verbatim term of both serious and non-AEs will be mapped to system organ 
class (SOC) and preferred terms (PT) using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 17.1.
Investigators will be instructed to report their assessment of the potential relatedness of each AE 
to protocol procedure and flortaucipir. The assessment of the relationship of an AE to the 
administration of the flortaucipir is a clinical decision based on all available information at the 
time of the completion of the eCRF. 
Investigators will also assess the severity of AE. Severity is classified as mild/moderate/severe 
(increasing severity). 
Serious AEs (SAEs) are events that result in one of the following outcomes or constitute one of 
the following events:

Death

Initial or prolonged 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


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
7
STATISTICAL METHODS
7.1
Definitions and Conventions
7.1.1
Analysis Programming Platform 
All analysis will be performed using SAS version 9.2 or higher.
7.1.2
Reporting Conventions
Data will be summarized using descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum [min], and maximum [max]) for continuous variables and 
using frequency count and percentage for discrete variables. Percentages will be rounded to one 
decimal place, except 100% will be displayed without any decimal places and percentages will 
not be displayed for zero counts.
The tables and listings will be numbered using a decimal system to reflect main levels of unique 
tables and listings and sub-levels of replicate tables and listings with maximum two digits per 
level (e.g., Table XX.YY.ZZ…). Tables will be numbered as 14.YY.ZZ.  Baseline analysis will 
be reported in table series 14.1, efficacy analysis in series 14.2, and safety analysis in series 14.3.  
Listings will be numbered as 16.YY.ZZ. 
7.1.3
Type I Error
Unless otherwise specified, hypothesis testing will be two-sided with type I error rate of 0.05.
7.1.4
Definition of Baseline
Baseline summaries will include all available data from the screening time point (i.e. MMSE, 
OSU TBI-ID, family and neurologic disease histories, etc.). For the purposes of safety analysis 
involving change calculations (e.g. vital signs), baseline will be defined as the measurement 
immediately prior to flortaucipir injection. All efficacy variables to be tested will be based on the 
initial imaging visit.
7.1.5
Age Calculation
Subjects’ ages (in years) will be calculated as the difference between their year of birth and their 
year of informed consent into the study.
7.2
Handling of Dropouts or Missing Data
Dropout subjects will not be replaced in this study.  For situations with no rules for handling 
missing data the default will be no imputation.


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
7.3
Interim Analyses and Data Monitoring
No interim analysis or data monitoring is planned for this study.
7.4
Multi-center Studies and Pooling of Centers
This is a multi-center study. Data from all sites will be pooled for the analysis outlined in this 
SAP.
  
7.5
Multiple Comparisons/Multiplicity
No multiple comparisons/multiplicity adjustment is planned.   
7.6
Examination of Subgroups
No subgroup analysis will be conducted for this study.


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
8
STATISTICAL ANALYSIS
8.1
Analysis Populations
8.1.1
Enrolled Population
The enrolled population will consist of all subjects who have signed the consent form and for 
whom data exists in the electronic data capture. The enrolled population will not include screen 
failures. Disposition will be summarized using the enrolled population.  
8.1.2
Safety Population
The safety population will consist of all subjects who received at least one injection of 
flortaucipir. All baseline and safety data will be summarized using the safety population.
8.1.3
Efficacy Population
The efficacy population will include all subjects with a valid quantitated PET image (available 
SUVr). All efficacy endpoints will be summarized using the efficacy population.     
8.2
Disposition and Withdraws
The enrolled population will be represented in the disposition table. The disposition table will 
summarize the analysis populations in section 8.1, as well as completed and discontinued 
subjects.
Discontinued subjects will be defined as any safety subject who fail to complete the 48-hour
safety follow-up. Termination status (i.e. ‘Completed’ and ‘Discontinued’) and reasons for 
discontinuation percentages will be based on the safety population. Screen failures will not be 
included in the summary of disposition. 


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
8.3
Baseline Subject Data
8.3.1
Demographic and Other Baseline Characteristics
All baseline summaries will be based on the safety population. Age (years), gender, race, 
ethnicity, education, and MMSE will all be summarized in a table and presented in a listing.
8.3.2
Medical and Surgical History
Medical and surgical histories were coded using MedDRA version 17.1 and will be presented in 
a listing for the safety population.
8.3.3
Concomitant Therapy 
Concomitant therapies were coded using WHODRUG Sep 2014 and will be presented in a listing
for the safety population.
8.3.4
Neurologic Disease History
Neurologic disease information captured on the case report form (CRF) will be presented in a 
listing for the safety population.
8.3.5
Pregnancy Test
Pregnancy testing information captured on the CRF will be presented in a listing for the safety 
population.
8.3.6
Family History
Family history information captured on the CRF will be presented in a listing for the safety 
population.
8.3.7
Electrocardiogram
ECG data captured on the CRF will be presented in a listing for the safety population.
8.3.8
MMSE & OSU TBI-ID
MMSE and OSU TBI-ID information captured on the CRF will be presented in listing.


Avid Radiopharmaceuticals
18F-AV-1451-A14
                 Statistical Analysis Plan
8.4
Analysis of Efficacy Parameters
8.4.1
Analysis of Primary Efficacy Variable
8.4.1.1
Quantitative Assessment of Images
The MUBADA SUVr (as described in section 6.4.1.1) from the available imaging visits will be 
summarized using descriptive statistics (n, mean, SD, min, max, and median) for the efficacy 
population by cognitive groups (CI and CN). An analysis of covariance (ANCOVA) model will 
be used to test significant differences in baseline MUBADA SUVr between the two cognitive 
groups adjusted for age. All descriptive statistics, including LSM (+/- SE), LSM differences 
(95% C.I.), and p-values will be reported in a table.
MUBADA SUVr will also be presented in a scatter plot by clinical group.


