Clinical trial NCT02516046
Conditions: Alzheimer's Disease
Sponsor: Avid Radiopharmaceuticals
Start date: 2015-09-01; Completion date: 2018-07-15
Enrollment: 156 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to test the relationship between ante-mortem flortaucipir Positron Emission Tomography (PET) imaging and tau neurofibrillary pathology associated with Alzheimer's disease (AD), as measured at autopsy.

Detailed description:

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

Protocol documents:
Prot_000.pdf: 
18F-AV-1451-A16 Protocol Amendment 2 
 
A Clinico-Pathological Study of the Correspondence Between 18F-AV-1451 PET Imaging and 
Post-Mortem Assessment of Tau Pathology 
 
NCT02516046 
Approval date: 18 Dec 2017


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18F-AV-1451-A16: “A Clinico-Pathological Study of the Correspondence Between 18F-
AV-1451 PET Imaging and Post-Mortem Assessment of Tau Pathology” 
 
Amendment 2 – 18Dec2017  
Page 2 of 50  
 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
Title of Study: 18F-AV-1451-A16 
A Clinico-Pathological Study of the Correspondence Between 18F-AV-1451 PET Imaging 
and Post-Mortem Assessment of Tau Pathology 
Study Participants:  
Planned number of subjects enrolled: Approximately 200 
Planned number of autopsies: Approximately 80 
Approximately 200 subjects with terminal medical conditions and projected life 
expectancy of ≤ 6 months will be enrolled and imaged with 18F-AV-1451 in order to 
obtain post-mortem histological data on approximately 80 subjects. Enrollment will not be 
formally stratified, but an effort will be made to enroll subjects with cognitive status 
ranging from normal cognition to mild cognitive impairment (MCI) and dementia to 
achieve a full range of tau pathology. It is expected that at least 65% of the subjects 
enrolled will have dementia or MCI. 
Front-Runners: 
Up to the first 6 subjects that come to autopsy will be considered front-runners. Avid will 
not be blinded to the front-runner imaging and pathology results and may use these to 
evaluate the study methods and refine the methods if needed for the subsequent blinded 
cases. Subjects that are part of the front-runners will not be included in the Primary 
Efficacy Population. 
Primary Efficacy Population:  
All subjects with valid autopsies that occur after the front-runner group has completed and 
before the sample size requirement/trial stopping criteria (below) have been met will be 
considered part of the Primary Efficacy Population.  Some subjects may have died and had 
autopsy material removed at the time the sample size requirement is met. Subjects for 
whom autopsies are ongoing at the time the sample size requirement is met will also be 
included in the Primary Efficacy Population.  
Name of compound: 18F-AV-1451 
Dose: 370 MBq (10 mCi) 
Route of Administration: Intravenous (IV) bolus 
Study Phase: III 
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Amendment 2 – 18Dec2017  
Page 3 of 50  
 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
Study Centers: Approximately 30 centers in the United States and Australia 
Primary Objective:  
This study is designed to test the relationship between ante-mortem 18F-AV-1451 Positron 
Emission Tomography (PET) imaging and tau neurofibrillary pathology associated with 
Alzheimer’s disease (AD), as measured at autopsy. To accomplish this goal, two primary 
analyses will be performed:  
Primary Analysis 1 
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 
18F-AV-1451 neocortical uptake that corresponds to Neurofibrillary Tangle (NFT) 
Score of B3 (Hyman et al., 2012; Montine et al., 2012) at autopsy will be evaluated; 
and if success criteria are met, 
Primary Analysis 2 
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 
18F-AV-1451 neocortical uptake that corresponds to high levels of AD neuropathologic 
change as defined by National Institute on Aging - Alzheimer’s Association (NIA-AA) 
criteria (Hyman et al., 2012) will be evaluated. For individuals with cognitive 
impairment, high levels of AD neuropathologic change are considered adequate to 
explain cognitive impairment or dementia symptoms. 
The trial will be considered successful if both co-primary endpoints are met according to 
the Statistical Analysis Plan.  
Secondary Objective: 
Secondary Analysis 1: To assess diagnostic performance of ante-mortem 18F-AV-1451 
PET imaging, based on majority interpretation of 5 independent readers, for detection 
of a pattern of 18F-AV-1451 neocortical uptake that corresponds to Neurofibrillary 
Tangle (NFT) Score of B3 and for detection of a pattern of 18F-AV-1451 neocortical 
