Clinical trial NCT03052972
Conditions: Cognitive Decline
Sponsor: Avid Radiopharmaceuticals
Start date: 2017-03-23; Completion date: 2018-08-17
Enrollment: 23 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to assess the imaging characteristics of Flortaucipir (18F-AV-1451) in subjects who participated in the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study at Johns Hopkins University.

Detailed description:

Arms: arm 1: Clinically normal amyloid positive subjects from BIOCARD study receiving a flortaucipir PET scan arm 2: Clinically normal amyloid negative subjects from BIOCARD study receiving a flortaucipir PET scan
Interventions: intervention 1: Flortaucipir F18 intervention 2: Brain PET scan
Intervention descriptions: intervention 1: 370 megabecquerel (MBq)(10 millicurie \[mCi\]) single dose intervention 2: positron emission tomography (PET) scan of the brain

Protocol documents:
Prot_000.pdf: 


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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
flortaucipir (18F) Injection  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Title of Study: “Flortaucipir (18F) PET Imaging in the BIOCARD Study”  
Planned number of subjects (Enrolled): Approximately 100 
 
Subjects will be recruited from the pool of participants in the Biomarkers of Cognitive Decline 
Among Normal Individuals study (BIOCARD) being conducted at Johns Hopkins University. The 
overall recruitment goal is that 80 percent of subjects are amyloid positive, and 20 percent are 
amyloid negative.  
   
Name of compound: flortaucipir (18F) Injection (also known as 18F-AV-1451) 
Dose: 370 MBq (10 mCi) 
Route of Administration:  Intravenous (IV) bolus 
Study Phase:  I 
Study Centers:  1 center in the United States 
Trial Objectives:  
The primary objectives of this study are: 
 To evaluate imaging characteristics of flortaucipir (18F) in respect to brain amyloid status in 
subjects who are enrolled in the BIOCARD study 
 To examine the relationship between cognitive and functional performance, other biomarker 
data, and tau deposition as measured by flortaucipir (18F) uptake in clinically normal 
subjects 
 
A secondary objective of this study is: 
 To expand the flortaucipir (18F) safety database. 
Eligibility: 
Only subjects duly consented and enrolled in the BIOCARD protocol (conducted by Johns Hopkins 
University with Dr. Marilyn Albert as Principal Investigator) will be considered for participation in 
this study (see Section 5.3, Selection of Subjects).  
Study Design: 
This is a phase I study that will evaluate imaging characteristics of flortaucipir (18F) in subjects 
enrolled in the BIOCARD study.  
 
Subjects enrolled in the BIOCARD study will be contacted to participate and must provide 
informed consent before starting any AV-1451-A20 study procedures. In addition to consenting to 
study procedures, participants will consent to have Magnetic Resonance Imaging (MRI) 
images/data, laboratory data, medical and neuropsychological assessments, as well as amyloid 


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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
flortaucipir (18F) Injection  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
status, and lumbar puncture results made available to this study to allow for analysis and 
comparison. This study hopes to recruit roughly 80 percent amyloid positive subjects, and 20 
percent amyloid negative subjects from the BIOCARD study. Amyloid positivity will be 
determined by quantification of the BIOCARD PiB scan, and a list of patients for recruitment 
blinded to amyloid status will be provided to the site. Subjects’ amyloid status will not be revealed 
as a part of recruitment or inclusion for this study.  
 
Screening assessments may take place over several days, within 90 days of the flortaucipir (18F) 
Positron Emission Tomography (PET) scan, and will include demographics, medical history and 
concomitant medications, a physical exam, and a safety evaluation. Additionally, participants will 
have an ECG with results reviewed prior to the initial flortaucipir (18F) imaging visit. If the ECG 
was performed within the last six to twelve months of the 18F -AV-1451 PET Imaging Visit and is 
available for review, the ECG does not need to be repeated. Subjects may be permitted to return for 
the flortaucipir (18F) PET scan after the 90 day window with sponsor approval if the investigator 
does not recognize any significant medical changes.  
 
Subjects who qualify for the study will return to the clinic at a later date for the flortaucipir (18F) 
PET imaging visit. For the flortaucipir (18F) PET imaging visit, an intravenous catheter will be 
placed for IV administration of flortaucipir (18F) injection.  Subjects will receive a single IV bolus 
injection with a target dose of 370 MBq (10 mCi) of flortaucipir (18F) injection followed by a saline 
flush. At approximately 75 minutes following injection, a continuous 30-minute brain scan will 
begin. Adverse events will be monitored continuously during the imaging session. A physician or a 
licensed/credentialed medical professional (i.e., a PET technologist, imaging center nurse or a 
regional equivalent) designated by the site principal investigator must assess or evaluate the subject 
prior to injection and prior to discharge from the imaging center. If a designee performs this 
activity, a physician must be available to provide medical consultation. 
 
A follow-up phone call to the subject, or informant where applicable, will be conducted between 2 
or 3 business days of each 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. 
 
Assessments and Endpoints: 
All subjects will have a screening visit, a flortaucipir (18F) PET imaging visit, and a follow-up 
phone call after the imaging visit.  
 
Details of additional assessments that will be performed at each visit are detailed in Section 7.1.   
Statistical Methods:   
Exploratory analyses will examine the relationship among flortaucipir (18F) SUVr measurements, 
cognitive and neuropsychiatric measurements, and other collected biomarkers in subjects.  


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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
flortaucipir (18F) Injection  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Additional retrospective analyses will be conducted to explore the possible risk factors of tau 
deposition. 
 
 
 


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Table of Contents 
Protocol Number: ................................................................................................................ 1 
Date and Version: ............................................................................................................... 1 
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:  flortaucipir (18F) (18F-AV-1451) .............................................. 12 
4.2 Radioactive Labeling ............................................................................................... 12 
4.3 Decay Characteristics .............................................................................................. 12 
a. 
Formulation and Dose flortaucipir (18F) Injection ................................................. 12 
b. 
Packaging flortaucipir (18F) Injection .................................................................... 13 
4.6 Storage and Handling flortaucipir (18F) Injection .................................................... 13 
5. INVESTIGATIONAL PLAN .................................................................................... 13 
5.1 Overall Design and Plan of Trial ............................................................................. 13 
5.2 
Planned Dosage and Duration of Treatment ...................................................... 14 
5.2.1 Dosage and Administration ............................................................................. 14 
5.2.2 Rationale for Dosage ........................................................................................ 14 
5.3 Selection of Subjects ............................................................................................... 15 
5.3.1 Inclusion Criteria ............................................................................................. 15 
5.3.2 Exclusion Criteria ............................................................................................ 15 
a. 
Prior and Concomitant Therapy ............................................................................. 16 
5.5 Removal of Subjects from Trial .............................................................................. 16 
5.6 Premature Termination of Trial/Closure of Center ................................................. 16 
6. WARNINGS/PRECAUTIONS .................................................................................. 16 
7. PROCEDURES AND METHODS ............................................................................ 17 
7.1 Assessment Periods ................................................................................................. 17 
7.1.1 Screening Visit: ................................................................................................ 17 
7.1.2 Imaging Visit(s) ................................................................................................ 17 
7.2 Observations and Measurements ............................................................................. 18 
7.3 Protocol for Image Collection ................................................................................. 19 
7.4 Good Clinical Practice and Monitoring ................................................................... 19 
7.5 Informed Consent and Subject Information ............................................................ 20 
7.6 Documentation......................................................................................................... 20 


