Conditions: Alzheimer Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 155
Healthy volunteers: no

Brief summary:
This protocol is designed to serve as a pre-screening study for subjects who are potentially eligible for Alzheimer's Disease (AD) therapeutic trials that require tau imaging for inclusion by means of a flortaucipir F18 Positron Emission Tomography (PET) scan.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Flortaucipir F18 intervention 2: Brain PET Scan
Intervention descriptions: intervention 1: 370 megabecquerel (MBq) IV single-dose intervention 2: positron emission tomography (PET) scan of the brain

Protocol document:
Prot_000.pdf: 
18F-AV-1451-A23 Protocol 
 
A Multicenter Screening Study With Flortaucipir F 18 in Patients With Early Symptomatic AD 
 
NCT03322462 
Approval date: 11 Sep 2017




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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
Flortaucipir F 18 (18F-
AV-1451)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Title of Study: 18F-AV-1451-A23 
A multicenter screening study with flortaucipir F 18 in patients with early symptomatic AD 
Planned number of subjects (Enrolled): Approximately 500 
Name of compound: flortaucipir F 18 (18F-AV-1451) 
Dose: 370 MBq (10 mCi) 
Route of Administration:  Intravenous (IV) bolus 
Study Phase:  II 
Study Centers: Approximately 15 centers in the United States and Canada 
Trial Objectives:  
 
The primary objective of the protocol is: 
• To pre-screen patients via a flortaucipir F 18 scan, who have objectively verified 
cognitive impairment and etiology diagnosed or suspected to be Alzheimer’s disease 
(AD), and have indicated their interest in participating in Lilly sponsored trials that 
require tau imaging for inclusion such as I5T-MC-AACG (AACG).  
 
The secondary objective of the protocol is: 
• To expand the flortaucipir F 18 safety database.  
 
Eligibility: See Section 5.3, Selection of Patients. 
Study Design: 
Study 18F-AV-1451-A23 is a multicenter screening study in patients with early symptomatic AD 
(where early symptomatic AD refers to the combination of 2 stages: prodromal AD [MCI-AD] 
and mild AD dementia). 
 
All patients will provide informed consent before starting any study procedures. This pre-
screening study targets patients who are interested in participating in AD therapeutic clinical 
trials and have expressed a preliminary interest in a trial like the AACG trial, and who are not 
known to meet any of the exclusion criteria for trials like AACG based on medical history and 
clinical examination. However, consent for this protocol does not constitute consent for the 


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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
Flortaucipir F 18 (18F-
AV-1451)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
AACG trial or any other trials, and subjects who qualify for this protocol may still fail to qualify 
for trials like AACG or other trials based on the results of this protocol or based on additional 
testing performed in those subsequent trials. 
 
Screening assessments will include demographic information, cognitive testing, disease history, 
concomitant medications, vital signs, ECG and medical history. Patients who are deemed 
eligible to continue will complete a flortaucipir F 18 PET scan.  
 
Patients who meet eligibility criteria will participate in this protocol until they have completed 
their flortaucipir F 18 PET scan, or they discontinue, withdraw consent, or if the sponsor 
decides to end this protocol early. 
Details of the assessments that will be performed at each visit are detailed in Section 7.1.  
The following will be completed: 
• Informed consent for patient; 
• Demographics (age, gender, years of education, race, ethnicity); weight 
• Medical history, concomitant medications; 
• Vital Signs (pulse, respiratory rate, supine blood pressure); 
• 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.  
• ApoE status, if available; 
• Disease history (date/months since symptom onset, date/months since diagnosis, 
family history of relevant neurologic disease); 
• Cognitive status interview, including MMSE;  
• A physician will see the patient during the screening visit. 
• For women of childbearing potential, a negative serum pregnancy test must be 
obtained at the screening visit 
Statistical Methods:   
Descriptive analyses will be applied to summarize patients’ demographic and baseline 
characteristics, and qualitative and quantitative assessments of the flortaucipir F 18 PET image.  


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TABLE OF CONTENTS 
1. 
INTRODUCTION .............................................................................. 9 
2. 
STUDY OBJECTIVES .................................................................... 11 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 12 
4. 
TEST DRUG AND CONTROL AGENTS ...................................... 13 
4.1. 
Descriptive Name:  18F AV-1451 ..................................................... 13 
4.2. 
Radioactive Labeling ........................................................................ 13 
4.3. 
Decay Characteristics ....................................................................... 13 
4.4. 
Packaging flortaucipir F 18 Injection ................................................ 13 
4.5. 
Storage and Handling flortaucipir F 18 Injection ............................. 13 
5. 
INVESTIGATIONAL PLAN ........................................................... 14 
5.1. 
Overall Design and Plan of the Study ............................................... 14 
5.2. 
Planned Dosage and Duration of Treatment ..................................... 14 
5.2.1. 
Flortaucipir F 18 Dosage and Administration .................................. 14 
5.2.2. 
Rationale for Dosages ....................................................................... 14 
5.3. 
Selection of Subjects ......................................................................... 15 
5.3.1. 
Inclusion Criteria .............................................................................. 15 
5.3.2. 
Exclusion Criteria ............................................................................. 15 
5.4. 
Prior and Concomitant Therapy ........................................................ 17 
5.5. 
Removal of Subjects from Study ...................................................... 17 
5.6. 
Premature Termination of Study/Closure of Center ......................... 17 
6. 
WARNINGS/PRECAUTIONS ........................................................ 19 
7. 
PROCEDURES AND METHODS .................................................. 20 
7.1. 
Assessment Periods .......................................................................... 20 
7.1.1. 
Screening Visit: ................................................................................ 20 
7.1.2. 
Imaging Visit .................................................................................... 20 
7.2. 
Observations and Measurements ...................................................... 21 
7.3. 
Protocol for Image Collection .......................................................... 23 
7.4. 
Good Clinical Practice and Monitoring ............................................ 23 
7.5. 
Informed Consent and Subject Information ..................................... 24 
7.6. 
Documentation .................................................................................. 24 
7.7. 
Adverse Events (AE) ........................................................................ 24 


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7.7.1. 
Adverse Event Monitoring ............................................................... 25 
7.7.2. 
Adverse Event Definitions ................................................................ 25 
7.7.3. 
Adverse Event Documentation ......................................................... 27 
7.7.4. 
Reporting of Serious Adverse Events ............................................... 27 
8. 
STATISTICAL ANALYSIS ............................................................ 28 
8.1. 
General Statistical Considerations .................................................... 28 
8.1.1. 
Population for Analysis .................................................................... 28 
8.2. 
Analysis ............................................................................................ 28 
9. 
USE OF DATA AND PUBLICATION ........................................... 29 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................. 30 
10.1. 
Institutional Review Board (IRB) ..................................................... 30 
10.2. 
Informed Consent ............................................................................. 30 
10.3. 
Protocol Adherence .......................................................................... 30 
10.4. 
Documents Necessary for Initiation of the Study ............................. 30 
10.5. 
Investigational Product Control ........................................................ 30 
10.6. 
Data Collection ................................................................................. 31 
10.7. 
Adverse Events ................................................................................. 31 
10.8. 
Records Retention ............................................................................. 32 
11. 
APPENDICES .................................................................................. 33 
11.1. 
References ......................................................................................... 33 
11.2. 
Study Flow Chart .............................................................................. 35 
12. 
INVESTIGATOR’S AGREEMENT TO PROTOCOL ................... 36 


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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AChEI 
Acetylcholinesterase inhibitor  
AD 
Alzheimer’s disease 
ADRs 
Adverse Drug Reactions 
Adverse Event 
(AE) 
Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. 
Audit 
A systematic and independent examination of the trial-related activities 
and documents to determine whether the evaluated trial-related activities 
were conducted, and the data were recorded, analyzed, and accurately 
reported according to the protocol, applicable standard operating 
procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s). 
Case Report Form 
(CRF) and 
electronic Case 
Report Form 
(eCRF) 
A printed or electronic form for recording study participants’ data during 
a clinical study, as required by the protocol. 
CNS 
Central Nervous System 
CRO 
Contract Research Organization: A person or organization (commercial, 
academic, or other) contracted by the sponsor to perform one or more of 
the sponsor’s trial-related duties and functions.  
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
US Food and Drug Administration  
FDG 
18F – Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


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ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug  
Institutional 
Review Board 
/Independent 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
the safety, welfare and human rights of the subjects participating in a 
clinical study are protected. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
IV 
Intravenous 
Kd 
Dissociation Constant 
keV 
Kiloelectron volt  
LAR 
Legally Authorized Representative 
MBq 
Megabecquerel 
mCi 
Millicurie 
MCI 
Mild Cognitive Impairment 
MHD 
Maximum Human Dose 
MMSE 
Mini Mental Status Exam 
MRI 
Magnetic Resonance Imaging 
mSv 
Millisievert  
NDA 
New Drug Application 
nM 
Nanometer  
NOAEL 
No Observable Adverse Effect Level 
PET 
Positron Emission Tomography 
PhRMA 
Pharmaceutical Research and Manufacturers of America  


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SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedures  