uptake that corresponds to high levels of AD neuropathologic change as defined by 
National Institute on Aging - Alzheimer’s Association (NIA-AA) criteria. 
Secondary Analysis 2: To assess agreement among readers of 18F-AV-1451 PET 
scans. 
Eligibility: 
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Amendment 2 – 18Dec2017  
Page 4 of 50 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
See Section 5.3, Selection of Subjects. 
Study Design: 
This study is a clinico-pathological study of the correspondence between 18F-AV-1451 
PET imaging and post-mortem assessment of tau pathology and associated NIA-AA 
pathological diagnosis. 
The screening and imaging procedures have been designed to be tolerable for eligible end-
of-life patients. Individuals with terminal medical conditions with projected life 
expectancy of ≤ 6 months and/or their legally authorized representative (LAR) will 
provide informed consent. The subject will then receive a PET scan with 18F-AV-1451 and 
will be followed to death. Subjects that have a historical brain Magnetic Resonance 
Imaging (MRI), acquired within 12 months of the 18F-AV-1451 PET imaging visit, may 
consent to have the scan made available to the designated imaging core lab. If death does 
not occur within nine months of the 18F-AV-1451 PET scan, the subject may be given the 
opportunity to undergo a second 18F-AV-1451 PET scan and continue in the protocol at 
the sponsor’s discretion (screening assessments will not need to be repeated). If the subject 
subsequently comes to autopsy, the second scan (nearest to time of death) will be used in 
the efficacy analyses. See below for exceptions related to cognitively normal subjects. 
Approximately 200 subjects may be enrolled and imaged with 18F-AV-1451 PET. It is 
expected that approximately 80 individuals will undergo post-mortem autopsy evaluation 
(including the Primary Efficacy Cohort and up to 6 subjects in a Front-Runner Cohort). 
The Primary Efficacy Cohort will form the basis for the tests of diagnostic performance 
(subjects for whom autopsies are ongoing at the time the sample size requirement is met 
will also be included in the Primary Efficacy Population). The primary efficacy cohort will 
include all subjects with a valid PET scan that come to autopsy before the sample size 
requirement/trial stopping criteria are met. In order to control for the potential progressive 
change in tau deposition over time, cognitively impaired subjects will not have an autopsy 
performed or be included in the primary efficacy cohort if death does not occur within 
nine months of a valid imaging session.  However, because cortical tau deposition is 
expected to occur very slowly, if at all, in cognitively normal (unimpaired) subjects, 
cognitively normal subjects will not be required to undergo repeat scans. Cognitively 
normal subjects will remain eligible for autopsy, regardless of time from first scan or 
second scan to autopsy, and will be included in the primary efficacy cohort if the subject 
comes to autopsy any time before the trial stopping criteria are met. 
Up to the first 6 subjects that come to autopsy will be considered front-runners. Results 
from the front-runners will be analyzed on a patient-by-patient basis and may be used to 
refine the PET or autopsy methods (e.g. pathology staining/quantitation methods). Upon 
completion of the final front-runner subject analysis, the final imaging and autopsy 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
methods will be specified. No additional PET image reads or autopsy analyses will be 
performed until the PET image read and autopsy methods have been finalized. The 
primary efficacy analyses will be performed on those subjects with valid imaging data that 
come to autopsy after the front-runners (Primary Efficacy Cohort). The front-runners will 
not be included in the primary efficacy analyses, but additional analyses of combined 
primary plus front-runner cases may be performed. 
The first 30 PET scans collected will be reviewed by an independent Data Monitoring 
Board (DMB). The DMB will assess whether the scans can be evaluated in a manner 
consistent with methods developed in Phase II (18F-AV-1451-A05 Exploratory Phase 
Cohort) as determined by criteria outlined in the Data Monitoring Board Charter. The 
DMB will have the ability to recommend unblinding the Sponsor to all 30 cases if a pre-
specified number of scans in the autopsy population have anomalies not present in the 
early phase studies. Study enrollment will continue during the DMB’s review. In the event 