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7.7 Adverse Events (AE) ............................................................................................... 20 
7.7.1 Adverse Event Monitoring ............................................................................... 21 
7.7.2 Adverse Event Definitions ................................................................................ 21 
7.7.3 Adverse Event Documentation ......................................................................... 23 
7.7.4 Reporting of Serious Adverse Events .............................................................. 23 
8. STATISTICAL ANALYSIS ...................................................................................... 24 
8.1 General Statistical Considerations ........................................................................... 24 
8.2 Safety Analysis ........................................................................................................ 24 
8.3 Image Analysis ........................................................................................................ 24 
8.4 Exploratory Analyses .............................................................................................. 24 
9. USE OF DATA AND PUBLICATION ..................................................................... 25 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ....................................... 25 
10.1 Institutional Review Board (IRB).......................................................................... 25 
10.2 Informed Consent .................................................................................................. 25 
10.3 Protocol Adherence ............................................................................................... 26 
10.4 Documents Necessary for Initiation of the Trial ................................................... 26 
10.5 Study Drug Control ............................................................................................... 26 
10.6 Data Collection ...................................................................................................... 26 
10.7 Adverse Events ...................................................................................................... 27 
10.8 Records Retention.................................................................................................. 27 
11. APPENDICES ............................................................................................................ 28 
11.1 References ............................................................................................................. 28 
11.2 Trial Flow Chart .................................................................................................... 29 
 
 
 


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ABBREVIATIONS AND DEFINITIONS 
Aβ 
Beta amyloid 
AD 
ADR 
Alzheimer’s disease 
Adverse Drug Reaction 
Adverse Event 
(AE) 
amu 
ANOVA 
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. 
Atomic mass unit 
A collection of statistical models used to analyze the differences 
between group means and their associated procedures 
Audit 
β+ 
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). 
Beta decay 
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. 
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.  
ECG 
Electrocardiogram 
Efficacy 
EOS 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
End of Synthesis 
FDA 
US Food and Drug Administration 


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FDG 
18F - Fluorodeoxyglucose 
GCP 
hERG 
IB 
Good Clinical Practice 
human Ether-à-go-go-Related Gene 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
Institutional 
Review Board 
/Independent 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
the safety, welfare and human rights of the subjects participating in a 
clinical study are protected. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
IV 
Intravenous 
Kd 
keV 
Dissociation Constant 
Kiloelectronvolt 
MBq 
Megabecquerel 
mCi 
MedDRA 
Millicurie 
Medical Dictionary for Regulatory Activities 
MHD 
Maximum Human Dose 
MRI 
Magnetic Resonance Imaging 
mSv 
MW 
N 
NDA 
Millisivert, a derived unit of ionizing radiation dose in the 
International System of Units 
Molecular weight 
Number, or total 
New Drug Application 
NOAEL 
No Observable Adverse Effect Level 


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PET 
PhRMA 
Positron Emission Tomography 
Pharmaceutical Research and Manufacturers of America 
v/v 
QT 
 
QTcB 
 
Percentage solution 
A measure of the time between the start of the Q wave and the end of 
the T wave 
Bazett’s correction formula of the QT interval  
 
SAP 
SAS 
SD 
Serious Adverse 
Event (SAE) 
 
 
 
SOP 
Statistical Analysis Plan 
Statistical Analysis System 
Standard Deviation 
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, 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. 
Standard Operating Procedure 
 
SOC 
SUVr 
TdP 
 
 
System Organ Class 
Standard Uptake Value Ratio  
Torsades de Pointes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION  
Of the 2 pathological protein deposits that are the hallmark of Alzheimer’s disease 
(AD), beta- amyloid (Aβ) is thought to accumulate very early in the disease process 
and is frequently observed in elderly subjects with no clinical symptoms, a 
condition that may represent a preclinical phase of the disease. Furthermore, as a 
biomarker, Aβ plaques as seen on PET amyloid imaging appear to plateau in 
intensity early in the symptomatic phase of the disease.  
In contrast to Aβ deposits, the density and distribution in the brain of 
phosphorylated tau, in the form of neocortical tangle pathology, has been shown in 
autopsy studies to be increased with AD-related cognitive impairment and appears 
to correlate with overall evidence of neurodegeneration across the entire spectrum 
of the illness (Duyckaerts et al. 1987; Nelson et al. 2012). Thus, an understanding 
of the onset and progression of tau pathology in relation to amyloid pathology and 
cognitive change may be critical to understanding the course of the disease.  
Flortaucipir (18F)  (originally named [F-18]T807 by Siemens Molecular Imaging 
Biomarker Research group) has been developed as a positron emitting 
radiopharmaceutical for in vivo imaging of tau protein aggregates (Xia et al., 2013). 
Autoradiography results using tissue sections from human brains showed a strong 
signal in the grey matter of cortical slices from tau positive brains but weak or no 
binding in tau negative, Aβ positive, or tau and A negative tissue. Scatchard analysis 
based on this heterogeneous autoradiography assay yielded an estimated Kd of 15nM. 
A saturation binding experiment using purified Paired Helical Fragment Tau isolated 
brains of AD patients yielded a Kd value of 0.54 nM. 
An updated summary of preclinical and clinical experience pertaining to safety of 
flortaucipir (18F) can be found in the investigator’s Brochure. Briefly, preclinical 
toxicity studies of 19F-AV-1451 (non-radioactive flortaucipir (18F), “AV-1451”) 
showed a good safety profile with no observable effects at high multiples of the 
intended maximum human dose. AV-1451 was positive in the in vitro hERG assay. 
However, the cardiovascular assessments performed during the dog toxicology 
studies showed no evidence that AV-1451 prolongs the QT interval at high multiples 
of relevant clinical doses, and therefore risk of QT prolongation is not included in the 
risk profile. Nonetheless, until sufficient human cardiovascular safety data are 
available, 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. 
Human dosimetry results for flortaucipir (18F) showed both hepatobiliary and renal 
excretion, and total effective dose similar to other approved F-18 
radiopharmaceuticals. The organs of the gastrointestinal tract (upper large intestine, 
small intestine and liver) received the greatest exposure. The whole body effective 
dose for a 10 mCi (370 MBq) dose of flortaucipir (18F) was calculated to be 
8.70 mSv. In human clinical studies so far, flortaucipir (18F) is generally well-
tolerated with a low incidence of mild and transient adverse events. 
Preliminary image assessment showed tracer deposition on brain PET scans to be 
consistent with that expected for a tracer of aggregated tau protein. Flortaucipir (18F) 


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initially entered the brain and was subsequently eliminated from the brain in normal 
subjects yielding only a diffuse pattern of background activity, whereas a regionally 
distinct gray matter distribution of increased tracer retention was observed in subjects 
with high probability AD. Interim cross-sectional efficacy results (study flortaucipir 
(18F) -A05) show a distribution pattern of aggregated tau across diagnostic groups 
paralleling that hypothesized on the basis of postmortem evaluation (Braak et al., 
2006).   
A relatively small number of subjects in the ongoing A05 study presented cognitively 
as clinically normal with elevated brain amyloid. It is important to evaluate additional 
subjects of this type to obtain information regarding the presence/onset of tau 
pathology because clinically normal amyloid positive subjects have been 
hypothesized to represent the earliest preclinical stage of AD (Sperling et al., 2011). 
The present study will obtain flortaucipir (18F) tau PET scans in 100 clinically normal 
subjects from the BIOCARD study that have been identified as having elevated brain 
amyloid by PET or CSF assays.  
 
2. TRIAL OBJECTIVES 
 
The primary objectives of this study are: 
 To evaluate imaging characteristics of flortaucipir (18F) in respect to brain 
amyloid status in subjects who are enrolled in the BIOCARD study 
 To examine the relationship between cognitive and functional performance, other 
biomarker data, and tau deposition as measured by flortaucipir (18F) uptake in 
clinically normal subjects 
 
A secondary objective of this study is: 
 To expand the flortaucipir (18F) safety database. 
 
3. SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 
 
The trial is sponsored by: 
 
Avid Radiopharmaceuticals 
3711 Market Street, 7th Floor 
Philadelphia, PA 19104 
Phone: +1 215-298-0700 
 
The medical contact is: 
 


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1-3 centers in the United States will participate in this trial. 
 
4. TEST DRUG AND CONTROL AGENTS  
 
 
  
4.1 Descriptive Name:  flortaucipir (18F) (18F-AV-1451)  
  
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole  
 
MW = 262.27 amu 
 
 
 
4.2 Radioactive Labeling 
      The compound is labeled with [18F] fluorine that decays by positron (β+) emission 
and has a half-life of 109.77 min.  The principal photons useful for diagnostic 
imaging are the 511 keV gamma photons, resulting from the interaction of the 
emitted positron with an electron. 
 