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1. 
INTRODUCTION  
Molecular imaging biomarkers have the potential to aid in the diagnosis of patients with 
cognitive impairment who are being evaluated for Alzheimer’s disease (AD) (Dubois, 
2010; McKhann, 2011).  Positron emission tomography (PET) ligands such as florbetapir 
F 18 (Wong, 2010) may provide a minimally invasive estimate of cortical beta amyloid 
(Aβ) neuritic plaque deposition, a hallmark pathology, and a required element for the 
evaluation of AD neuropathologic diagnosis (Hyman 2012).  Multiple studies comparing 
amyloid PET scans to histopathologic assessment of amyloid burden, in subjects for 
whom biopsy samples were available or who came to autopsy after receiving a PET 
amyloid scan, support the relationship between PET amyloid imaging results and cortical 
neuritic plaque density (Clark 2011, 2012; Leinonen, 2008; Sojkova, 2011; Kantarci, 
2011; Burack, 2010).  The largest of these studies (Clark 2012) demonstrated a high 
sensitivity and specificity for florbetapir PET to discriminate subjects with subsequent 
autopsy findings of no or sparse neuritic plaques (amyloid negative) from those with 
moderate to frequent plaques (amyloid positive). 
The ability to image brain amyloid with compounds such as florbetapir is an important 
advance for diagnosis of neurological disease.  An amyloid negative florbetapir PET scan 
indicates the absence of a hallmark pathology and is inconsistent with a diagnosis of AD.  
However, because amyloid is believed to accumulate very early in the disease process 
(Jack et al., 2010) and may be present in other diseases or in clinically normal elderly 
subjects (Sperling et al. 2011; Price and Morris, 1999), the density or distribution of 
amyloid in subjects with a positive scan is not associated with Alzheimer’s disease 
severity, has not been established to predict rate of future deterioration and has not been 
established as a tool to predict or monitor response to therapy. 
In contrast to Aβ neuritic plaques, the density and distribution of phosphorylated tau, 
aggregated in neurofibrillary tangles, increases with AD-related cognitive impairment 
and correlates with neurodegeneration (Dickson et al., 1997; Duyckaerts et a., 1987).  
Thus, a PET imaging agent that binds to phosphorylated tau has potential application as a 
biomarker for disease severity/neurodegeneration and may be useful both for selecting 
patients for therapy and for monitoring disease progression in therapeutic trials. 
Flortaucipir F 18 (18F-AV-1451) (originally named [F-18]T807 by Siemens Molecular 
Imaging Biomarker Research group) has been developed as a positron emitting 
radiopharmaceutical for in vivo imaging of tau protein aggregates (Xia et al., 2013).  
Autoradiography results using tissue sections from human brains showed a strong signal 
in the grey matter of cortical slices from tau positive brains but weak or no binding in tau 
negative, Aβ positive, or tau and Aβ negative tissue.  Scatchard analysis based on this 
heterogeneous autoradiography assay yielded an estimated Kd of 15nM. A saturation 
binding experiment using purified Paired Helical Fragment Tau isolated brains of AD 
patients yielded a Kd value of 0.54 nM. 
An updated summary of preclinical and clinical experience pertaining to the 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 


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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 the risk of QT prolongation is not included in the risk profile.   
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. 
Image assessment showed tracer deposition on brain PET scans to be consistent with that 
expected for a tracer of aggregated tau protein. Flortaucipir (18F) initially entered the 
brain and was subsequently eliminated from the brain in clinically normal and amyloid 
negative cognitively impaired subjects, yielding only a diffuse pattern of background 
activity, whereas a regionally distinct gray matter distribution of increased tracer 
retention was observed in amyloid positive cognitively impaired subjects (Pontecorvo et 
al., 2017).  Preliminary analyses of our Phase II longitudinal study (A05, exploratory 
cohort) also indicate a relationship between the level and pattern of flortaucipir uptake at 
baseline, and the rate of decline on cognitive tests over an 18 month period (Mintun, 
AAIC 2017).  These results suggest that it may be possible to use flortaucipir PET scans 
to enrich clinical studies for subjects with a desired level of AD pathology and a more 
homogeneous rate of cognitive decline, thus increasing power to detect a treatment effect. 
Specifically, Lilly and Avid desire to conduct treatment trials at the earliest stage of AD 
neuropathology to maximize potential patient benefit.   
AACG is a proposed anti-amyloid trial that intends to target patients with a certain 
distribution and density of tau neurofibrillary tangles that are hypothesized to be 
appropriate for such a trial. It is thought that patients with no tau will progress so slowly 
that a clinical treatment effect could not be discerned, and those with a large tau burden 
may not be responsive to anti-amyloid therapy as their cognitive impairment is driven 
primarily by tau pathology.  The overarching goal of this protocol is to test this 
hypothesis by pre-screening patients with flortaucipir F 18 who have been diagnosed with 
suspected Alzheimer’s disease and have indicated their interest to consider participation 
in trials such as the AACG Lilly therapeutic clinical trial.  
  


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2. 
STUDY OBJECTIVES  
The primary objective is to pre-screen patients via a flortaucipir F 18 scan, who have 
objectively verified cognitive impairment and etiology diagnosed or suspected to be 
Alzheimer’s disease, and have indicated their interest in participating in Lilly sponsored 
trials that require tau imaging for inclusion such as I5T-MC-AACG (AACG).  
 
The secondary objective of the study is to expand the flortaucipir F 18 safety database.  


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3. 
SPONSOR, INVESTIGATOR(S) AND OTHER 
PARTICIPANTS 
The study is sponsored by: 
Avid Radiopharmaceuticals, Inc. 
 
The medical contact is: 
 
Approximately 15 centers in the United States and Canada will participate. 


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4. 
TEST DRUG AND CONTROL AGENTS  
4.1. 
Descriptive Name:  18F AV-1451 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole 
 
MW = 262.27 amu 
4.2. 
Radioactive Labeling 
The compounds are labeled with [18F] fluorine that decays by positron (β+) emission and 
has a half-life of 109.77 min.  The principal photons useful for diagnostic imaging are the 
511 keV gamma photons, resulting from the interaction of the emitted positron with an 
electron. 
4.3. 
Decay Characteristics 
The time course of radioactive decay for Fluorine [18F] is shown below 
Min. 
Fraction Remaining 
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
Physical decay chart for Fluorine [18F].  Half-life = 109.77 min. 
4.4. 
Packaging flortaucipir F 18 Injection 
Each package of flortaucipir F 18 Injection includes a sterile apyrogenic sealed glass vial 
or sterile apyrogenic syringe containing flortaucipir F 18 Injection, a surrounding 
protective lead shield canister, and an outside delivery case. 
4.5. 
Storage and Handling flortaucipir F 18 Injection 
Flortaucipir F 18 Injection is stored at room temperature. Flortaucipir F 18 Injection 
should be stored within the original container or equivalent radiation shielding.   


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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Design and Plan of the Study 
 
Study 18F-AV-1451-A23 is a multicenter screening study in patients with early 
symptomatic AD (where early symptomatic AD refers to the combination of 2 stages: 
prodromal AD [MCI-AD] and mild AD dementia). 
 
All patients will provide informed consent before starting any study procedures. This pre-
screening study targets patients who are interested in participating in AD therapeutic 
clinical trials and have expressed a preliminary interest in a trial like the AACG trial, and 
who are not known to meet any of the exclusion criteria for trials like AACG based on 
medical history and clinical examination. However, consent for this protocol does not 
constitute consent for the AACG trial or any other trials, and subjects who qualify for this 
protocol may still fail to qualify for trials like AACG or other trials based on the results 
of this protocol or based on additional testing performed in those subsequent trials. 
 
Screening assessments will include demographic information, cognitive testing, disease 
history, concomitant medications, vital signs, ECG and medical history. Patients who are 
deemed eligible to continue will complete a flortaucipir F 18 PET scan.  
 
Patients who meet eligibility criteria will participate in this protocol until they have 
completed their flortaucipir F 18 PET scan, or they discontinue, withdraw consent, or if 
the sponsor decides to end this protocol early.. 
5.2. 
Planned Dosage and Duration of Treatment 
5.2.1. 
Flortaucipir F 18 Dosage and Administration 
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 
mCi) of flortaucipir F 18 Injection. 
5.2.2. 
Rationale for Dosages  
Flortaucipir F 18 will be administered IV in a radioactive dose of 370 MBq (10mCi) 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 8.70 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable to 
the effective dose of approved 18F-labeled compounds such as FDG and florbetapir F 18 
injection. 
The proposed dose has been shown to have acceptable image quality in 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 
Patients must meet the following criteria to enroll in this study: 
1. Men or women, at least 60 to 85 years of age at the time of consent; 
2. Patients with gradual and progressive change in memory function for ≥6 months; 
3. Patients who have a Mini Mental State Examination (MMSE) score between 20-
27 inclusive;  
4. Patients who are willing to undergo a PET scan using flortaucipir F 18;  
5. Patients who give informed consent or have a legally authorized representative 
(LAR) to consent for enrollment; and 
5.3.2. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible to enroll: 
1. Patients who lack, in the investigator’s opinion, adequate premorbid literacy, 
adequate vision, or adequate hearing to complete the required psychometric 
testing; 
2. 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 screening 
and negative urine β-HCG prior to flortaucipir F 18 injection) or breastfeeding at 
screening. Females should agree to avoid becoming pregnant by refraining from 
sexual activity or using reliable contraceptive methods for 24 hours following 
administration of flortaucipir F 18 injection; 
3. Have significant neurological disease affecting the CNS, other than AD, that may 
affect cognition or ability to complete the study, including but not limited to, 
other dementias, serious infection of the brain, Parkinson’s disease, multiple 
concussions, or epilepsy or recurrent seizures (except febrile childhood seizures);     
4. Patients with any current primary psychiatric diagnosis other than AD if, in the 
judgment of the investigator, the psychiatric disorder or symptom is likely to 
confound interpretation of drug effect, affect cognitive assessment, or affect the 
patient’s ability to complete the study [Patients with history of schizophrenia or 
other chronic psychosis are excluded.]; 
5. Intend to use drugs known to significantly prolong the QT interval within 14 days 
or 5 half-lives, whichever is longer, of a scheduled screening/baseline flortaucipir 
F 18 PET scan, or have medical history of risk factors for Torsades de Pointes.  
6. Have an average ECG corrected QT (QTcF) interval measurement >450 msec 
(men) or >470 msec (women) at screening (as determined at the investigational 
site).  