the Sponsor proceeds with a DMB recommendation for unblinding, the unblinded subjects 
will be excluded from the Primary Efficacy Cohort (neither the scans nor any autopsies 
will be used in the primary analyses) or the study may be terminated. If unblinding occurs, 
it must be completed before the final image read and autopsy methods are specified. 
Avid personnel will be blinded to the Primary Efficacy Cohort 18F-AV-1451 PET images.  
A single Avid member will perform periodic quality assurance (QA) by reviewing a listing 
of the PET image header data (not to exceed 20% unless issues identified that warrant 
additional review). These QA reviews will serve to ensure image quality control processes 
at the imaging core laboratory are adequately performed. Avid staff performing the PET 
image data header QA assessment will not be aware of the clinical status for the 
subjects/images being reviewed. The independent blinded readers and DMB will be 
blinded to the subject clinical status and autopsy results. The pathology core lab(s) will be 
blinded to the subject clinical status, PET scan images, and read results. All other Avid 
personnel will be blinded to the Primary Efficacy Cohort 18F-AV-1451 read results and 
pathology data. 
Visits and Assessments: 
Each subject will have a screening visit, up to two 18F-AV-1451 PET imaging visits, and a 
follow-up phone call after each imaging visit. Subjects who come to autopsy during the 
study period will receive a post-mortem evaluation.  
Specific details of assessments that will be performed at each visit are detailed in Section 
7.1. 
Evaluation of Imaging 
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Page 6 of 50  
 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
18F-AV-1451 retention on PET images from subjects with valid autopsy data will be 
interpreted by visual examination as either  
• Neocortical Uptake Not Consistent with an AD Pattern (AD-: no increased neocortical 
activity in any region or increased activity is isolated to the mesial temporal, 
anterolateral temporal or frontal region(s)); 
• Neocortical Uptake Consistent with an AD Pattern (AD+: increased neocortical tracer 
activity in the posterolateral temporal (PLT), parietal (including precuneus), or 
occipital region(s)); or 
• Neocortical Uptake Consistent with an AD Pattern and with Likelihood of Disease 
Progression (AD++, which is a subset of AD+ (neocortical uptake consistent with an 
AD pattern) where increased tracer activity is found in the parietal (including 
precuneus) region(s) regardless of uptake elsewhere, or frontal region in addition to 
PLT, occipital, or parietal region(s)). 
For the purpose of testing the primary analyses, a scan interpretation will be considered 
positive (hypothesized to correspond to a B3 neuropathology score in Primary Analysis 1 
and an NIA-AA score of high AD pathology in Primary Analysis 2) if the scan is 
interpreted as at least consistent with an AD pattern (AD+ or AD++). 
Details of the visual PET image review methods will be provided in the Blinded Read 
Manual. 
Images will also be assessed quantitatively (semi-automated computerized measurement 
of Standard Uptake Value Ratios [SUVRs]) for exploratory analysis purposes. Details of 
the analysis methods will be provided in the Quantitative Methodology Document.  
The 18F-AV-1451 PET imaging results will not be shared with the investigator sites or 
subjects and their families prior to the end of the study. 
Neuropathology Evaluation 
All neuropathological measurements on brain tissue in this trial will be evaluated in a 
standardized and blinded (with respect to PET image results and subject 
identifying/clinical information) fashion in a qualified laboratory. A Technical Autopsy 
Manual and Neuropathology Analysis Plan will be developed for this study containing all 
methods and measurement procedures. Neuropathological assessment will be derived from 
the NIA-AA guidelines (Hyman et al., 2012; Montine et al., 2012). Sections from brain 
regions recommended for pathological assessment of AD, as well as additional, pre-
specified neocortical regions will be sampled. Staining will follow the procedures 
recommended in the NIA-AA practical approach guidelines. NFT extent will be assessed 
using standard procedures and NFT scores (B0-B3) will be recorded (Hyman et al., 2012; 
Montine et al., 2012). The Truth Standard (TS) for Primary Analysis 1 will be constructed 
from NFT scores as shown in Table 1. 
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Page 7 of 50  
 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
Table 1: 
Autopsy NFT Score Truth Standard (Primary Analysis 1) 
 