 
  
4.3 Decay Characteristics 
 
 
The time course of radioactive decay for Fluorine [18F] is shown below. 
 
Min. 
Fraction Remaining 
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
 
       
Physical decay chart for Fluorine [18F].  Half-life = 109.77 min. 
 
a. Formulation and Dose flortaucipir (18F) Injection 
 


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Flortaucipir (18F) injection is a sterile, apyrogenic clear solution for intravenous 
bolus administration. Flortaucipir (18F) injection contains flortaucipir (18F) (drug 
substance) formulated in 10% (v/v) ethanol, USP in 0.9% sodium chloride 
injection, USP. 
The shelf-life of flortaucipir (18F) injection is dependent on the strength or 
specific activity calculated at End-of-Synthesis (EOS) but is not more than 10 
hours post EOS. The flortaucipir (18F) injection expiration time and date will be 
provided on the label on the secondary packaging of each vial or syringe.  
 
b. Packaging flortaucipir (18F) Injection 
 
Each package of flortaucipir (18F) injection includes a sterile apyrogenic sealed 
glass vial or sterile apyrogenic syringe containing flortaucipir (18F) injection, a 
surrounding protective lead shield canister, and an outside delivery case. 
 
  
4.6 Storage and Handling flortaucipir (18F) Injection 
 
Flortaucipir (18F) injection is stored at room temperature. Flortaucipir (18F) 
injection should be stored within the original container or equivalent radiation 
shielding.   
5. INVESTIGATIONAL PLAN 
 
 
  
5.1 Overall Design and Plan of Trial 
This is a phase I study that will evaluate imaging characteristics of flortaucipir 
(18F) in subjects enrolled in the BIOCARD study.  
 
Subjects enrolled in the BIOCARD study will be contacted to participate and 
must provide informed consent before starting any AV-1451-A20 study 
procedures. In addition to consenting to study procedures, participants will 
consent to have BIOCARD-related data, including Magnetic Resonance Imaging 
(MRI) images/data, laboratory data, medical and neuropsychological assessments, 
as well as amyloid status, and lumbar puncture results, made available to this 
study to allow for analysis and comparison. This study hopes to recruit roughly 80 
percent amyloid positive subjects, and 20 percent amyloid negative subjects from 
the BIOCARD study. Amyloid positivity will be determined by quantification of 
the BIOCARD PiB scan, and a list of patients for recruitment blinded to amyloid 
status will be provided to the site. Subjects’ amyloid status will not be revealed as 
a part of recruitment or inclusion for this study.  
 
Screening assessments may take place over several days, within 90 days of the 
flortaucipir (18F) Positron Emission Tomography (PET) scan, and will include 
demographics, medical history and concomitant medications, a physical exam, 
and a safety evaluation. Additionally, participants will have an ECG with results 
reviewed prior to the initial flortaucipir (18F) imaging visit. If the ECG was 


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performed within the last six to twelve months of the 18F -AV-1451 PET Imaging 
Visit and is available for review, the ECG does not need to be repeated. Subjects 
may be permitted to return for the flortaucipir (18F) PET scan after the 90 day 
window with sponsor approval if the investigator does not recognize any 
significant medical changes.  
 
Subjects who qualify for the study will return to the clinic at a later date for the 
flortaucipir (18F) PET imaging visit. For the flortaucipir (18F) PET imaging visit, 
an intravenous catheter will be placed for IV administration of flortaucipir (18F) 
injection.  Subjects will receive a single IV bolus injection with a target dose of 
370 MBq (10 mCi) of flortaucipir (18F) injection followed by a saline flush. At 
approximately 75 minutes following injection, a continuous 30-minute brain scan 
will begin. Adverse events will be monitored continuously during the imaging 
session. A physician or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by the site 
principal investigator must assess or evaluate the subject prior to injection and 
prior to discharge from the imaging center. If a designee performs this activity, a 
physician must be available to provide medical consultation. 
 
A follow-up phone call to the subject, or informant where applicable, will be 
conducted between 2 or 3 business days of each imaging day, but not before 48 
hours post-injection, to confirm subject well-being and to collect information 
about any new adverse events.  If both of these days are not business days, the 
follow-up phone call can occur the following business day. 
 
5.2 Planned Dosage and Duration of Treatment 
 
5.2.1 Dosage and Administration 
All subjects will receive a single IV bolus administration of approximately 
370 MBq (10 mCi) of flortaucipir (18F) injection. 
 
5.2.2 Rationale for Dosage  
Flortaucipir (18F) will be administered IV in a radioactive dose of 370 MBq 
(10 mCi) with a maximum human dose (MHD) limited to 20 µg of compound 
by weight.  This dose is 150 fold lower than the NOAEL observed in the rat 
single dose toxicity study and is 50 fold lower than the NOAEL observed in 
the rat and dog repeat dose toxicity studies. 
 
Human dosimetry has been obtained in nine subjects. The results estimated an 
Effective Dose of 8.92 mSv for an anticipated 370 MBq (10 mCi) injection 
and is comparable to the effective dose of approved 18F-labeled compounds 
such as FDG and florbetapir F 18 injection. 
 
The proposed dose has been shown to have acceptable image quality in 
previous human studies. No treatment related adverse events have been 
reported using this regimen.   


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5.3 Selection of Subjects 
 
5.3.1 Inclusion Criteria 
All subjects must meet all of the following criteria to enroll in this trial: 
 
1. Male or females that have consented and are currently enrolled in the 
BIOCARD protocol 
2. Can tolerate PET scan procedures; and 
3. Have the ability to provide informed consent for study procedures (if the 
patient is ineligible to give informed consent, based on local standards, the 
patient’s legal representative may consent on behalf of the patient, but the 
patient must still confirm assent). 
 
5.3.2 Exclusion Criteria 
Subjects will be excluded from enrollment if they: 
1. Has any condition by history or abnormal findings on physical 
examination or screening tests that, in the investigator’s opinion, could 
increase risk to the participant, limit the participant’s ability to tolerate 
the experimental procedures (e.g., chronic back pain which might limit 
the ability to lie still during the scanning procedures), or interfere with 
analysis of the data.   
2. Has a history of risk factors for Torsades de Pointes or is taking 
medications known to prolong QT interval. A list of restricted 
medications will be provided. 
3. Have ECG obtained prior to the initial flortaucipir (18F) scan that in the 
opinion of the investigator is clinically significant with regard to the subject’s 
participation in the study. Bazett’s corrected QT (QTcB) interval must be 
evaluated and must not exceed 458 msec in males, or 474 msec in females.  
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 β-hCG at the time of screening and negative urine β-
hCG on imaging day) or breastfeeding at screening. Females must agree 
to avoid becoming pregnant, and refrain from sexual activity or to use 
reliable contraceptive methods for 24 hours following administration of 
flortaucipir (18F). 
5. Has hypersensitivity to flortaucipir (18F) or any of its excipients. 
6. Have a current clinically significant infectious disease, endocrine or 
metabolic disease, pulmonary, renal or hepatic impairment, or cancer that the 
investigator believes would affect study participation or scan results; 
7. Have had a non-study related radiopharmaceutical imaging or treatment 
procedure within 7 days prior to the flortaucipir (18F) imaging session;  
8. In the opinion of the investigator, are otherwise unsuitable for a study of 
this type. 


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a. Prior and Concomitant Therapy 
 
Except as noted in the exclusion criteria, all medications (prescription or over-the-
counter) that have been started prior to screening may be continued during the 
course of the trial.  All medications, including investigational medications that are 
continued from the start of the trial, or that are started during the trial (other than 
the study medication), must be documented on the Concomitant Medication Page 
of the electronic Case Report Form (eCRF).   
 