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7. Have ocular pathology that significantly limits ability to reliably evaluate vision 
or the retina; 
8. Have a history of alcohol or drug disorder (except tobacco use disorder) within 2 
years before the screening visit; 
9. Have a current serious or unstable illnesses including retinal, cardiovascular, 
hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic (other 
than AD), psychiatric, immunologic, or hematologic disease and other conditions 
that, in the investigator’s opinion, could interfere with the analyses in this study; 
or has a life expectancy of <24 months;  
10. Has a history of cancer within the last 5 years, with the exception of non-
metastatic basal and/or squamous cell carcinoma of the skin, in situ cervical 
cancer, non-progressive prostate cancer, or other cancers with low risk of 
recurrence or spread; 
11. Patients with a past history (suspected or confirmed) of Hepatitis B or Hepatitis 
C;   
12. History of vitiligo and/or current evidence of post-inflammatory 
hypopigmentation; 
13. Have had prior treatment with a passive anti-amyloid immunotherapy <5 half-
lives prior to randomization; 
14. Have previously participated in any other study investigating active immunization 
against Aβ;  
15. Patients that are currently enrolled in any other interventional clinical trial 
involving an investigational product or any other type of medical research judged 
not to be scientifically or medically compatible with this study 
16. Contraindication to PET; 
17. Has hypersensitivity to flortaucipir F 18 or any of its excipients; 
18. Present or planned exposure to ionizing radiation that, in combination with the 
planned administration of study PET ligands, would result in a cumulative 
exposure that exceeds local recommended exposure limits; 
19. Has previous MRI evidence of significant abnormality that would suggest another 
potential etiology for progressive dementia or a clinically significant finding that 
may impact the patient’s ability to safely participate in the study;  
20. Have any contraindications for MRI, including claustrophobia or the presence of 
contraindicated metal (ferromagnetic) implants/cardiac pacemaker; 
21. Have poor venous access;  
22. Are investigator site personnel directly affiliated with this study and/or their 
immediate families; immediate family is defined as spouse, parent, child, or 
sibling whether biological or legally adopted; 


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23. Are Lilly employees or are employees of third-party organizations (TPOs) 
involved in a study that requires exclusion of their employees; 
24. In the opinion of the investigator, are otherwise unsuitable for a study of this type. 
Prior/Concomitant Therapy 
25. Have received treatment with a stable dose of an acetylcholinesterase inhibitor 
(AChEI) and/or memantine for less than 2 months before randomization [If a 
patient has recently stopped an AChEI and/or memantine, he or she must have 
discontinued treatment at least 2 months before randomization.]. 
26. Current use of strong inducers of CYP3A; 
27. Are currently on medication(s) known to significantly prolong the QT interval;  
28. Have allergies to either monoclonal antibodies, diphenhydramine, epinephrine, or 
methylprednisolone; 
29. Have known allergies to LY3002813, related compounds, or any components of 
the formulation; or history of significant atopy;  
30. Have known allergies to LY3202626, related compounds, or any components of 
the formulation; 
31. Changes in concomitant medications that could potentially affect cognition and 
their dosing should be stable for at least 1 month before screening, and between 
screening and randomization (does not apply to medications discontinued due to 
exclusions or with limited duration of use, such as antibiotics). 
5.4. 
Prior and Concomitant Therapy 
All medications that are continued from the start of the study or that are started during the 
study (other than the study medication) must be documented in the case record form on 
the Concomitant Medication Page of the Case Record Form (CRF). 
5.5. 
Removal of Subjects from Study 
Subjects must be removed from the study 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 study. 
Subjects may be withdrawn from the study if a serious adverse event occurs.  The date 
and reason for discontinuation should be noted on the CRF. Subjects who discontinue 
prematurely should be seen for a final evaluation.  
5.6. 
Premature Termination of Study/Closure of Center 
The sponsor may discontinue the pre-screener at any time.  Reasons for discontinuation 
may include, but are not limited to requests from regulatory authorities, safety or changes 
in business priorities.  Reasons for center closure may include, but are not limited to, 


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excessive protocol violations, inadequate regard for patient safety, failure to follow 
recommended procedures (e.g., documentation), failure or inability to accommodate 
Avid/Contract Research Organization (CRO) or to provide required access to data and 
source documents, staff turnover, inadequate staffing, and inadequate enrollment.   


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6. 
WARNINGS/PRECAUTIONS 
The most up-to-date and complete information regarding the use of flortaucipir F 18 
injection can be found in the investigator's brochure.  
In brief, flortaucipir F 18 injection is an experimental imaging agent that will be used at 
relatively low (tracer) doses.  Because flortaucipir F 18 injection is under clinical 
investigation, it is recommended that subjects receiving flortaucipir F 18 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, Study Flow Charts. 
7.1.1. 
Screening Visit:  
Screening may take place over several days. All screening assessments will be performed 
within 30 days prior to flortaucipir F 18 injection. 
Screening assessments will include: 
• Informed consent for patient; 
• Demographics (age, gender, years of education, race, ethnicity); weight;  
• Medical history, concomitant medications; 
• Vital Signs (pulse, respiration rate, supine blood pressure) 
• 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. ApoE status, if available; 
• Disease history (date/months since symptom onset, date/months since 
diagnosis, family history of relevant neurologic disease); 
• Cognitive status interview, including MMSE;  
• A physician will see the patient during the screening visit. 
• For women of childbearing potential, a negative serum pregnancy test must be 
obtained at the screening visit 
7.1.2. 
Imaging Visit  
Flortaucipir F 18 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 F 18 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 (HCG) 
must be obtained in advance of flortaucipir F 18 dose administration; 
• Subjects will receive a single IV bolus injection target dose of 370 MBq (10 
mCi) of flortaucipir F 18 injection followed by a saline flush. The volume of 
flortaucipir F 18 dose may be adjusted by adding normal saline to the syringe 
per the Investigator’s Brochure.  


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• 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 at the injection site; 
• Adverse events will be continuously monitored during the flortaucipir F 18 
PET imaging visit. Subjects who experience an adverse event will not be 
discharged from the imaging center until the event has resolved or stabilized;  
• A physician or a licensed/credentialed medical professional (i.e., a PET 
technologist, imaging center nurse or a regional equivalent) designated by the 
site principal investigator must assess or evaluate the subject prior to 
discharge from the imaging center to evaluate the subject’s readiness for 
discharge. If a designee performs this activity, a physician must be available 
to provide medical consultation; 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 patients and their LAR, if applicable, will be allowed to read a written informed 
consent form.  The principal investigator, or designee, will explain all procedures, risks, 
and alternatives to the patient and LAR, if applicable. The patient and LAR, if applicable, 
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 
pre-screener (see Section 7.5). A copy of the signed informed consent will be given to the 
patient and study partners.  
 
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 physician or designee will obtain an updated history at the screening visit. 
• Relevant demographic information  
• Diagnosis 
• Review of body systems 
• Social history 
• Medical and surgical history 


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• History/results of genetic testing relevant to AD 
• Concurrent medications 
Whenever possible, the medical history will be confirmed by medical records. 
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 center nurse 
or a regional equivalent) designated by the site principal investigator must assess or 
evaluate the subject prior to administration of flortaucipir F 18 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.  
Women not of childbearing potential are defined as those who are: 
a. Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), 
b. Post-menopausal – defined as either 
i. A woman 55 or older not on hormone therapy, who 
has had at least 6 months of spontaneous amenorrhea; 
or 
ii. A woman at least 55 years of age with a diagnosis of 
menopause prior to starting hormone replacement 
therapy.  
Urine beta hCG: performed at the flortaucipir F 18 imaging visit prior to injection for 
females of childbearing potential (defined as pre-menopausal, less than 2 years post-
menopausal or not surgically sterile). 
 
Mini-Mental State Examination (MMSE)  
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive function 
in elderly patients.  The instrument is divided into 2 sections.  The first section measures 
orientation, memory, and attention.  The maximum score for the first section is 21.  The 
second section tests the ability of the patient to name objects, follow verbal and written 
commands, write a sentence, and copy figures.  The maximum score for the second 
section is 9.  The range for the total MMSE score is 0 to 30.  For inclusion in this study, 
patients should have an MMSE score between 20-27 (inclusive).  
Electrocardiogram (ECG) 


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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. 
Vital Signs 
Vital signs (pulse rate, respiratory rate, supine blood pressure) will be taken at the 
Screening Visit. Weight will be measured, lightly clothed during the imaging visit.   
 
Protocol for Image Collection 
 
An imaging manual will be created for the flortaucipir F 18 PET scan procedures and 
distributed to participating imaging centers prior to site initiation.   
 
Required scan data sets and transmission instructions will be provided to the PET centers 
for all scans acquired under this protocol.  
 