Braak 
Stage 
NFT Scorea 
Truth 
Standard 
(TS) 
0 (no NFTs) 
B0  
Negative 
 
I-II 
B1 
III-IV 
B2 
V-VI 
B3 
Positive 
 a adapted from Hyman et al., 2012 
 
Amyloid pathology will be evaluated using Thal and CERAD rating systems. Distribution 
of amyloid (Thal plaque Score A0-A3; Montine et al., 2012) will be recorded. The 
frequency of neuritic amyloid plaques will be evaluated semi-quantitatively (CERAD 
score: none, sparse, moderate or frequent). Using Thal plaque score, CERAD score and 
NFT score, level of AD neuropathologic change will be recorded as none, low, 
intermediate or high per NIA-AA guidelines (Hyman et al. 2012). The TS for Primary 
Analysis 2 will be constructed from levels of AD neuropathologic change as shown in 
Table 2.  
Table 2: 
NIA-AA Autopsy Diagnosis Level of AD Neuropathologic Change 
Truth Standard (Primary Analysis 2) 
Level of AD 
Neuropathologic Change 
Presenta 
Truth Standard 
(TS) 
Not 
Negative 
 
Low 
Intermediate 
High 
Positive 
a adapted from Table 2 in Hyman et. al, 2012 
 
Statistical Methods: 
This study is designed to test the relationship between ante-mortem 18F-AV-1451 PET 
imaging and tau neurofibrillary pathology associated with AD, as measured at autopsy. To 
accomplish this goal, two primary analyses will be performed:  
Primary Analysis 1 
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18F-AV-1451-A16: “A Clinico-Pathological Study of the Correspondence Between 18F-
AV-1451 PET Imaging and Post-Mortem Assessment of Tau Pathology” 
 
Amendment 2 – 18Dec2017  
Page 8 of 50  
 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 
18F-AV-1451 neocortical uptake that corresponds to NFT Score of B3 (Hyman et al., 
2012; Montine et al., 2012) at autopsy will be evaluated; and if success criteria are 
met, 
Primary Analysis 2  
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 
18F-AV-1451 neocortical uptake that corresponds to high levels of AD neuropathologic 
change as defined by NIA-AA criteria (Hyman et al., 2012) will be evaluated. For 
individuals with cognitive impairment, high levels of AD neuropathologic change are 
considered adequate to explain cognitive impairment or dementia symptoms. 
The trial will be considered successful if both co-primary endpoints are met according to 
the Statistical Analysis Plan.  
For Primary Analysis 1, the hypothesis to be tested is that for the same 3 out of 5 
independent readers the lower bound of the two-sided 95% confidence intervals (CI) for 
both sensitivity and the specificity of 18F-AV-1451 PET reading results will be ≥ 50%. As 
detailed in Table 1 above, NFT scores for autopsy cases will be categorized as either 
B0/B1/B2 or B3 level and will serve as the NFT Score TS for this analysis. 18F-AV-1451 
PET imaging will be classified as either AD- or AD+/AD++ by each reader. Sensitivity 
and specificity will be calculated for each reader as the proportions of True Positive (TP) 
and True Negative (TN) cases correctly identified as such, according to Table 3 below: 
Table 3: 
Primary Analysis 1: Diagnostic Performance Calculations for AV-1451 
PET Scan Reader Interpretation vs. Autopsy NFT Score TS 
 
 
 
Autopsy NFT Score TS 
Physician Reader 
Interpretation 
NFT Score B3 
[Truth Positive] 
NFT Score B0–B2 
[Truth Negative] 
AV-1451 Neocortical uptake; 
AD pattern (AD+ or AD++) 
 