5.5 Removal of Subjects from Trial 
 
Subjects must be removed from the trial if: 
1. Informed consent is withdrawn; or 
2. The investigator or the sponsor believes it is in the best interest of the subject 
to be removed from the trial.   
Subjects may be withdrawn from the trial if a SAE occurs. The date and reason 
for discontinuation should be noted on the eCRF. Subjects who discontinue 
prematurely should be seen for a final evaluation.  
 
5.6 Premature Termination of Trial/Closure of Center 
 
The sponsor may discontinue the trial at any time.  Reasons for discontinuation of 
the trial may include, but are not limited to, new information on safety or efficacy, 
requests from regulatory authorities, or changes in business priorities.  Additional 
reasons for center closure may include, but are not limited to, excessive protocol 
violations, inadequate regard for subject safety, failure to follow recommended 
procedures (e.g., documentation), failure or inability to accommodate 
Avid/Contract Research Organization (CRO) monitors or to provide required 
access to data and source documents, staff turnover, 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 flortaucipir (18F) 
injection can be found in the investigator's brochure.  
 
In brief, flortaucipir (18F) injection is an experimental imaging agent that will be used 
at relatively low (tracer) doses.  Because flortaucipir (18F) injection is under clinical 
investigation, it is recommended that subjects receiving flortaucipir (18F) injection be 
followed closely by means of adverse event reporting. 
 
 
 


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7. PROCEDURES AND METHODS 
 
7.1 Assessment Periods (See Section 11.2, Trial Flow Chart) 
       
 
The study will consist of the following sequence of activities:  
 
7.1.1 Screening Visit: 
Subjects currently enrolled in the BIOCARD study protocol will be contacted 
to participate. Screening assessments may take place over several days, within 
90 days of the flortaucipir (18F) PET scan, and will include: 
 Informed Consent will take place before any AV-1451-A20 study 
procedures; 
 Demographics (birth year, gender, race, ethnicity, education, alcohol, drug 
use and smoking); 
 Medical history and concomitant medications; 
 For women of childbearing potential, a negative serum pregnancy test 
must be obtained at the screening visit.  
 A physician will see the subject during the screening assessments.   
 An ECG will be performed to assess the participant’s cardiac status. If an 
ECG was performed within the last 12 months of the flortaucipir (18F) 
PET Imaging Visit and is available for review, the ECG does not need to 
be repeated.  
 
7.1.2 Imaging Visit(s)  
 
Flortaucipir (18F) PET Imaging Visit 
 A physician or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by 
the site principal investigator must assess or evaluate the subject prior to 
administration of flortaucipir (18F) injection to determine if they are still 
suitable to undergo the scan. If a designee performs this activity, a 
physician must be available to provide medical consultation; 
 For women of childbearing potential, a negative urine pregnancy test must 
be obtained on the day of flortaucipir (18F) dose administration; 
 Subjects will receive a single IV bolus injection target dose of 370 MBq 
(10 mCi) of flortaucipir (18F) injection followed by a saline flush.  
 At approximately 75 minutes following injection, a continuous 30-minute 
brain scan will begin;   
 The injection site will be observed for excessive inflammation or damage 
to the surrounding tissue where the dose was injected; 
 Adverse events will be continuously monitored during the flortaucipir 
(18F) PET imaging visit. Subjects who experience an adverse event will 


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not be discharged from the imaging center until the event has resolved or 
stabilized;  
 A physician or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by 
the site principal investigator must assess or evaluate the subject prior to 
discharge from the imaging center to evaluate the subject’s readiness for 
discharge. If a designee performs this activity, a physician must be 
available to provide medical consultation; and 
 A follow-up phone call to the subject, or informant where applicable, will 
be conducted within 2 or 3 business days of the imaging day, but not 
before 48 hours post-injection, to confirm subject well-being and to collect 
information about any new adverse events.  If both of these days are not 
business days, the follow-up phone call can occur the following business 
day. 
 
  
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 the subject.  The subject will have an opportunity to have 
all questions answered.  The appropriate parties will then sign and date the 
informed consent form, indicating willingness to participate in the study (see 
Section 7.5). A copy of the signed informed consent will be given to the subject.  
 
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 (ECG) 
A resting 12-lead electrocardiogram will be recorded as part of the screening visit, 
unless an ECG was performed within twelve months of the flortaucipir (18F) PET 
Imaging Visit and is available for review. 
 
Physician Visit 
A physician must see the subject during the screening visit. A physician or a 
licensed/credentialed medical professional (i.e., a PET technologist, imaging 


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center nurse or a regional equivalent) designated by the site principal investigator 
must assess or evaluate the subject prior to administration of flortaucipir (18F) 
injection and prior to discharge from the imaging center. If a designee performs 
this activity, a physician must be available to provide medical consultation. At 
discharge, the physician or licensed/credentialed medical professional should 
review all safety data and briefly examine/query the subject regarding potential 
adverse events or other treatment issues.   
 
Pregnancy Testing  
 Serum beta hCG, qualitative:  performed at screening for females of 
childbearing potential (defined as pre-menopausal, less than 2 years post-
menopausal or not surgically sterile).  A serum pregnancy test may also be 
obtained prior to injection at the imaging visit if required by the local site. 
 Urine beta hCG: performed at the flortaucipir (18F)  imaging visit prior to 
injection for females of childbearing potential (defined as pre-menopausal, 
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 flortaucipir (18F) 
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 
5. The termination of a center or the trial if conditions apply, as outlined in 
Section 5.6. 
 


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7.5 Informed Consent and Subject Information 
 
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.  The subject will have an opportunity to have all questions 
answered by a physician.  The subject will then sign and date the informed 
consent form, indicating willingness to participate in the study.   
 
If the subject is not capable of giving consent, consent may be given by a legally 
authorized representative.  However, it is expected that all subjects entering this 
study should at least have the capacity to understand that they are engaging in a 
research study and should affirm that they do not object to participating, by 
signing on the Subject Assent line of the consent form.  If the legal guardian is 
also the informant, the guardian must still sign the informant line of the form, 
indicating their own willingness to participate as an informant. 
 
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB).  No study related procedures shall 
be performed prior to completion of the informed consent process, and signing of 
the consent form.  A copy of the signed informed consent should be given to the 
patient for their records. 
 
 
  
7.6 Documentation 
 
Flortaucipir (18F) PET scans will be saved in an appropriate electronic format as 
specified in the imaging manuals.  A copy of all scans, including the MRI scans 
conducted per BIOCARD study protocol, will be saved at the site/imaging center 
and a copy of each will be forwarded to the sponsor described in the imaging 
manuals.  All other data required by the protocol will be recorded in the eCRFs.  
All data in the eCRFs will be substantiated by “source documents,” which consist 
of the subject’s medical files, laboratory result sheets, ECG tracings, etc.  All 
source documentation must be available to Avid, and its 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.  
The 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 


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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”). 
 
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 event 
resolution).  Additionally, any clinically significant findings from study 
procedures including those that result in a diagnosis should be reported as an AE 
to Avid, or its designee.  
 
7.7.1 Adverse Event Monitoring 
  
Each patient must be carefully monitored for adverse events.  This includes 
clinical laboratory test variables.  An assessment must be made of the 
severity/intensity and relationship to the administration of the study drug. 
 
7.7.2 Adverse Event Definitions 
Adverse Events 
 
An adverse event is any undesirable experience occurring to a subject during a 
clinical trial, whether or not considered related to the study drug. 
 
For reporting purposes, Avid will distinguish among pre-existing conditions, 
trial-emergent adverse events and treatment-emergent adverse events.   
 
Pre-existing conditions (i.e., undesirable experiences, signs or symptoms that 
begin prior to the Screening Visit) will be recorded on the medical history 
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(s) (started prior to dose of 
study medication) do not have to be recorded in the AEs section of the eCRF, 
unless there is an increase in frequency and severity. 
 
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 the study drug at the imaging visit.  
 
 
Treatment-emergent adverse events are any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug 
related.  For the purposes of this study, untoward medical occurrences will be 
considered associated with the use of flortaucipir (18F), and thus be reported as 
adverse events, if they occur within 48 hours after flortaucipir (18F) 
administration.  