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8.4.1.2
Correlation between MMSE and MUBADA SUVr 
Depending on available data, Spearman’s correlation coefficient will be used to measure the 
relationship between MMSE and MUBADA SUVr at baseline. This relationship will also be 
presented in a scatter plot.
8.5
Analysis of Safety
8.5.1
Exposure
The total dose administered (MBq) of flortaucipir will be summarized for each visit in a table 
using descriptive statistics and presented in a listing.
8.5.1.1
Dose Unit Conversion 
All exposure tables and listings will display dose administered in MBq. Dose recorded in mCi 
will be converted to MBq as follows:
mCi
MBq

37
8.5.2
Treatment Emergent Adverse Events
A summary of TEAEs will be reported in the tables including number of all TEAEs and number 
of subjects who experienced at least one TEAE. The summary of TEAEs will be broken down 
further in descending frequency by SOC and PT, and by PT only in separate tables. A subject 
will be counted once if the subject reported one or more events in a given level of 
summarization.
All AEs (regardless of treatment emergence) will be presented in a listing.
8.5.2.1
Severity
TEAE severity will be reported in a table in the same manner as outlined in 8.5.2. 
Events recorded with missing intensity will be summarized as ‘Severe’.  If the same TEAE is 
reported more than once for a subject within an SOC/PT, the TEAE with the worst severity 
will be summarized in the table.
8.5.2.2
Relationship to Flortaucipir
TEAE relationship to flortaucipir will be reported in a table in the same manner as outlined in 
8.5.2. TEAEs with a missing relationship to flortaucipir will be summarized as ‘Related’ to 
flortaucipir. If the same TEAE is reported more than once for a subject within an SOC/PT, the 
TEAE most related to flortaucipir will summarized in the table.
8.5.2.3
Relationship to Study Procedure
TEAE relationship to study procedure will be reported in a table in the same manner as outlined 
in 8.5.2. TEAEs recorded with a missing relationship to study procedure will be regarded as


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related to study procedure. If the same TEAE is reported more than once for a subject within 
that SOC/PT, the TEAE most related to study procedure will summarized in the table.
8.5.2.4
Serious Adverse Events
Serious TEAEs will be summarized in a similar manner as described in Section 8.5.2. TEAEs 
recorded with a missing seriousness will be summarized as ‘Serious’. If more than one serious 
TEAE was reported for a subject with the same SOC or PT, the TEAE will be counted only once 
in that SOC or PT.
8.5.2.5
Adverse Events Leading to Study Discontinuation
TEAEs leading to study discontinuation will be summarized in a similar manner as described in 
section 8.5.2.
8.5.2.6
Adverse Events Leading to Death
TEAEs leading to death will be summarized in a similar manner as described in section 8.5.2.
8.5.2.7
Missing and Partial AE Onset Dates
If the AE onset dates are missing, then the most conservative approach will be used to decide if 
the AE is TEAE or not, as detailed in the table below:
Table 4: Imputation Algorithm for Missing AE Date/Time
Scenario
Imputation
Missing AE 
start date/time
if AE stop date is missing or after injection date, then TEAE ='Y'. If AE stop 
date is prior to the injection date, then TEAE=N'
Missing AE 
start time
Impute time as 23:59, and follow TEAE definition in section 6.6.2
Partial Date
If AE start day is missing then:

If AE start month and year are the same as injection date month and 
year then TEAE=’Y’, otherwise impute missing days as the first day of 
the respective AE start month, and follow TEAE definition in section 
6.6.2
If AE start month is missing then:

If AE start year is the same as injection year then TEAE=’Y’, 
otherwise TEAE = ‘N’


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8.5.3
Vital Signs
Systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), pulse rate (PR) 
(bpm), and respiratory rate (RR) (breaths/min) were collected Immediately Prior to (within 30
minutes) Flortaucipir Injection and Prior to Discharge during the Flortaucipir Imaging Visit. 
Immediately Prior to Injection will be considered the baseline value for all vital sign change 
from baseline (CFB) calculations.
The data from each available visit and time point, along with calculated CFB, as defined as the 
difference from the Prior to Injection to Prior to Discharge values will be summarized by 
diagnosis groups in a table using descriptive statistics. A paired t-test will be performed on the 
aggregate data of each vital sign to assess if any significant changes occurred.
Vital signs and changes (where applicable) will be presented in a listing.
8.5.3.1
Potentially Clinically Significant Vital Sign Changes
Vital sign at visit and CFB will be monitored for potentially clinically significance (PCS) using 
the following criteria:
Table 5: Potentially Clinically Significant Criteria
Vital Sign
PCS Criteria
Low
High
SBP
90 and 20 
decrease
180 and 20 
increase
DBP
50 and 15 
decrease
105 and 15 
increase
PR
50 and 15 
decrease
120 and 15 
increase
RR
10
8.5.4
Follow-up Contact Data
The follow-up contact information captured on the CRF will be presented in a listing for the 
safety population.


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                 Statistical Analysis Plan
9
APPENDICES
9.1
References
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent for
Alzheimer’s disease,” Alzheimers Dement. 2013, 1-11.
Corrigan, J.D., & Bogner, J. (2007). Initial reliability and validity of the Ohio State
University TBI identification method. Journal of Head Trauma Rehabilitation, 22, 318 –
329.
Folstein, M.R., Folstein, S.E., and McHugh, P.R. “Mini Mental State: A practical method
for grading the cognitive status of patients for the clinician.” Journal of Psychiatric
Research, 12: 189-198, 1975.


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