PET scan images must be de-identified and assigned a unique patient number prior to 
submission to Avid. 
Feedback regarding the flortaucpir F 18 scan will be provided to the investigator.   
7.3. 
Protocol for Image Collection 
The sponsor will prepare and distribute a PET Imaging Manual for flortaucipir F 18 
imaging.  
7.4. 
Good Clinical Practice and Monitoring 
All clinical studies performed under the direction of Avid/CRO will be conducted in 
accordance with applicable regulatory requirements and International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) and Avid/CRO Standard Operating 
Procedures (SOP).  
This includes: 
1. IRB/IEC approval:  An investigation will be initiated at a study site only after the 
IRB/IEC for that study site has given their written approval of the protocol and 
informed consent;    
2. Informed Consent:  Study procedures will not be initiated until the subject and/or 
their legally authorized representative (as appropriate) signs the informed consent 
form;   
3. Recording and monitoring of adverse events as outlined in Section 7.7.3 including 
the notification of study site clinical investigators, local IRBs and the FDA 
regarding serious adverse event; 
4. Avid RP’s obligation to monitor the participating center on a regular basis; and 
5. The termination of a center or the study if conditions apply, as outlined in Section 
5.6. 


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7.5. 
Informed Consent and Subject Information 
Potential subjects, or their legally authorized representative (as appropriate), will be 
allowed to read a written informed consent form.  The principal investigator or designee 
will explain all study procedures, risks, and alternative therapies.  The subject and legally 
authorized representative will have an opportunity to have all questions answered by a 
physician.  The subject will then sign and date the informed consent form, indicating 
willingness to participate in the study. 
Subjects with AD are potentially a vulnerable population with compromised mental 
capacity.  Investigators should take extra care to evaluate a patient’s ability to give 
consent.  If the subject is capable of giving informed consent then the subject should sign 
on the consent line of the informed consent form.  When applicable the legally authorized 
representative should sign as well, indicating that they have witnessed the subject’s 
consent. 
If the subject is not capable of giving consent, consent may be given by a legally 
authorized representative.  However, it is expected that all subjects entering this study 
should at least have the capacity to understand that they are engaging in a research study 
and should affirm that they do not object to participating, by signing on the Subject 
Assent line of the consent form.   
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB).  No study related procedures shall be 
performed prior to completion of the informed consent process, and signing of the 
consent form.  A copy of the signed informed consent should be given to the patient 
and/or their legally authorized representative for their records. 
7.6. 
Documentation 
Flortaucipir F 18 PET scans will be saved in an appropriate electronic format as specified 
in the imaging manuals.  A copy of all scans will be saved at the site/imaging center and 
a copy of each will be forwarded to Avid as 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 patient’s medical files, 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. 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 


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designee, via electronic data entry the circumstances and data leading to any such 
discontinuation of treatment. In cases where the investigator notices an unanticipated 
benefit to the patient, study site personnel should report “unexpected benefit” with the 
actual event term to Avid, or its designee (for example, the complete actual term would 
be “unexpected benefit- sleeping longer”). 
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/or 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 F 18, and thus be reported as treatment-emergent adverse events, if they 
occur within 48 hours after flortaucipir F 18 administration.  
The end of study, for the purpose of adverse event reporting, is defined as 48 hours after 
the last administration of flortaucipir F 18. 
Serious Adverse Event (SAE) 
A SAE is an AE that results in one of the following outcomes or constitutes one of the 
following events: 


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• 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: 
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. 


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7.7.3. 
Adverse Event Documentation 
All adverse events must be fully recorded on the Adverse Event Page via the Electronic 
Data Capture (EDC) system.  Documentation must be supported by an entry in the 
subject file.  Laboratory test, vital signs and ECG abnormalities considered by the 
Investigator to be clinically relevant should be reported on the Adverse Event page of the 
eCRF.  Signs and symptoms of each AE should be described in detail (e.g., start and stop 
dates, severity/intensity, relationship to investigational product, action taken, and 
outcome). 
Adverse events 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 Lilly or its designee of any SAE within 24 hours of their 
awareness of the event via a sponsor-approved method.  Alerts issued via telephone are to 
be immediately followed with official notification on study-specific SAE forms.  
Serious adverse events occurring after a subject receive a dose of investigational product 
will be collected until 48 hours after the  dosing of the investigational product, regardless 
of the investigator’s opinion of causation.  Therefore, SAEs that occur later than 48 hours 
after the dosing of the investigational product are not required to be reported unless the 
investigator feels the events were related to either investigational product or a protocol 
procedure. 
If a patient experiences an SAE after signing informed consent, but prior to receiving 
investigational product, the event will NOT be reported unless the investigator feels the 
event may have been caused by a protocol procedure.  Previously planned (prior to 
signing the ICF) surgeries should not be reported as SAEs unless the underlying medical 
condition has worsened during the course of the study. 


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8. 
STATISTICAL ANALYSIS  
8.1. 
General Statistical Considerations 
Patients’ demographic and baseline characteristics data will be summarized using 
descriptive statistics (number of patients [N], mean, standard deviation [SD], median, 
quartiles, minimum, and maximum) for continuous variables and using frequency count 
and percentage for discrete variables.  
Patient listings of all data from the eCRFs as well as any derived variables will be 
presented. 
8.1.1. 
Population for Analysis 
The safety analysis population will include all eligible patients who enroll in 18F-AV-
1451-A23 (A23) and have received at least one dose of flortaucipir F 18 injection. 
Efficacy analysis population will include all subjects in safety population, and with a 
valid flortaucipir F 18 scan assessment (quantitative and/or qualitative). 
8.2. 
Analysis 
Descriptive analyses will be applied to summarize patients’ demographic and baseline 
characteristics, and qualitative and quantitative assessments of the flortaucipir F 18 PET 
image. 
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. 
 


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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).  Our policy is briefly summarized below: 
•
We commit to timely communication of meaningful results of controlled
clinical trials, regardless of outcome.
•
As a sponsor, we may recommend that the Investigator(s) delay or decline
publication in cases where the study design, conduct, or data are insufficient
to allow meaningful interpretation.  Avid and the Investigator(s) will discuss
the study design and data in advance of the study, and again after completion,
and will strive, through appropriate scientific debate, to reach a consensus
regarding the potential merits of publication.
•
Avid retains the right to review any manuscripts, presentations, or abstracts
before they are submitted for publication. Where differences of opinion or
interpretation exist regarding data planned for publication, the parties (Avid
and the Investigator) should try to resolve them through appropriate scientific
debate.  Avid retains the right to delay publication for up to 60 days to protect
intellectual property.
•
Anyone who provides substantial contributions should receive appropriate
recognition as an author or contributor when the manuscript is published.
This is a multi-center study. The primary analysis will include data from all centers.  A 
multicenter publication, reporting the primary analysis data set, with authorship from all 
contributing centers, should precede any other publications. 


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10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
All clinical work conducted under this protocol is subject to Good Clinical Practice 
regulations; this may include an inspection by Avid and/or Health Authority 
representatives (FDA, EMA or international regulatory authorities) at any time. 
10.1. 
Institutional Review Board (IRB) 
The intent of the research program, the trial protocol, the patient information/informed 
consent form and any advertising material used to recruit subjects must be submitted to 
the clinical investigator’s local IRB/IEC and its approval must be obtained prior to its 
use.  A copy of the approval must be forwarded to Avid.  When necessary, an extension 
or renewal of IRB/IEC approval must be obtained and also forwarded to Avid. 
10.2. 
 Informed Consent 
A signed, written informed consent must be obtained from each patient.  A copy of the 
signed informed consent should be given to the patient for their records.  A copy of the 
local IRB/IEC’s approved version of the informed consent form must be forwarded to 
Avid or designee for review prior to being used to obtain patient consent. 
10.3. 
 Protocol Adherence 
The protocol must be read thoroughly and the instructions must be followed exactly.  
Where a deviation occurs, it must be documented, the sponsor/monitor informed, and a 
course of action agreed upon. 
10.4. 
 Documents Necessary for Initiation of the Study 
Avid must be provided with the following documents prior to the enrollment of any 
subjects: 
• Original signed and dated Statement of Agreement page; 
• Copy of the IRB/IEC and radiation safety committee approval (if applicable); 
• Copy of the IRB/IEC stamped approved consent form; 
• Name and location of the laboratory utilized for laboratory assays, and other 
facilities conducting tests, including laboratory certification number and date 
of certification if available.  Avid may be responsible for supplying these to 
the investigator if a central laboratory is used;  
• List of reference range laboratory values.  Avid may be responsible for this if 
a central laboratory is used; and 
• Any additional licenses required in order to order flortaucipir F 18. 
10.5. 
Investigational Product Control 
The receipt of clinical supplies (i.e. starting material for flortaucipir F 18) must be 
documented at the site. 