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The end of study, for the purpose of adverse event reporting, is defined as 48 
hours after the last administration of flortaucipir (18F). 
 
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; 
 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 IB. 
 
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, in order to determine the 
intensity (severity) of the event.  
 
The following classifications should be used: 
 


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Page 23 of 30 
 
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 event 
resolution). 
 
Adverse events and laboratory test abnormalities fulfilling the definition of a 
serious adverse event should, in addition, be reported on the Serious Adverse 
Event Reporting Form. 
 
7.7.4 Reporting of Serious Adverse Events  
Study site personnel must alert Eli Lilly, or its designee, of any SAE within 24 
hours of their awareness of the event via a sponsor-approved method.  Alerts 
issued via telephone are to be immediately followed with official notification 
on study-specific SAE forms.  
 
Serious adverse events occurring after a subject receives a dose of 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. 


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8. STATISTICAL ANALYSIS 
 
 
  
8.1 General Statistical Considerations 
 
All statistical analyses will be performed using SAS® version 8.2 or higher. 
 
The study data collected under the BIOCARD protocol, such as but not limited to 
subjects’ demographic and baseline characteristics, medical history, neurological 
and behavioral evaluations, neuropsychological test results, MRI, and other 
biomarker studies will be transferred to Avid for analysis purposes. 
 
Additional details concerning statistical analyses will be included in the Statistical 
Analysis Plan (SAP) to be completed per Avid SOP. 
 
 
  
8.2 Safety Analysis 
 
Adverse events including injection site reactions will be summarized in terms of 
number and percentage of subjects experiencing an AE. The summary will be 
further broken down by system organ class (SOC) and preferred term using 
Medical Dictionary for Regulatory Activities (MedDRA) terms. Adverse events 
will also be presented by severity, relationship to treatment and seriousness. All 
subjects who experience SAEs, or who discontinue due to AEs, will be 
summarized. 
 
Discontinuation  
 
All subjects who discontinued participation prior to completing the study will be 
listed and their discontinuation reasons will be tabulated. 
 
 
  
8.3 Image Analysis 
All flortaucipir (18F) PET images obtained starting at 75 minutes post injection 
will be analyzed. Additional details concerning image analyses will be included in 
a separate document to be completed prior to the end of the study.  
8.4 Exploratory Analyses 
Exploratory analyses will examine the relationship among flortaucipir (18F) 
uptake measurements, cognitive and neuropsychiatric measurements, and other 
collected biomarkers in subjects, and will explore whether the flortaucipir (18F) 
uptake measurements are correlated with other biomarkers, cognitive status, and 
clinical presentation. Additional retrospective analyses will be conducted to 
explore the possible risk factors of tau deposition. 
  


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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). Avid’s policy is briefly 
summarized below: 

We commit to timely communication of meaningful results of controlled clinical
trials, regardless of outcome.

As a sponsor, we may recommend that the Investigator(s) delay or decline
publication in cases where the study design, conduct, or data are insufficient to
allow meaningful interpretation. Avid and the Investigator(s) will discuss the
study design and data in advance of the study, and again after completion, and
will strive, through appropriate scientific debate, to reach a consensus regarding
the potential merits of publication.

Avid retains the right to review any manuscripts, presentations, or abstracts before
they are submitted for publication. Where differences of opinion or interpretation
exist regarding data planned for publication, the parties (Avid and the
Investigator) should try to resolve them through appropriate scientific debate.
Avid retains the right to delay publication for up to 60 days to protect intellectual
property.

Anyone who provides substantial contributions should receive appropriate
recognition as an author or contributor when the manuscript is published.
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 its designee, for review prior to being used to obtain patient 
consent. 


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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;  
• 
List of reference range laboratory values; and 
• 
Any additional licenses required in order to order to use flortaucipir (18F). 
 
 
  
10.5 Study Drug Control 
The receipt of clinical supplies (e.g. starting material for flortaucipir (18F)) 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. Flortaucipir (18F) should be prepared by a qualified PET 
manufacturing site and administered by a qualified individual under the 
investigator’s supervision. An up-to-date drug inventory/dispensing record must 
be maintained and all drug supplies must be justified. 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 as 
specified in the imaging manual.   
 


BIOCARD Protocol 20Jan2017 Amendment 1  
 
 
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Each patient’s source file should include an original signed informed consent 
form. When the trial is completed, the informed consent form should be kept on 
file with other trial related records. 
 
All original laboratory reports must be available for review in each patient’s file.  
It is important that the original reports be available for review because of the 
possibility of inaccuracies or errors in transcribing data from original records to 
the eCRF. 
 
The eCRFs must be kept in order and up-to-date so that they always reflect the 
latest observations on the subjects that are enrolled in the trial. The eCRFs must 
be completed for each patient enrolled in the trial and signed by the investigator. 
This should be done as soon as possible after completion of the patient’s 
participation in the trial. A monitor will verify the source data for all information 
on the eCRF. 
 
 
  
10.7 Adverse Events 
 
All adverse events encountered during the clinical trial must be documented on 
the eCRF, whether or not considered drug-related. 
 
Eli Lilly must be notified immediately (as soon as possible, and in all cases within 
24 hours) of a drug experience, condition, development, or event, which is 
considered serious. Eli Lilly must be notified immediately of any findings with 
the use of the drug that may suggest significant hazards, contraindications, 
adverse drug reactions (ADRs) and precautions pertinent to the safety of the drug.  
The investigator will be requested to complete a separate report form in addition 
to the information on the 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. 
 


BIOCARD Protocol 20Jan2017 Amendment 1  
 
 
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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. 
 
11. APPENDICES 
 
 
11.1 References 
 
 
Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., Del Tredici, K. “Staging of 
Alzheimer disease-associated neurofibrillary pathology using paraffin sections and 
immunocytochemistry”. Acta Neuropathologica. 2006, 389-404.  
 
Duyckaerts, C., Brion, J.P., Hauw, J.J., Flament-Durand, J. ““Quantitative assessment 
of the density of neurofibrillary tangles and senile plaques in senile dementia of the 
Alzheimer type. Comparison of immunocytochemistry with a specific antibody and 
Bodian's protargol method”. Acta Neuropathologica. 1987, 167-170. 
 
Nelson, P.T., et al. ““Correlation of Alzheimer disease neuropathologic changes with 
cognitive status: a review of the literature”. Journal of Neuropathology & 
Experimental Neurology. 2012, 362-381. 
 
Riley K.P., Snowdon D.A., Markesbery W.R.. Alzheimer's neurofibrillary pathology 
and the spectrum of cognitive function: Findings from the Nun Study. Ann Neurol 
2002; 51: 567-77. 
 
Sperling, R.A., et al. “Toward defining the preclinical stages of Alzheimer’s disease: 
Recommendations from the National Institute on Aging and the Alzheimer’s 
Association workgroup”. Alzheimer’s & Dementia. 2011, 1-13. 
 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent 
for Alzheimer’s disease”. Alzheimers Dement. 2013, 1-11. 
 