True Positive (TP) 
False Positive (FP) 
 Neocortical uptake not 
consistent with AD (AD-) 
False Negative 
(FN) 
True Negative (TN) 
 
Two-sided 95% CIs for sensitivity and specificity will be calculated using the Wilson 
score method. The first primary endpoint is considered to be met if for the same 3 out of 5 
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Amendment 2 – 18Dec2017  
Page 9 of 50  
 
Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
readers, the lower bound of the 95% CIs for both sensitivity and specificity are ≥ 50% 
(i.e., statistically significant at two-sided significance level of 0.05).  
Like Primary Analysis 1, the hypothesis to be tested for Primary Analysis 2 is that for the 
same 3 out of 5 readers, the lower bound of the 95% CIs for both sensitivity and the 
specificity will be ≥ 50%. For Primary Analysis 2, autopsy cases will be categorized as 
either [not, low or intermediate] vs. [high] level of AD neuropathologic change according 
to NIA-AA criteria, considering Braak stage, Thal plaque score, and CERAD amyloid 
neuritic plaque score, and this level of AD neuropathologic change will be used as the 
NIA-AA Autopsy Diagnosis TS (Table 2, above).  
18F-AV-1451 PET images will be interpreted by visual examination as either AD- or 
AD+/AD++ by each reader. Sensitivity and specificity will then be calculated for each 
reader as the proportions of True Positive (TP) and True Negative (TN) cases correctly 
identified as such, according to Table 4 below: 
Table 4: 
Primary Analysis 2: Diagnostic Performance Calculations for AV-1451 
PET Scan Reader Interpretation vs. NIA-AA Autopsy Diagnosis TS 
 
 
 
NIA-AA Autopsy Diagnosis TS 
Physician Reader 
Interpretation 
High AD 
Neuropathologic 
Change 
[Truth Positive] 
Not, Low or 
Intermediate AD 
Neuropathologic 
Change 
[Truth Negative] 
AV-1451 Neocortical uptake; 
AD pattern (AD+, AD++) 
 
True Positive (TP) 
False Positive (FP) 
AV-1451 Neocortical uptake 
not consistent with AD pattern 
(AD-) 
False Negative 
(FN) 
True Negative (TN) 
Two-sided 95% CIs will be calculated using the Wilson score method. The second primary 
endpoint is met if for the same 3 out of 5 readers the lower bounds of the 95% CIs for both 
sensitivity and specificity are ≥ 50%. 
The secondary efficacy analyses will assess the performance of the blinded 18F-AV-1451 
PET scan readers in the following two ways:  
Secondary Analysis 1: Assess diagnostic performance of ante-mortem 18F-AV-1451 PET 
imaging based on majority interpretation of 5 independent readers: Diagnostic 
performance will be assessed relative to the Autopsy NFT score TS as per Primary 
Analysis 1 and again relative to the NIA-AA Autopsy Diagnosis TS as per Primary 
Analysis 2. In each case (image), a majority reading result will be derived using each 
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Amendment 2 – 18Dec2017  
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
individual reader’s scan interpretation results. Sensitivity and specificity, and two-sided 
95% CI thereof, will be calculated for the majority interpretation results relative to the 
appropriate TS. The hypotheses to be tested are: 
1a: the majority reading result will have the lower bounds of two-sided 95% CI ≥ 55% 
for both sensitivity and specificity for detection of tau neurofibrillary pathology that 
corresponds to NFT Scores of B3, and 
1b: the majority reading result will have the lower bounds of two-sided 95% CI ≥ 55% 
for both sensitivity and specificity for detection of a pattern of 18F-AV-1451 
neocortical uptake that corresponds to high levels of AD neuropathologic change as 
defined by NIA-AA criteria. 
Secondary Analysis 2: Assess agreement among readers of 18F-AV-1451 PET scans: 
Fleiss’ Kappa statistics will be used to assess inter-reader agreement for the diagnostic 
decisions associated with Primary Analyses 1 and 2. For evaluation of agreement in the 
context of Primary Analysis 1, kappa will be calculated according to the reader 
interpretation classification in Table 3. If Primary Analysis 1 is successful, a second kappa 
will be performed using the reader interpretation classification in Table 4 . The hypothesis 
to test is the observed kappa values are ≥ 0.64 and the lower bound of the two-sided 95% 
CIs for this assessment are ≥ 0.55. 
Safety data will be tabulated. 
 