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All drug supplies for this trial should be retained in a safe and secure place at all times 
during the trial. Flortaucipir F 18Injection should be prepared by a qualified PET 
manufacturing site and administered by a qualified individual under the investigator’s 
supervision.  An up-to-date drug inventory/dispensing record must be maintained.  All 
drug supplies must be accounted for.  After completion of the trial, all remaining clinical 
supplies must be returned to the sponsor or their representative.   
10.6. 
Data Collection 
Electronic case report forms (eCRFs) will be used for this study.  Individual patient files 
should include appropriate source documents, including but not limited to patient’s 
medical records and laboratory test results.  The files should include information such as 
visit dates, records of medical history, examinations administered, laboratory, 
concomitant treatment, any adverse event encountered and other notes as appropriate.  
These constitute “source data”.  All entries on the eCRFs must be backed up by source 
data.  Original electronic versions of imaging studies are also considered source data and 
should be kept on file by the site/imaging center, and appropriate copies should be 
forwarded to Avid or a designated Imaging Core Lab as specified in the Imaging Manual.   
Each patient’s source file should include an original signed informed consent form.  
When the study is completed, the informed consent form should be kept on file with other 
study 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 study.  The eCRFs must be completed 
for each patient enrolled in the study and signed by the investigator.  This should be done 
as soon as possible after completion of the patient’s participation in the study.  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. 
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. Lilly 
must be notified immediately of any findings with the use of the drug that may suggest 
significant hazards, contraindications, adverse drug reactions (ADRs) and precautions 
pertinent to the safety of the drug.  The investigator will be requested to complete a 
separate report form in addition to the information on the CRF.  See section 7.7.4 for 
reporting serious adverse events 
If an SAE is determined to be unexpected (not previously reported or described by Avid), 
and study drug-related, Lilly will notify the investigator in writing.  The investigator 
should forward this notification to the IRB/IEC within 24 hours of receipt. 


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10.8. 
Records Retention 
All correspondence (e.g., with Avid, IRB/IEC, etc.) relating to this study should be kept 
in appropriate file folders.  Records of subjects, source documents, and drug inventory 
sheets pertaining to the study must be kept on file.  Records must be retained until the 
date a marketing application (NDA) is approved for the drug for the indication for which 
it is being investigated, or until 3 years following the date of clinical study termination or 
completion, whichever is later.   If no application is to be filed or if the application is not 
approved for such indication, records should be kept until 3 years following the date of 
clinical study termination or completion. 
If an investigator moves, withdraws from an investigation, or retires, the responsibility 
for maintaining the records may be transferred to another person who will accept the 
responsibility.  Notice of transfer must be made to and agreed upon by Avid. 


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11. 
APPENDICES 
11.1. 
References 
Alaka K, Campbell G, Fleisher A, Hake A, Irizarry M, Miller B, Pontecorvo M, Siemers 
E, Sims J, Yaari R.  The nosology of Alzheimer’s disease and application of concepts to 
amyloid-targeting treatments:  an internal summary of Lilly thinking.  White Paper.  
2015.  
Albert, M. S., DeKosky, S. T., Dickson, D., et al. “The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging and Alzheimer’s Association workgroup.”  The Alzheimer’s Association. 
Alzheimer’s and Dementia, 1-10, 2011. 
Burack, M.A., Hartlein, J., Flores, H.P., Taylor-Reinwald, L., Perlmutter, J.S., Cairns, 
N.J. “In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia”. 
Neurology. 2010;74(1):77-84. 
Chien, D.T., Bahri, S., Szardenings, A.K., Walsh, J.C., Mu, F., Su, M.Y., Shankle, W.R., 
Elizarov, A., Kolb, H.C., “Early clinical PET imaging results with the novel PHF-tau 
radioligand [18F]-T807.” J Alzheimers Dis, 2013 Jan 1l34(2):467-68 
Clark, C.M., Pontecorvo, M.J., Beach, T.G., Bedell, B.J., Coleman, R.E., Doraiswamy, 
P.M., Fleisher, A.S., Reiman, P.E.M., Sabbagh, M.N., Sadowsky, C.H., Schneider, J.A., 
Arora, A.,  Carpenter, A.P., Flitter. M.L., Joshi, A.D., Krautkramer, M.J., Lu, M., 
Mintun, M.A., Skovronsky, D.M.  “Florbetapir PET for Detection of Amyloid Neuritic 
Plaques, Comparison to Neuropathology at Autopsy: A Prospective Cohort Study.”  The 
Lancet Neurology, 2012; 11: 669–78. 
Clark, C.M., Schneider, J.A., Bedell, B.J., et al. “Use of florbetapir-PET for imaging 
beta-amyloid pathology”. JAMA. 2011;305(3):275-283. 
Dickson, T.C., Saunder, H.L., Vickers, J.C.  “Relationship between apolipoprotein E and 
the amyloid deposits and dystrophic neuritis of Alzheimer’s disease.”  Neuropathol Appl 
Neurobiol.  1997; (23):483-491.  
Dubois B., Feldman H.H., Jacova C., et al. “Revising the definition of Alzheimer's 
disease: a new lexicon”. Lancet Neurol. 2010;9(11):1118-1127.   
Duyckaerts, C., Brion, J.P., Hauw, J.J., Flament-Durand, J.  “Quantitative assessment of 
the density of neurofibrillary tangles and senile plaques in senile dementia of the 
Alzheimer type.  Comparison of immunocytochemistry with a specific antibody and 
Bodian’s protargol method.”  Acta Neuropathol. 1987;(7):129-135. 
Folstein, M.R., Folstein, S.E., and McHugh, P.R. “Mini Mental State: A practical method 
for grading the cognitive status of patients for the clinician.”  Journal of Psychiatric 
Research, 12: 189-198, 1975.  
Hyman, B.T., Phelps, C.H., Beach, T.G., et al. “National Institute on Aging-Alzheimer's 
Association guidelines for the neuropathologic assessment of Alzheimer's disease”. 
Alzheimers Dement. 2012;8(1):1-13. 


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Jack, C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., 
Petersen, R.C., Trojanowski, J.Q.  “Hypothetical model of dynamic biomarkers of the 
Alzheimer’s pathological cascade.”  Lancet Neurol 9:119-128, 2010. 
Kantarci, K., Lowe, V.J., Boeve, B.F., Weigand, S.D., Senjem, M.L., Przybelski, S.A., et 
al. “Multimodality imaging characteristics of dementia with Lewy bodies”. Neurobiol 
Aging 2011: Oct 20. [Epub ahead of print]. 
Leinonen, V., Alafuzoff, I., Aalto S., Suotunen, T., Savolainen, S., Nagren, K., et al. 
“Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron 
emission tomography with carbon 11-labeled Pittsburgh Compound B”. Arch Neurol 
2008; 65(10):1304–1309. 
McKhann, G.M., Knopman, D.S., Chertkow, H., et al. “The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease”. Alzheimers 
Dement. May 2011;7(3):263-269.   
Mintun MA, Devous MD, Lu M, Pontecorvo MJ, Joshi AD, Southekal S, Siderowf A, 
Lowrey MJ, Devine M, Benedum TE, Pearson C, Lim NC, Case MG, L Sundell K, 
Siemers E. PET biomarkers in the EXPEDITION 3 trial of patients with Mild AD.  
Alzheimer’s Association International Congress, July 2017, London UK   
Pontecorvo MJ, Devous MD Sr, Navitsky M, Lu M, Salloway S, Schaerf FW, Jennings 
D, Arora AK, McGeehan A, Lim N,  Xiong H, Joshi AD, Siderowf A, Mintun MA for 
the 18F-AV-1451-A05 Investigators. Relationships between Flortaucipir (18F-AV-1451) 
Positron Emission Tomography Tau Binding and Amyloid Burden Clinical Diagnosis, 
Age and Cognition. Brain.  2017; 140:748-763. 
Price, J.L., Morris, J.C. ”Tangles and plaques in nondemented aging and “preclinical”  
Alzheimer’s disease.” Ann Neurol 45:358–368, 1999. 
Sojkova J., Driscoll I., Iacono D., Zhou Y., Codispoti K., Kraut M., et al. “In vivo 
fibrillar beta-amyloid detected using [11C] PiB positron emission tomography and 
neuropathologic assessment in older adults”. Arch Neurol 2011;68(2):232–240. 
Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., 
Iwatsubo, T., Jack, C.R., Jr., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, 
C.C., Siemers, E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, M., 
Wagster, M.V., Phelps, C.H. 2011. “Toward defining the preclinical stages of 
Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease”. Alzheimers 
Dement 7(3), 280-92.  
Wong, D.F., Rosenberg, P.B., Zhou, Y., et al. “In vivo imaging of amyloid deposition in 
Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)”. J 
Nucl Med. 2010;51(6):913-920. 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent for 
Alzheimer’s disease,” Alzheimers Dement. 2013, 1-11 


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11.2. 
Study Flow Chart 
 
 
a. 
Screening may take place over several days.  All assessments must be performed within 30 days of the 18F-AV-1451 imaging 
session. 
b. 
Vital signs (pulse, respiratory rate, supine blood pressure).  Weight will be taken at the imaging visit. 
c. 
Serum beta-hCG pregnancy test at screening for females of childbearing potential. 
d. 
For women of childbearing potential, a negative urine pregnancy test must be obtained within 24 hours prior to the flortaucipir F 
18 injection. 
e. 
A physician or physician designee  
 
Evaluations/Procedures 
 
Screening Visita 
Flortaucipir F 18 
Imaging Visit 
End of  Flortaucipir F 18 
Imaging (prior to 
discharge) 
Follow-up Phone Call 
Signed Consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical History/Neurologic 
Disease History 
X 
 
 
 
Concomitant Meds 
X 
X 
 
 
Vital Signsb 
X 
 
 
 
ECG 
X 
 
 
 
MMSE  
X 
 
 
 
Serum beta-hCG c 
X 
 
 
 