BIOCARD Protocol 20Jan2017 Amendment 1 
 
 
 
 
 
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11.2 Trial Flow Chart 
 
a. 
Screening may take place over several days.  All assessments must be performed within 90 days prior to the flortaucipir (18F) imaging session. Subjects may be permitted to return for the 
flortaucipir (18F) PET scan after the 90 day window with sponsor approval if the investigator does not recognize any significant medical changes. 
b. 
A follow-up phone call to the subject, or information where applicable, will be conducted within 2 or 3 business days of each 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. 
c. 
ECG (with results reviewed prior to flortaucipir (18F) administration). 
d. 
Subjects will receive a single IV bolus injection target dose of 370 MBq (10 mCi) of flortaucipir (18F) injection followed by a saline flush.  
e. 
At approximately 75 minutes following flortaucipir (18F) injection, a continuous 30-minute brain scan will begin. 
f. 
Or a licensed/credentialed medical professional (i.e. PET technologist, imaging center nurse or a regional equivalent) designated by the site principal investigator. If a designee performs this 
activity, the physician must be available to provide medical consultation.  
g. 
Or physician designee. 
h. 
Serum pregnancy test 
i. 
Urine pregnancy test prior to flortaucipir (18F) injection  
 
Evaluations 
Screening 
Assessmentsa 
18F-AV- 1451 Imaging 
Visit 
End of 18F-AV- 1451 Imaging 
(prior to discharge) 
Follow-up Phone Callb 
Signed Informed Consent 
X 
 
 
 
Demographics 
 
X 
 
 
 
Medical History 
X 
 
 
 
Concomitant Medications 
X 
 
 
 
ECG 
Xc 
 
 
 
PET Brain Scan 
 
X d, e 
 
 
Evaluation by a physician   
X 
Xf 
Xg 
 
Pregnancy Test 
Xh 
Xi 
 
 
Adverse Events  
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 


BIOCARD Protocol 20Jan2017 Amendment 1 
 
 
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Page 30 of 30 
 
 
INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol 18F-AV-1451-A20: “Flortaucipir (18F) PET Imaging in the BIOCARD Study” 
 
 
Date and Version: 20 JANUARY 2017 
 
                    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 
 
 

SAP_001.pdf: 
Avid Radiopharmaceuticals
Study 18F-AV-1451-A20
                 Statistical Analysis Plan
Protocol No. 18F-AV-1451-A20
Flortaucipir (18F) PET Imaging in the BIOCARD Study
Statistical Analysis Plan
Prepared by:
Avid Radiopharmaceuticals, Inc
Final Version 1.0
14 March 2019
Revision History
Version
Date
Author
Revisions
0.1
04MAR2019
Initial Draft
1.0
14MAR2019
Finalized document
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.


Avid Radiopharmaceuticals
Study 18F-AV-1451-A20
                 Statistical Analysis Plan
Table of Contents
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS......................................................... 4
2
INTRODUCTION.................................................................................................................................. 5
3
STUDY OBJECTIVES.......................................................................................................................... 5
4
STUDY DESIGN.................................................................................................................................... 5
4.1
GENERAL DESIGN ............................................................................................................................. 5
4.2
METHOD OF ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS ....................................................... 6
4.3
BLINDING ......................................................................................................................................... 6
4.4
DETERMINATION OF SAMPLE SIZE ..................................................................................................... 6
5
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES............................... 7
5.1
CHANGES IN THE CONDUCT OF THE STUDY ........................................................................................ 7
6
BASELINE, EFFICACY AND SAFETY EVALUATIONS.................................................................. 8
6.1
SCHEDULE OF EVALUATIONS............................................................................................................. 8
6.2
TIME POINT ALGORITHMS ................................................................................................................. 9
6.2.1
Windows................................................................................................................................... 9
6.3
SCREENING AND BASELINE ASSESSMENTS ......................................................................................... 9
6.4
EFFICACY VARIABLES....................................................................................................................... 9
6.4.1
Primary Efficacy Variable(s)..................................................................................................... 9
6.4.1.1
Tau Status Based on Flortaucipir ..........................................................................................................9
6.4.1.2
Flortaucipir Quantitation ......................................................................................................................9
6.4.1.3
Amyloid Status ..................................................................................................................................10
6.4.2
Additional Efficacy Variables.................................................................................................. 10
6.4.2.1
Cognitive Assessments.......................................................................................................................10
6.4.2.2
Functional Assessments......................................................................................................................10
6.5
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETIC PARAMETERS............................. 11
6.5.1
Handling of Pharmacokinetic Parameter Outliers ................................................................... 11
6.6
SAFETY ASSESSMENTS.................................................................................................................... 11
6.6.1
Extent of Exposure and Compliance to Study Treatment .......................................................... 11
6.6.1.1
Unit Conversion for Radioactive Dose................................................................................................11
6.6.2
Adverse Events ....................................................................................................................... 11
7
STATISTICAL METHODS................................................................................................................ 13
7.1
DEFINITIONS AND CONVENTIONS..................................................................................................... 13
7.2
HANDLING OF DROPOUTS OR MISSING DATA ................................................................................... 13
7.3
INTERIM ANALYSES AND DATA MONITORING .................................................................................. 13
7.4
MULTI-CENTER STUDIES AND POOLING OF CENTERS ........................................................................ 13
7.5
MULTIPLE COMPARISONS/MULTIPLICITY......................................................................................... 13
7.6
EXAMINATION OF SUBGROUPS......................................................................................................... 13
8
STATISTICAL ANALYSIS ................................................................................................................ 14
8.1
ANALYSIS POPULATIONS................................................................................................................. 14
8.1.1
Enrolled Population................................................................................................................ 14
8.1.2
Safety Population.................................................................................................................... 14
8.1.3
Efficacy Population................................................................................................................. 14
8.2
DISPOSITION AND WITHDRAWS ....................................................................................................... 14
8.3
BASELINE SUBJECT DATA ............................................................................................................... 15
8.3.1
Demographic and Other Baseline Characteristics................................................................... 15
8.3.2
Medical and Surgical History.................................................................................................. 15
8.3.3
Concomitant Therapy.............................................................................................................. 15


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8.3.4
Pregnancy Test....................................................................................................................... 15
8.3.5
Electrocardiogram.................................................................................................................. 15
8.4
ANALYSIS OF EFFICACY PARAMETERS............................................................................................. 15
8.4.1
Analysis of Primary Efficacy Variable..................................................................................... 15
8.4.1.1
Qualitative Assessment of Images.......................................................................................................15
8.4.1.2
Quantitative Assessment of Images.....................................................................................................15
8.4.1.3
Correlation between MMSE and MUBADA SUVr in Clinically Normal Subjects................................16
8.4.1.4
Correlation between FAQ and MUBADA SUVr in Clinically Normal Subjects....................................16
8.5
ANALYSIS OF SAFETY ..................................................................................................................... 16
8.5.1
Exposure ................................................................................................................................ 16
8.5.2
Treatment Emergent Adverse Events ....................................................................................... 16
8.5.3
Severity................................................................................................................................... 16
8.5.4
Relationship to Flortaucipir.................................................................................................... 16
8.5.5
Relationship to Study Procedure ............................................................................................. 16
8.5.6
Serious Adverse Events........................................................................................................... 17
8.5.7
Adverse Events Leading to Study Discontinuation.................................................................... 17
8.5.8
Adverse Events Leading to Death............................................................................................ 17
8.5.9
Missing and Partial AE Onset Dates ....................................................................................... 17
8.5.10
Follow-up Contact Data ......................................................................................................... 17
APPENDIX I: ALGORITHMS TO HANDLE MISSING AND PARTIAL DATES................................. 18
1.1.
MISSING AND PARTIAL AE ONSET AND END DATES ......................................................................... 18


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1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table 1: Abbreviations and Definitions of Terms
AAL
Automated anatomical labeling
Aβ
amyloid-β
AD
Alzheimer’s disease
AE
adverse event
BIOCARD
Biomarkers of Cognitive Decline Among Normal Individuals
CRF
Case report form
CSF
cerebrospinal fluid
CSR
clinical study report
ECG
electrocardiogram
IV
intravenous
MBq
megabecquerel
mCi
millicuries
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini-Mental State Examination
MUBADA
Multiblock Barycentric Discriminant Analysis
PERSI
parametric estimated signal reference intensity
PET
positron emission tomography
PiB
Pittsburgh compound B
PT
preferred term
SAE
Serious adverse event
SAP
statistical analysis plan
SAS
Statistical analysis software
SOC
system organ class
SUVr
standardized uptake value ratio
TEAE
treatment-emergent adverse event
WHO
World Health Organization