Sample Size Calculation and Trial Stopping Criteria 
Assuming sensitivity/specificity of approximately 80%, a minimum of 14 autopsy cases in 
each of the truth standard groups (pathological positive or negative) is required for the 
lower bound of the two-sided 95% CI to be > 50% for each individual reader.  The sponsor 
is blinded to the pathology results (truth standard) until after the study is completed and 
the database is locked.  Therefore, in order to ensure that an adequate number of subjects 
are recruited and come to autopsy for each truth standard group, the sponsor will assume 
that subjects diagnosed on clinical grounds as having dementia due to AD will be truth 
standard positive, subjects diagnosed as having no cognitive impairment (cognitively 
normal) will be truth standard negative.  Based on these assumptions, the study sample 
size requirement and trial stopping criteria will be deemed to have been met when  
• the number of subjects diagnosed as having impairment due to AD that have come to 
autopsy, is greater than or equal to 14, AND 
• the number of subjects diagnosed as having no cognitive impairment that have come to 
autopsy is greater than or equal to 14 
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Sponsor: 
Avid Radiopharmaceuticals 
Name of Compound: 
18F-AV-1451  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-
yl)-5H-pyrido[4,3-b]indole 
The sponsor recognizes that there may be some errors in clinical diagnosis such that some 
patients diagnosed clinically as having impairment due to AD may have a nonAD 
pathology, or limited amounts of AD tau pathology, and thus be truth standard negative, 
and, less often, subjects considered clinically normal may have AD pathology and be truth 
standard positive.  However, given the excess frequency of cases with AD diagnoses 
relative to clinically normal subjects already recruited in this trial population, any 
diagnostic errors will likely help ensure a minimum of 14 truth standard negative subjects 
without jeopardizing the criterion for truth standard positive subjects. 
In addition to subjects diagnosed as clinically normal or AD patients, it is expected that 
approximately 10-15 subjects with nonAD impairments will be enrolled and come to 
autopsy in this trial.  However, the proportion of these that will have truth standard 
positive/negative AD tau pathology is very difficult to predict and will depend on the 
precise cases enrolled.  Thus, it is not expected that these cases will be useful in estimating 
when a sufficient number of cases have occurred in each truth standard group and are not 
employed in the stopping criteria.  
No new autopsies will begin once the sample size requirement/trial stopping criteria are 
met.  However, some subjects may have died and had autopsy material removed at the 
time the sample size requirement is met. Histology analysis will be completed in subjects 
for whom autopsies are ongoing at the time the sample size requirement is met and these 
subjects will also be included in the Primary Efficacy Population. 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................ 16 
2. 
TRIAL OBJECTIVES ...................................................................... 19 
2.1. 
Primary Objective: ............................................................................ 19 
2.2. 
Secondary Objective: ........................................................................ 20 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 20 
4. 
TEST DRUG AND CONTROL AGENTS ...................................... 20 
4.1. 
Descriptive Name: 18F-AV-1451 ...................................................... 20 
4.2. 
Radioactive Labeling ........................................................................ 21 
4.3. 
Decay Characteristics ....................................................................... 21 
4.4. 
Formulation and Dose 18F-AV-1451 Injection ................................. 21 
4.5. 
Packaging 18F-AV-1451 Injection .................................................... 21 
4.6. 
Storage and Handling 18F-AV-1451 Injection .................................. 22 
5. 
INVESTIGATIONAL PLAN ........................................................... 22 
5.1. 
Overall Design and Plan of Trial ...................................................... 22 
5.2. 
Planned Dosage and Duration of Treatment ..................................... 24 
5.2.1. 
Dosage and Administration .............................................................. 24 
5.2.2. 
Rationale for Dosage ........................................................................ 24 
5.3. 
Selection of Subjects ......................................................................... 24 
5.3.1. 
Inclusion Criteria .............................................................................. 24 