Urine Pregnancy Testd 
 
X 
 
 
flortaucipir F 18 scan 
 
X 
 
 
Evaluation by a physiciane 
X 
X  
X 
 
Adverse Events  
X  
X 
X 
X 
Serious Adverse Events 
 X 
X 
X 
X 
 


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12. 
INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol:  18F-AV-1451-A23 
A multicenter screening study with flortaucipir F 18 in patients with  
early symptomatic AD  
 
 
 
Date and Version:  11 September 2017  
 
 
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: 
18F-AV-1451-A23 SAP v1.0 
 
A Multicenter Screening Study With Flortaucipir F 18 in Patients With Early Symptomatic AD 
 
NCT03322462 
Approval date: 26 Nov 2018


Avid Radiopharmaceuticals                                                                                               
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CONFIDENTIAL 
 
Protocol No. 18F-AV-1451-A23 
 
A MULTICENTER SCREENING STUDY WITH FLORTAUCIPIR F 18 IN 
PATIENTS WITH EARLY SYMPTOMATIC AD 
 
 
Statistical Analysis Plan 
 
Prepared for: 
Avid Radiopharmaceuticals, Inc 
 
Final Version 1.0 
Date 26 Nov 2018 
 
 
Prepared by: 
 
Chiltern International Inc. 
Revision History 
Version 
Date 
Revision Author 
Comments 
Draft 1.0 
26Oct2018 
Original Draft 
Draft 2.0 
31 Oct 2018 
Incorporated Avid 
Comments to date From 
 
Final 1.0 
26 Nov 2018 
Incorporated Avid 
Additional Comments  
 
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                                                                                               
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SIGNATURE PAGE 
 
Author: 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Reviewed by: 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 


Avid Radiopharmaceuticals                                                                                               
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Table of Contents 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................ 5 
2 
INTRODUCTION ........................................................................................................................................ 6 
3 
STUDY OBJECTIVES ................................................................................................................................ 6 
4 
STUDY DESIGN .......................................................................................................................................... 7 
4.1 
GENERAL DESIGN .................................................................................................................................... 7 
4.2 
DISCUSSION OF STUDY DESIGN ............................................................................................................... 8 
4.3 
METHOD OF ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS .......................................................... 8 
4.4 
BLINDING ................................................................................................................................................ 8 
4.5 
DETERMINATION OF SAMPLE SIZE ........................................................................................................... 8 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ................................. 8 
5.1 
CHANGES IN THE CONDUCT OF THE STUDY ............................................................................................. 8 
5.2 
CHANGES FROM THE ANALYSES PLANNED IN THE PROTOCOL/CIP ......................................................... 9 
6 
BASELINE, EFFICACY AND SAFETY EVALUATIONS ................................................................... 10 
6.1 
SCHEDULE OF EVALUATIONS ................................................................................................................ 10 
6.2 
TIME POINT ALGORITHMS ..................................................................................................................... 11 
6.2.1 Relative Day ........................................................................................................................................ 11 
6.2.2 Windows .............................................................................................................................................. 11 
6.3 
SCREENING ASSESSMENTS .................................................................................................................... 11 
6.4 
EFFICACY VARIABLES ........................................................................................................................... 12 
6.4.1 Qualitative assessment for Flortaucipir and Diagnostic Performance ............................................... 12 
6.4.2 Quantitative assessment of images for Flortaucipir (SUVr based) ..................................................... 12 
6.4.3 Increased neocortical Flortaucipir activity ......................................................................................... 12 
6.5 
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETIC PARAMETERS ............................... 13 
6.6 
SAFETY ASSESSMENTS .......................................................................................................................... 13 
6.6.1 Extent of Exposure and Compliance to Study Treatment .................................................................... 13 
6.6.2 Adverse Events ..................................................................................................................................... 13 
6.6.3 Other Observations Related to Safety .................................................................................................. 15 
6.6.3.1 Vital Signs ..................................................................................................................................................... 15 
6.6.3.2 Electrocardiogram (ECG) .............................................................................................................................. 15 
6.7 
PHARMACODYNAMICS PARAMETERS .................................................................................................... 15 
7 
STATISTICAL METHODS ...................................................................................................................... 15 
7.1 
GENERAL METHODOLOGY .................................................................................................................... 15 
7.2 
ADJUSTMENTS FOR COVARIATES .......................................................................................................... 15 
7.3 
HANDLING OF DROPOUTS OR MISSING DATA ........................................................................................ 15 
7.4 
INTERIM ANALYSES AND DATA MONITORING ....................................................................................... 15 
7.5 
MULTI-CENTER STUDIES AND POOLING OF CENTERS ............................................................................ 16 
7.6 
MULTIPLE COMPARISONS/MULTIPLICITY .............................................................................................. 16 
7.7 
ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE .......................................................... 16 
7.8 
EXAMINATION OF SUBGROUPS .............................................................................................................. 16 


Avid Radiopharmaceuticals                                                                                               
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8 
STATISTICAL ANALYSIS ...................................................................................................................... 16 
8.1 
ANALYSIS POPULATIONS ....................................................................................................................... 16 
8.1.1 Enrolled Population ............................................................................................................................ 16 
8.1.2 Safety Population ................................................................................................................................. 16 
8.1.3 Efficacy Population ............................................................................................................................. 16 
8.2 
DISPOSITION OF SUBJECTS ..................................................................................................................... 17 
8.3 
PROTOCOL DEVIATIONS/VIOLATIONS ................................................................................................... 17 
8.4 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................................................... 17 
8.5 
RELEVANT FAMILY HISTORY ................................................................................................................ 17 
8.6 
DISEASE HISTORY ................................................................................................................................. 17 
8.7 
PREGNANCY TEST ................................................................................................................................. 18 
8.8 
CONCOMITANT THERAPY ...................................................................................................................... 18 
8.9 
MEDICAL AND SURGICAL HISTORY ....................................................................................................... 18 
8.10 
ANALYSIS OF EFFICACY PARAMETERS .................................................................................................. 18 
8.10.1 Qualitative Assessment of Images...................................................................................................... 18 
8.10.2 Quantitative Assessment of Images .................................................................................................... 18 
8.10.3 Other Efficacy Variables ................................................................................................................... 19 
8.10.3.1 
Increased Neocortical Activity ................................................................................................................. 19 
8.11 
ANALYSIS OF SAFETY ............................................................................................................................ 19 
8.11.1 Extent of Exposure and Compliance to Study Treatment .................................................................. 19 
8.11.1.1 Unit Conversion and Volume Calculation ................................................................................................... 19 
8.11.2 Adverse Events ................................................................................................................................... 19 
8.11.3 Vital Signs .......................................................................................................................................... 20 
8.11.4 Electrocardiogram (ECG) ................................................................................................................. 20 
8.12 
PHARMACODYNAMICS ........................................................................................................................... 20 
9 
COMPUTER SOFTWARE ....................................................................................................................... 20 
 


Avid Radiopharmaceuticals                                                                                               
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1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Table 1: Abbreviations and Definitions of Terms 
 
 
 
 
Aβ 
amyloid-ß 
AD 
Alzheimer’s disease 
AE 
adverse event 
ATC 
Anatomical therapeutic chemical classification 
BMI 
body mass index 
CIP 
Clinical investigational plan 
cm 
centimeters 
CRO 
contract research organization 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
IND 
investigational new drug 
IV 
Intravenous 
Kd 
dissociation constant 
kg 
Kilograms 
max 
Maximum 
MBq 
Megabecquerel 
mCi 
Millicuries 
MCI 
mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minimum 
MMSE 
Mini-Mental State Examination 
mSv 
Millisievert 
MUBADA 
Multiblock barycentric discriminant analysis 
n 
number of subjects 
nM 
Nanomolar 
PET 
positron emission tomography 
SAE 
Serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
SUVr 
standardized uptake value ratio 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 


Avid Radiopharmaceuticals                                                                                               
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2 
INTRODUCTION 
 
Flortaucipir F 18 (18F-AV-1451) (originally named [F-18]T807 by Siemens Molecular 
Imaging Biomarker Research group) is a positron emitting radiopharmaceutical developed 
for in vivo imaging of tau protein aggregates (Xia et al., 2013). Image assessment showed 
tracer deposition on brain PET scans to be consistent with that expected for a tracer of 
aggregated tau protein. Flortaucipir (18F) initially entered the brain and was subsequently 
eliminated from the brain in clinically normal and amyloid negative cognitively impaired 
subjects, yielding only a diffuse pattern of background activity, whereas a regionally distinct 
gray matter distribution of increased tracer retention was observed in amyloid positive 
cognitively impaired subjects (Pontecorvo et al., 2017). Preliminary analyses of our Phase II 
longitudinal study (A05, exploratory cohort) also indicate a relationship between the level 
and pattern of flortaucipir uptake at baseline, and the rate of decline on cognitive tests over 
an 18-month period (Mintun, AAIC 2017). These results suggest that it may be possible to 
use flortaucipir PET scans to enrich clinical studies for subjects with a desired level of AD 
pathology and a more homogeneous rate of cognitive decline, thus increasing power to detect 
a treatment effect. Specifically, Lilly and Avid desire to conduct treatment trials at the 
earliest stage of AD neuropathology to maximize potential patient benefit. 
 