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2
INTRODUCTION
Of the 2 pathological protein deposits that are the hallmark of Alzheimer’s disease (AD), 
beta- amyloid (Aβ) is thought to accumulate very early in the disease process and is 
frequently observed in elderly subjects with no clinical symptoms, a condition that may 
represent a preclinical phase of the disease. Furthermore, as a biomarker, Aβ plaques as 
seen on PET amyloid imaging appear to plateau in intensity early in the symptomatic 
phase of the disease.
In contrast to Aβ deposits, the density and distribution in the brain of phosphorylated tau, 
in the form of neocortical tangle pathology, has been shown in autopsy studies to be 
increased with AD-related cognitive impairment and appears to correlate with overall 
evidence of neurodegeneration across the entire spectrum of the illness (Duyckaerts et al. 
1987; Nelson et al. 2012). Thus, an understanding of the onset and progression of tau 
pathology in relation to amyloid pathology and cognitive change may be critical to 
understanding the course of the disease.
It is important to evaluate cognitive normal subjects with elevated brain amyloid to
obtain information regarding the presence/onset of tau pathology because clinically 
normal amyloid positive subjects have been hypothesized to represent the earliest 
preclinical stage of AD (Sperling et al., 2011). The present study planned to obtain 
flortaucipir (18F) tau positron emission tomography (PET) scans in up to 100 clinically 
normal subjects from the Biomarkers of Cognitive Decline Among Normal Individuals 
(BIOCARD) study that have been identified as having elevated brain amyloid by PET or 
cerebrospinal fluid (CSF) assays.
3
STUDY OBJECTIVES
The primary objectives of this study are:

To evaluate imaging characteristics of flortaucipir (18F) with respect to brain 
amyloid status in subjects who are enrolled in the BIOCARD study

To examine the relationship between cognitive and function performance, other 
biomarker data, and tau deposition as measured by flortaucipir (18F) uptake in 
clinically normal subjects
A secondary objective of this study is:

To expand the flortaucipir safety database.
4
STUDY DESIGN
4.1
General Design
This is a phase I study that will evaluate imaging characteristics of flortaucipir in subjects 
enrolled in the BIOCARD study. Subjects enrolled in the BIOCARD study were
contacted to participate and must have provided informed consent before starting any 
AV-1451-A20 study procedures. In addition to consenting to study procedures, 
participants consented to have Magnetic Resonance Imaging (MRI) images/data, 


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laboratory data, medical and neuropsychological assessments, as well as amyloid status, 
and lumbar puncture results made available to this study to allow for analysis and
comparison. This study hoped to recruit roughly 80 percent amyloid positive subjects, 
and 20 percent amyloid negative subjects from the BIOCARD study. Amyloid positivity
(Aβ+/Aβ-) was determined based on a visual read of the BIOCARD Pittsburgh 
compound B (PiB) amyloid PET scan. A list of subjects to be targeted for recruitment, 
including appropriate numbers of both amyloid positive and amyloid negative cases, was
provided to the site. The subjects’ amyloid status were not revealed to the site or subjects 
as part of recruitment or inclusion for this study.
Flortaucipir PET Imaging Session: 
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 370 megabecquerel (MBq) (10 millicuries (mCi)) of flortaucipir injection 
followed by a saline flush. At approximately 80 minutes post dose, a continuous 20-
minute brain scan (4 acquisitions of 5-minute duration) was obtained. If at any point 
during the imaging session it was determined that the subject was not able to continue, or 
that it was not in the best interest of the subject to continue, the protocol specified that 
imaging would be discontinued, and the image data that had been collected up to that 
point would be analyzed. Clinical laboratory tests were obtained prior to injection and 
upon completion of each imaging session. Adverse events (AE) were monitored 
continuously during the imaging session. Subjects who experienced any AE during an 
imaging session were not discharged until the event had resolved or stabilized. 
4.2
Method of Assignment of Subjects to Treatment Groups
Subjects who qualify for the study will return to the clinic at a later date for the 
flortaucipir (18F) PET imaging visit. For the flortaucipir PET imaging visit, an 
intravenous catheter will be placed for IV administration of flortaucipir (18F) injection. 
Subjects will receive a single IV bolus injection with a target dose of 370 MBq (10 mCi) 
of flortaucipir (18F) injection followed by a saline flush.
4.3
Blinding
The study recruited roughly 80 percent Aβ+ subjects and 20 percent Aβ- subjects from 
the BIOCARD study. Amyloid positivity was determined by an Avid expert reader’s 
visual interpretation. A list of subjects for recruitment was randomly selected, stratifying 
by amyloid status to maintain an approximately 80% Aβ+ subjects. The list was provided 
to the site with amyloid status blinded. The subjects’ amyloid status were not revealed as 
a part of recruitment or inclusion for this study.
4.4
Determination of Sample Size
No power or sample size calculation was done for this exploratory study. Twenty-three 
(23) subjects were dosed with flortaucipir and had an accompanying visual read or 
imaging quantification.


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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 statistical 
analysis plan (SAP).


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6
BASELINE, EFFICACY AND SAFETY EVALUATIONS
6.1
Schedule of Evaluations


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6.2
Time Point Algorithms
6.2.1
Windows
For all analyses, results will be summarized at the planned study visit they were obtained. 
6.3
Screening and Baseline Assessments
Screening assessments took place over several days, within 90 days of the flortaucipir 
PET scan, and included demographics, medical history and concomitant medications, a 
physical exam, and a safety evaluation. Additionally, participants had an 
electrocardiogram (ECG) with results reviewed prior to the initial flortaucipir imaging 
visit.
6.4
Efficacy Variables
6.4.1
Primary Efficacy Variable(s)
6.4.1.1
Tau Status Based on Flortaucipir
The 18F-AV-1451 PET scan image was visually interpreted according to the following 
criteria:
Read Outcome
Objective Image Features
Not consistent with AD pattern 
(τAD-)
No increased neocortical activity, or increased neocortical 
activity isolated to the mesial temporal, anterolateral temporal, 
and/or frontal regions.
AD pattern (τAD)
τAD+
In either hemisphere, increased neocortical activity in the 
posterolateral temporal (PLT) or occipital region(s). 
τAD++
In either hemisphere, increased neocortical activity in the 
parietal/precuneus region(s), or frontal region(s) with increased 
uptake in the PLT, parietal, or occipital region(s). 
6.4.1.2
Flortaucipir Quantitation
Standard uptake value ratios (SUVr) were 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 


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                 Statistical Analysis Plan
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 any efficacy analysis involving flortaucipir
quantitation. All regional SUVrs will be presented in listings.
6.4.1.3
Amyloid Status
Aβ is thought to accumulate very early in the AD process and is frequently observed in 
elderly subjects with no clinical symptoms. Furthermore, as a biomarker, Aβ plaques as 
seen on PET amyloid imaging appear to plateau in intensity early in the symptomatic 
phase of the disease. Amyloid positivity (Aβ+ or Aβ-) was determined by an Avid expert 
reader’s visual interpretation.
6.4.2
Additional Efficacy Variables
6.4.2.1
Cognitive Assessments
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.
MMSE was recorded in the BIOCARD data. The MMSE measurement collected closest 
to the flortaucipir scan will be used for the purposes of the correlation analysis.
6.4.2.2
Functional Assessments
Pfeffer Functional Activities Questionnaire (FAQ), (Pfeffer et al. 1982) 
Functional status is conceptualized as the “ability to perform self-care, self-maintenance 
and physical activities.” The FAQ was developed to assess instrumental activities of daily 
living involving higher level functional skills such as shopping alone, writing checks, 
remembering appointments, etc. The FAQ asks the informant to rate the patient’s ability 
using the following scoring system: Dependent = 3; Requires assistance = 2; Has 
difficulty but does by self = 1; Normal = 0; Never did [the activity] but could do now = 0; 
Never did and would have difficulty now = 1. The sum scores ranges from 0-30, where 
higher scores indicate greater functional impairment. FAQ sum score will be used as a 
continuous variable in the primary objective analysis. 
FAQ was recorded in the BIOCARD data. The FAQ measurement collected closest to the 
flortaucipir scan will be used for the purposes of the correlation analysis.