5.3.2. 
Exclusion Criteria ............................................................................. 25 
5.4. 
Prior and Concomitant Therapy ........................................................ 25 
5.5. 
Removal of Subjects from Trial ....................................................... 25 
5.6. 
Premature Termination of Trial/Closure of Center .......................... 26 
6. 
PRODUCT RISK ASSESSMENT ................................................... 26 
7. 
PROCEDURES AND METHODS .................................................. 26 
7.1. 
Assessment Periods .......................................................................... 26 
7.1.1. 
Screening Visit: ................................................................................ 27 
7.1.2. 
18F-AV-1451 PET Imaging Visit(s): ................................................ 27 
7.1.3. 
Death and Autopsy: .......................................................................... 28 
7.1.4. 
Additional PET Imaging ................................................................... 28 
7.2. 
Observations and Measurements ...................................................... 29 
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7.3. 
Protocol for Image Collection .......................................................... 31 
7.4. 
Good Clinical Practice and Monitoring ............................................ 31 
7.5. 
Informed Consent and Subject Information ..................................... 32 
7.6. 
Documentation .................................................................................. 32 
7.7. 
Adverse Events (AE) ........................................................................ 33 
7.7.1. 
Adverse Event Monitoring ............................................................... 33 
7.7.2. 
Adverse Event Definitions ................................................................ 33 
7.7.3. 
Adverse Event Documentation ......................................................... 35 
7.7.4. 
Reporting of Serious Adverse Events ............................................... 35 
8. 
STATISTICAL ANALYSIS ............................................................ 36 
8.1. 
General Statistical Considerations .................................................... 36 
8.2. 
Populations for Analysis ................................................................... 36 
8.2.1. 
Primary Objective Analyses ............................................................. 36 
8.2.2. 
Secondary Objective Analyses ......................................................... 38 
8.3. 
Safety Analysis ................................................................................. 39 
8.4. 
18F-AV-1451 Image Analysis ........................................................... 39 
8.5. 
Neuropathology Analysis ................................................................. 40 
8.6. 
Sample Size Calculation and Trial Stopping Criteria ....................... 41 
9. 
USE OF DATA AND PUBLICATION ........................................... 42 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................. 42 
10.1. 
Institutional Review Board (IRB) ..................................................... 43 
10.2. 
Informed Consent ............................................................................. 43 
10.3. 
Protocol Adherence .......................................................................... 43 
10.4. 
Documents Necessary for Initiation of the Trial .............................. 43 
10.5. 
Investigational Product Control ........................................................ 43 
10.6. 
Data Collection ................................................................................. 44 
10.7. 
Adverse Events ................................................................................. 44 
10.8. 
Records Retention ............................................................................. 44 
11. 
APPENDICES .................................................................................. 46 
11.1. 
References ......................................................................................... 46 
11.2. 
Trial Flow Chart ............................................................................... 48 
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ABBREVIATIONS AND DEFINITIONS  
Aβ 
Beta amyloid  
AD 
Alzheimer’s disease 
Adverse Event 
(AE) 
Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. 
electronic Case 
Report Form 
(eCRF) 
An electronic form for recording study participants’ data during a clinical 
study, as required by the protocol. 
CNS 
Central Nervous System 
CRO 
Contract Research Organization: A person or organization (commercial, 
academic, or other) contracted by the sponsor to perform one or more of 