I5T-MC-AACG is a proposed anti-amyloid trial that intends to target subjects with a certain 
distribution and density of tau neurofibrillary tangles that are hypothesized to be 
appropriate for such a trial. It is thought that patients with no tau will progress so slowly 
that a clinical treatment effect could not be discerned, and those with a large tau burden 
may not be responsive to anti-amyloid therapy as their cognitive impairment is driven 
primarily by tau pathology. The overarching goal of AV-1451-A23 is to test this 
hypothesis by pre-screening subjects with flortaucipir F 18 who have been diagnosed with 
suspected Alzheimer’s disease and have indicated their interest to consider participation in 
trials such as the AACG Lilly therapeutic clinical trial.  
 
3 
STUDY OBJECTIVES 
 
The primary objective is to pre-screen subjects via a flortaucipir scan, who have objectively 
verified cognitive impairment and etiology diagnosed or suspected to be due to 
Alzheimer’s disease, and have indicated their interest in participating in Lilly sponsored 
trials that require tau imaging for inclusion such as AACG. 
 
The secondary objective of the study is to expand the flortaucipir F 18 safety database. 
 
 


Avid Radiopharmaceuticals                                                                                               
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4 
STUDY DESIGN 
 
4.1 General Design 
 
Study 18F-AV-1451-A23 is a multicenter screening study in subjects with early symptomatic 
AD (where early symptomatic AD refers to the combination of 2 stages: prodromal AD 
[MCI-AD] and mild AD dementia). 
 
All subjects will provide informed consent before starting any study procedures. This 
prescreening study targets subjects who are interested in participating in AD therapeutic 
clinical trials and have expressed a preliminary interest in a trial like the AACG trial, and 
who are not known to have met any of the exclusion criteria for trials like AACG based on 
medical history and clinical examination. However, consent for this protocol does not 
constitute consent for the AACG trial or any other trials, and subjects who qualify for this 
protocol may still fail to qualify for trials like AACG or other trials based on the results 
of this protocol or based on additional testing performed in those subsequent trials. 
 
Screening assessments may take place over several days and will be performed within 30 
days prior to flortaucipir F 18 injection. Screening assessments will include demographic 
information, cognitive testing, disease history, concomitant medications, vital signs, ECG 
and medical history. Subjects who are deemed eligible to continue will complete a 
flortaucipir PET scan.  
 
A physician or a licensed/credentialed medial 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 F 18 injection to determine if 
they are still suitable to undergo the scan.  
 
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) of 
flortaucipir F 18 injection followed by saline flush. At approximately 75 minutes following 
injection, a continuous 30-minute brain scan will be performed.  
 
The injection site will be observed for excessive inflammation or damage to the surrounding 
tissue at the injection site.  Adverse events will be continuously monitored during the 
flortaucipir PET imaging visit.  Subjects who experience an adverse event will not be 
discharged from the imaging center until the event has resolved or stabilized.  A follow-up 
phone call to the subject, or 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 any new adverse events.  
 


Avid Radiopharmaceuticals                                                                                               
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A physician or a licensed/credentialed medial 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.  
 
Subjects who meet eligibility criteria will participate in this protocol until they  
complete their flortaucipir PET scan, or they discontinue, withdraw consent, or if 
the sponsor decides to end this protocol early. 
 
 
4.2 Discussion of Study Design 
 
This trial is designed to pre-screen subjects via a flortaucipir scan, who have objectively 
verified cognitive impairment and etiology diagnosed or suspected to be Alzheimer’s 
disease, and have indicated their interest in participating in Lilly sponsored trials that require 
tau imaging for inclusion, such as AACG. 
 
4.3 Method of Assignment of Subjects to Treatment Groups 
 
Flortaucipir F 18:  
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) of 
flortaucipir F 18 Injection. 
 
 
4.4 Blinding 
 
A blinded design is not used for this trial, because all subjects will receive the same 
medication.  
 
 
4.5 Determination of Sample Size 
 
This is a pre-screening study that targets subjects who are interested in participating in AD 
therapeutic clinical trials and have expressed a preliminary interest in a trial like the AACG 
trial. Therefore, approximately 500 subjects will be enrolled in this study. 
 
 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
 
5.1 Changes in the Conduct of the Study 
 


Avid Radiopharmaceuticals                                                                                               
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There were no changes in the conduct of the study at the time of preparing this statistical 
analysis plan. 
 
5.2 Changes from the Analyses Planned in the Protocol/CIP 
 
There were no changes in the analyses planned in the Protocol/CIP at the time of preparing 
this statistical analysis plan. 
 
 
 
 


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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 Relative Day 
 
The date of first dose of study drug (flortaucipir F 18) will be considered relative day 1, 
and the day before the first dose of study drug will be relative day -1.  Relative days will 
be calculated as follows only when the full assessment date is known (i.e., partial dates 
will have missing relative days): 
 
For days on or after the first dose of study drug: 
Date of Assessment – Date of First Dose of Study Drug + 1. 
 
For days before the first dose of study drug: 
Date of Assessment – Date of First Dose of Study Drug. 
 
6.2.2 Windows 
 
No window algorithm is being used for this study. 
 
6.3 Screening Assessments 
 
Screening may take place over several days. All screening assessments will be performed 
within 30 days prior to flortaucipir F 18 injection. Screening assessments will include: 
 
• Informed consent for subject; 
• Demographics (age, gender, years of education, race, ethnicity); weight; 
• Medical history, concomitant medications; 
• Vital Signs (pulse, respiration rate, supine blood pressure) 
• A resting 12 lead ECG will be performed to assess the subject’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.  
• ApoE status, if available; 
• Disease history (date/months since symptom onset, date/months since 
            diagnosis, family history of relevant neurologic disease); 
• Cognitive status interview, including MMSE; 
• A physician will see the subject during the screening visit. 
• For women of childbearing potential, a negative serum pregnancy test must be 
            obtained at the screening visit 
 
 
Weight will be displayed in kilograms (kg), height will be displayed in centimeters (cm). 
Weights and heights recorded in alternate units will be converted to the units being 


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displayed using standard conversion formulas. Body mass index (BMI) will be calculated 
as weight (kg) divided by height squared (cm2). 
 
APOE4 Positive is any subject with at least one of their two APOE alleles as an E4 allele.  
 
Each subject’s age (years) will be calculated based on his/her date of informed consent 
and will be truncated to a whole number.  Because only year of birth is collected, January 
1 will be imputed for the month and day of birth.  Age will be calculated as the number of 
months between the date of informed consent and the imputed birthdate, divided by 12. 
Age will be rounded to the nearest integer. 
 
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive function 
in elderly subjects. The instrument is divided into 2 sections. The first section measures 
orientation, memory, and attention. The maximum score for the first section is 21. The 
second section tests the ability of the subject to name objects, follow verbal and written 
commands, write a sentence, and copy figures. The maximum score for the second 
section is 9. The range for the total MMSE score is 0 to 30, the sum of each correct 
answer, with higher scores indicating better cognition.  
 
 
6.4 Efficacy Variables 
 
 
6.4.1 Qualitative assessment for Flortaucipir and Diagnostic 
Performance 
 
The flortaucipir scan image will be visually interpreted. The scans will be classified as 
either  
• Not consistent with an AD pattern (τAD-) 
• AD pattern (τAD+) 
• AD pattern and likely to progress (τAD++)  
 
6.4.2 Quantitative assessment of images for Flortaucipir (SUVr based) 
 
For the flortaucipir image, standard uptake value ratios (SUVr) will be calculated to 
estimate tau globally. SUVr will be calculated after the  visual read and only on scans 
that were τAD+ or τAD++.  For global assessment, a target region derived statistically 
with a Multiblock Barycentric Discriminant Analysis (MUBADA) method will be used.  
 
6.4.3 Increased neocortical Flortaucipir activity 
 
The hemisphere and region of increased neocortical flortaucipir activity will be 
identified. 


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The hemisphere will be classified as either left or right and the region is classified as  
• Anterior Lateral Temporal  
• Posterior Lateral Temporal 
• Occipital 
• Parietal 
• Precuneus 
• Frontal 
 
6.5 Drug Concentration Measurements and Pharmacokinetic 
Parameters 
 
 
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 session, subjects will receive a single IV bolus 
administration target dose of 370 MBq (10 mCi) of flortaucipir F 18 injection followed 
by a saline flush. At approximately 75 minutes following injection, a continuous 30-
minute brain scan will begin.  Exposure to study drug will be summarized using the total 
administered dose at the scan visit for flortaucipir F 18 injection. 
 
6.6.2 Adverse Events 
 
The investigator’s verbatim term of adverse events will be mapped to system organ class 
(SOC) and preferred terms using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 
 
Treatment-emergent AEs (TEAEs) are undesirable experiences, signs, or symptoms that 
begin or worsen in intensity or frequency at the time of or after the administration of 
study drug at the imaging visit, and prior to the end of observation windows defined as 
following: the TEAE window will be from injection of flortaucipir F 18 until 48 hours 
post flortaucipir F 18 injection. These will be recorded on the AE page of the electronic 
case report form (eCRF).  
 
Serious AEs (SAEs) are events that result in one of the following outcomes or constitute 
one of the following events: 


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• Death 
• Initial or prolonged hospitalization (other than that required by protocol; “social 
hospitalization” or any hospitalization for non-medical reasons does not constitute 
an SAE 
• A life-threatening experience (that is, immediate risk of dying) 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Considered significant by the investigator for any other reason 
 
Important medical events that may not result in death, are 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. 
 
For the summarization of TEAEs by seriousness, events recorded with missing 
seriousness will be summarized as serious. 
 