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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.
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 370 MBq (10 mCi) of flortaucipir injection.
All exposure information will be summarized in a table and presented in a listing.
6.6.1.1
Unit Conversion for Radioactive Dose
All exposure tables and listings will display volume in MBq. Volume collected in mCi 
will be converted to MBq as follows:
mCi
MBq

37
6.6.2
Adverse Events
An AE is any undesirable experience occurring to a subject during a clinical trial, 
whether or not considered related to the study drug. 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, whether or not considered drug related.  For 
the purposes of this study, untoward medical occurrences will be considered associated 
with the use of flortaucipir, and thus be reported as 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 19.1.
Severity is classified as mild/moderate/severe (increasing severity). If a subject reports a 
TEAE more than once within that SOC/PT, the TEAE with the worst case severity will 
be used in the corresponding severity summaries.
Serious AEs (SAEs) are events that result in one of the following outcomes or constitute 
one of the following events:

Death


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                 Statistical Analysis Plan

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


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7
STATISTICAL METHODS
7.1
Definitions and Conventions
All analysis will be performed using SAS version 9.2 or higher.
Data will be summarized using descriptive statistics (number of subjects [n], mean, 
standard deviation [SD], median, minimum [min], and maximum [max]) for continuous 
variables and using frequency count and percentage for discrete variables. Percentages 
will be rounded to one decimal place, except 100% will be displayed without any decimal 
places and percentages will not be displayed for zero counts.
The tables and listings will be numbered using a decimal system to reflect main levels of 
unique tables and listings and sub-levels of replicate tables and the listings with 
maximum two digits per level (e.g., Table XX.YY.ZZ…). Tables will be presented in 
clinical study report (CSR) section 14, and thus will be numbered as 14.YY.ZZ.  Baseline 
analysis will be reported in table series 14.1, efficacy analysis in series 14.2, and safety 
analysis in series 14.3.  Listings will be presented in in CSR section 16, and thus will be 
numbered as 16.YY.ZZ. 
Unless otherwise specified, hypothesis testing will be two-sided with type I error rate of 
0.05.
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.
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 single center study. The pooled data will be analyzed and presented. 
  
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.


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8
STATISTICAL ANALYSIS
8.1
Analysis Populations
8.1.1
Enrolled Population
The enrolled population will consist of all BIOCARD study subjects who have signed the 
consent form for AV-1451-A20 and data exists in the electronic data capture system set 
for this AV-1451-A20.  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 and listed using the safety 
population. All efficacy variables described in section 6.4 will be presented in listings for 
the safety population.
8.1.3
Efficacy Population
The efficacy population will include all subjects with a valid, interpretable baseline PET 
image (visual read and/or 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, completed, and discontinued 
subjects.
Discontinued subjects will be defined as any safety subject who fail to complete the 24-
48 hour safety follow-up. Termination status (i.e. ‘Completed’ and ‘Discontinued’) 
percentages will be based on the safety population. Percentages outlining discontinuation 
reasons will be based on the number of discontinued subjects.


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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, ApoE genotyping, alcohol, drug use, and smoking 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 19.1, and will be 
presented in a listing for the safety population.
8.3.3
Concomitant Therapy 
Concomitant therapies were coded using WHODRUG 3Q 2016. All concomitant 
medications data will be presented in listing.
8.3.4
Pregnancy Test
Pregnancy testing information captured on the case report form (CRF) will be presented 
in a listing for the safety population.
8.3.5
Electrocardiogram
ECG data captured on the CRF will be presented in a listing for the safety population.
8.4
Analysis of Efficacy Parameters
8.4.1
Analysis of Primary Efficacy Variable
8.4.1.1
Qualitative Assessment of Images
The visual read results as described in section 6.4.1.1 will be summarized for the efficacy 
population using descriptive statistics by amyloid status (Aβ+, Aβ-) in a 2x3 table.
8.4.1.2
Quantitative Assessment of Images
The MUBADA SUVr as described in section 6.4.1.2 will be summarized for the efficacy 
population using descriptive statistics by amyloid status (Aβ+, Aβ-).


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8.4.1.3
Correlation between MMSE and MUBADA SUVr in Clinically Normal Subjects
Spearman’s correlation coefficient will be used to measure the relationship between 
baseline MMSE and MUBADA SUVr in clinically normal subjects. This relationship 
will also be presented in a scatter plot.
8.4.1.4
Correlation between FAQ and MUBADA SUVr in Clinically Normal Subjects
The same analysis as described in section 8.4.1.3 will be applied, correlating FAQ with 
MUBADA SUVr.
8.5
Analysis of Safety
8.5.1
Exposure
The total dose administered (MBq) of flortaucipir will be summarized in a table using 
descriptive statistics by imaging visits and collectively, and presented in a listing.
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 will be presented in a listing.
8.5.3
Severity
TEAE severity will be reported in a table in the same manner as outlined in 8.5.2. 
For the summarization of TEAEs by intensity, events recorded with missing intensity 
will be summarized as Severe.  If a subject reports the same AE more than once within 
an SOC/PT, the AE with the worst case severity will be summarized in the table.
8.5.4
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 regarded as
related to flortaucipir. If a subject reports the same AE more than once within an
SOC/PT, the AE most related to flortaucipir will summarized in the table.
8.5.5
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 with a missing relationship to study procedure will be regarded 


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as related to study procedure. If a subject reports the same AE more than once within 
that SOC/PT, the AE with the worst case relationship to study procedure will be used in 
the corresponding relationship summaries.
8.5.6
Serious Adverse Events
Serious TEAEs will be summarized in a similar manner as described in Section 8.5.2.  If 
a subject reported more than one serious TEAE with the same SOC or PT, the TEAE will 
be counted only once in that SOC or PT. For the summarization of TEAEs by 
seriousness, events recorded with missing seriousness will be summarized as Serious.
8.5.7
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.
8.5.8
Adverse Events Leading to Death
TEAEs leading to death will be summarized in a similar manner as described in section 
8.5.2.
8.5.9
Missing and Partial AE Onset Dates
See appendix 1.1 for specific algorithms to impute missing start and stop dates.
8.5.10 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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APPENDIX I: ALGORITHMS TO HANDLE MISSING AND PARTIAL DATES
1.1.MISSING AND PARTIAL AE ONSET AND END DATES
If the AE onset dates are missing, then the most conservative approach will be used to 
decide if the AE is TEAE or not, as detailed in the table below:
AE ONSET 
DATE/TIME
AE STOP 
DATE/TIME
ACTION
Partial, but 
known 
components 
show that it 
cannot be on 
or after an 
injection 
date/time 
and within 
48 hours 
post-
injection
Known
Not TEAE
Partial
Not TEAE
Missing
Not TEAE
Partial, could 
be on or after 
an injection 
date/time 
and within 
48 hours 
post-
injection
Known
If stop date/time < flortaucipir injection date/time, 
then not TEAE
If stop date/time >= flortaucipir injection 
date/time, then TEAE
Partial
Impute stop date as latest possible date (i.e. 59 if 
minutes unknown or 23:59 if hours and minutes 
unknown; last day of month if day unknown or 
31st December if day and month unknown), then:
If stop date/time < flortaucipir injection date/time, 
then not TEAE
If stop date/time >= flortaucipir injection 
date/time, then TEAE
Missing
Assumed TEAE
Missing
Known
If stop date/time < flortaucipir injection date/time, 
then not TEAE
If stop date/time >= flortaucipir injection 
date/time, then TEAE
Partial
Impute stop date as latest possible date (i.e. 59 if 
minutes unknown or 23:59 if hours and minutes 
unknown; last day of month if day unknown or 


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AE ONSET 
DATE/TIME
AE STOP 
DATE/TIME
ACTION
31st December if day and month unknown), then:
If stop date/time < flortaucipir injection date/time, 
then not TEAE
If stop date/time >= flortaucipir injection 
date/time, then TEAE
Missing
Assumed TEAE


Leo Document ID = b9e6f9ff-92af-4092-bb6e-571c13a139ff
Approver: 
Approval Date & Time: 14-Mar-2019 17:30:12 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 14-Mar-2019 18:18:43 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 14-Mar-2019 18:23:12 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 14-Mar-2019 19:08:13 GMT
Signature meaning: Approved