Investigators will be instructed to report their assessment of the potential relatedness of 
each AE to protocol procedure or study drug. The assessment of the relationship of an AE 
to the administration of the investigational product is a clinical decision based on all 
available information at the time of the completion of the eCRF. For the summarization 
of TEAEs by relationship to study drug or protocol procedure, events recorded with 
missing relationship will be summarized as Related. 
 
In addition to assessing the relationship of the administration of the investigational 
product to AEs, an assessment is required of the severity of the event. The following 
classifications should be used: 
 
Mild: 
A mild AE is an AE, usually transient in nature and generally not interfering with normal 
activities. 
 
Moderate: 
A moderate AE is an AE that is sufficiently discomforting to interfere with normal 
activities. 
 
Severe: 
A severe AE is an AE 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. 
 


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For the summarization of TEAEs by intensity, events recorded with missing intensity will 
be summarized as Severe. 
 
6.6.3 Other Observations Related to Safety 
 
6.6.3.1 Vital Signs 
 
Vital signs (pulse rate, respiratory rate, and supine blood pressure) will be taken at the 
screening visit. Weight will be measured, lightly clothed during the imaging visit. 
 
6.6.3.2 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 PET Imaging Visit and 
is available for review. 
 
6.7 Pharmacodynamics Parameters 
 
No pharmacodynamics parameters will be collected during this study. 
 
7 
STATISTICAL METHODS 
 
7.1 General Methodology 
 
All values will be summarized as a single group, early symptomatic AD. Frequency 
distributions including counts and percentages will be reported for all categorical 
outcomes. Summary statistics including number of subjects [N], mean, standard deviation 
[SD], median, quartiles, minimum and maximum values will be presented for all 
continuous outcomes.  
 
All statistical analyses will be performed using SAS® version 9.3 or higher. Patient 
listings of all data form the eCRF as well as any derived variables will be presented. 
 
7.2 Adjustments for Covariates 
 
Not applicable for the primary analyses. 
 
7.3 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. 
 
7.4 Interim Analyses and Data Monitoring  
 


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No interim analysis or data monitoring is planned for this study 
 
7.5 Multi-center Studies and Pooling of Centers 
 
This study will be conducted in approximately 15 centers. The data from all centers will 
be pooled. The pooled data will be analyzed and presented. 
   
7.6 Multiple Comparisons/Multiplicity 
 
No adjustment for multiplicity will be performed in this study.   
 
7.7 Active-Control Studies Intended to Show Equivalence 
 
Not applicable to this study. 
 
7.8 Examination of Subgroups 
 
No subgroup analysis will be performed. 
 
8 
STATISTICAL ANALYSIS 
 
8.1 Analysis Populations 
 
8.1.1 Enrolled Population 
 
The enrolled population will consist of all subjects who signed inform consent and have 
data captured in the clinical database. Disposition information will be summarized using 
the enrolled population. 
 
8.1.2 Safety Population 
 
The safety analysis population will include all eligible subjects who enroll in 18F-AV-
1451-A23 (A23) and have received at lease on dose of flortaucipir F 18 injection. 
 
All demographic, baseline and safety endpoints will be using the safety population. 
 
8.1.3 Efficacy Population 
 
Efficacy analysis population will include all subjects in safety population, with a 
valid flortaucipir scan assessment [SUVr (quantitative) and/or visual reads (qualitative)]. 
 
For flortaucipir SUVr related analyses, any scans deemed to be unquantifiable due to 
technical reasons will be excluded from analyses.  


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All analyses involving imaging outcomes will be based on the efficacy population.  
 
8.2 Disposition of Subjects 
 
The enrolled population will be represented in the disposition table. The disposition table 
will include a summary of the analysis populations, number of completed and 
discontinued subjects, and the reasons for discontinuation. All percentages will be based 
on the safety population. 
 
Disposition data will be presented in a listing. 
 
8.3 Protocol Deviations/Violations 
 
Subjects who entered the study even though they did not satisfy one or more of the 
inclusion/exclusion criteria will be listed.  Deviations/violations from the protocol will be 
documented, the Avid/contract research organization (CRO) monitor will then be 
informed and a course of action will be agreed upon.  
 
8.4 Demographic and Other Baseline Characteristics 
 
All baseline summaries will be based on the safety population. 
 
Frequency distributions and summary statistics for demographic and baseline variables 
will be presented across all subjects. Key demographic and baseline characteristics to be 
summarized include: age, gender, race, ethnicity, height, weight, BMI, highest level of 
education, alcohol history, recreational drug use history, smoking history, MMSE, and 
ApoE Genetic testing.   
 
All demographic and baseline characteristics data will be presented in listings. 
 
8.5 Relevant Family History 
 
Data from Family History CRF will be summarized in a table with counts and 
percentages and presented in a listing for the safety population. 
 
8.6 Disease History 
 
Months since symptom onset and diagnosis will be summarized in a table using 
descriptive statistics and presented in a listing for the safety population. 
 
For subjects with dates of diagnosis or symptom onset, months will be calculated as the 
difference of symptom onset/diagnosis date and the date of their flortaucipir injection. 


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For partial symptom onset/diagnosis date, if only the day is missing, then impute the day 
as the first day of the month; if both the day and month are missing, then imputed it as 01 
January of the year. 
 
8.7 Pregnancy Test 
 
Data from Pregnancy Test CRF will be presented in a listing for the safety population. 
 
 
 
8.8 Concomitant Therapy  
 
 
A current version of the World Health Organization (WHO) Drug Dictionary will be used 
to classify medications by preferred term and WHO Anatomical Therapeutic Chemical 
(ATC) classification of ingredients. ATC classification level 3 will be used. If level 3 is 
missing, then level 2 will be used. If level 2 is missing, then level 1 will be used. 
 
All concomitant medications data will be presented in listings for the safety population. 
 
8.9 Medical and Surgical History 
 
Medical and Surgical History will be coded using MedDRA Version 21.1. Medical and 
surgical history will be presented in a listing for the safety population. 
 
8.10 Analysis of Efficacy Parameters 
 
All efficacy information as well as related data (flortaucipir PET scan information and 
flortaucipir PET results) will be presented in the listings. 
 
8.10.1 Qualitative Assessment of Images 
 
The visual read results will be categorized as τAD+, τAD++ and τAD-.  The visual read 
results will be summarized by frequency distribution (count and percentage) for the 
efficacy population by subject eligibility and overall. 
 
8.10.2 Quantitative Assessment of Images 
 
 
 
The Screening MUBADA SUVr will be summarized using descriptive statistics [n, mean, 
SD, median, minimum and maximum values, and quartiles (25th and 75th percentile)] by 
visual read results (τAD+, τAD++ subject eligibility and overall.   
 
 


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8.10.3 Other Efficacy Variables 
 
8.10.3.1 Increased Neocortical Activity 
 
Increased neocortical flortaucipir activity by hemisphere and region will be presented in a 
listing. 
 
     
 
8.11 Analysis of Safety 
 
 
8.11.1 Extent of Exposure and Compliance to Study Treatment 
 
The total dose administered (MBq) of Flortaucipir F 18 will be summarized using 
descriptive statistics. All exposure data captured on the CRF will be presented in listings 
for the safety population. 
 
Because this is a study with only one bolus of study medication per imaging visit, 
compliance will not be summarized.   
 
8.11.1.1 Unit Conversion and Volume Calculation 
 
All exposure tables will display volume in MBq. Radioactive dose collected in 
millicuries (mCi) will be converted to MBq as follows: 
 
mCi
MBq

= 37
 
8.11.2 Adverse Events 
 
TEAEs will be summarized by descending frequency, then alphabetically by SOC and 
preferred term. A subject will only be counted once per SOC and once per preferred term.  
Subject counts and percentages will be presented for the following summaries: 
 
1. All TEAEs by system organ class (SOC) and preferred term; 
2. All TEAEs by preferred term (in order of descending frequency); 
3. All TEAEs by relationship to study drug, SOC, and preferred term; 
4. All TEAEs by relationship to protocol procedure, SOC and preferred term; 
5. All TEAEs by severity, SOC and preferred term 
6. All Serious TEAEs by system organ class (SOC) and preferred term; 
7. All TEAE leading to study termination by system organ class (SOC) and preferred 
term 
 


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For the summary of TEAEs by severity, if a subject has multiple events occurring in the 
same SOC or same preferred term, the event with the highest severity will be counted.   
 
TEAEs by relationship to study drug and protocol procedure will be summarized as 
Related vs. Not Related.  If a subject has multiple events occurring in the same SOC or 
same preferred term, the related event will be summarized.   
 
All AE will be presented in the listings. 
 
8.11.3 Vital Signs 
 
Vital signs (systolic and diastolic blood pressure, pulse, respiration rate) will be 
summarized using descriptive statistics.  
 
All vital signs data will be presented in the listings. 
 
8.11.4 Electrocardiogram (ECG) 
 
Electrocardiogram (ECG) Results (Normal, Abnormal – Not Clinically Significant, 
Abnormal – Clinically Significant) will be summarized using counts and percentage. 
 
All ECG data will be presented in the listings. 
 
 
8.12 Pharmacodynamics 
 
No pharmacodynamics analyses are planned for this study. 
 
9 
COMPUTER SOFTWARE 
 
All analyses will be performed by Chiltern using SAS Version 9.3 or later.  All 
summary tables and data listings will be prepared utilizing SAS software. 
 
The standard operating procedures (SOPs) of Chiltern will be followed in the creation 
and quality control of all data displays and analyses.