the sponsor’s trial-related duties and functions.  
CT 
Computed Tomography 
DMB 
Data Monitoring Board 
Efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
FDA 
US Food and Drug Administration  
FDG 
18F – Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
Institutional 
Review Board 
/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 
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Kd 
Dissociation Constant 
LAR 
Legally Authorized Representative 
MBq 
Megabecquerel 
mCi 
Millicurie 
MCI 
Mild Cognitive Impairment 
MHD 
Maximum Human Dose 
MRI 
Magnetic Resonance Imaging 
NIA-AA 
National Institute on Aging – Alzheimer’s Association 
NFT 
Neurofibrillary Tangle 
NOAEL 
No Observable Adverse Effect Level 
OCN 
Older Cognitively Normal 
PET 
Positron Emission Tomography 
QA 
Quality Assurance 
SUVRs 
Standard Uptake Value Ratios 
TN 
True Negative 
TP 
True Positive 
TS 
Truth Standard 
YCN 
Young Cognitively Normal 
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1. 
INTRODUCTION  
Molecular imaging biomarkers have the potential to aid in the diagnosis of patients with 
cognitive impairment (Dubois et al., 2010; McKhann et al., 2011). PET ligands such as 
florbetapir F 18 (Wong et al., 2010) provide a minimally invasive estimate of cortical 
beta amyloid (Aβ) neuritic plaque deposition, which is a hallmark pathology of 
Alzheimer’s disease (AD) and a required element for the neuropathologic diagnosis of 
AD (Hyman et al., 2012). More recently, imaging biomarkers for tau protein, the other 
required pathology for AD, have become available (Chien et al., 2103; Xia et al., 2013). 
Amyloid is believed to accumulate very early in the AD disease process (Jack et al., 
2010) and may be present in other diseases or as an incidental finding in patients with 
other dementias (Siderowf et al., 2014; Serrano et al., 2014). While amyloid deposition is 
required for the diagnosis of AD, its density or distribution is not associated with disease 
duration or severity (Nelson et al., 2012).  
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 al., 1987; 
Nelson et al., 2012). Thus, a PET imaging agent that binds to phosphorylated tau has 
potential application as a biomarker for disease severity and may be useful for selecting 
patients for therapy, monitoring disease progression and assessing response to putative 
disease modify treatments. 
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; Chien 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 Filament (PHF) Tau isolated brains of 
AD patients yielded a Kd value of 0.54 nM. 
AV-1451 was assessed in competitive binding assays against a panel of 72 of the most 
common central nervous system (CNS) targets and no clinically relevant inhibition was 
seen. AV-1451 was positive in the in vitro hERG assay; however, in vivo cardiovascular 
safety pharmacology assessments in dogs showed no evidence of QT prolongation at 
doses up to 50x the intended maximum human dose (MHD). Nonetheless, until sufficient 
human cardiovascular safety data are available, clinical studies will exclude subjects with 
a history of risk factors for Torsades de Pointes and subjects taking drugs known to 
prolong the QT interval. 
In vivo safety pharmacology studies were also conducted in rats to determine potential 
effects on the CNS and respiratory systems. In these studies no clinically relevant effects 
were reported at doses exceeding 100x the intended MHD. Additionally, non-radioactive 
AV-1451 has been tested in single and repeat-dose toxicology studies in rat and dog. In 
each of these studies the no observable adverse effect levels (NOAELs) were the highest 
doses tested (150x MHD for single, 50x MHD for repeat). 
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Potential genotoxicity of non-radioactive AV-1451 was tested in both in vitro and in vivo 
assays. In the in vitro assays, AV-1451 tested positive for potential genotoxicity. 
However, in the in vivo rat micronucleus assay at doses up to 750x MHD (scaled 
allometrically), AV-1451 showed no evidence of genotoxicity. The different results in the 
in vitro genotoxicity assays and the in vivo micronucleus study are likely related to 
differences in the exposure conditions encountered by the target cells in the different test 
systems. In vivo, AV-1451 is cleared rapidly; however, the in vitro experiments employ 
static, prolonged exposure of cells to high concentrations of the test article. While the in 
vitro data show the potential for genotoxicity, the in vivo data provide assurance that 
genotoxicity is unlikely to occur at clinically-relevant doses for human diagnostic studies. 
Three human clinical studies have been completed with 18F-AV-1451. A total of 59 
subjects have been exposed to 18F-AV-1451 in these studies. The following side effects 
have been reported in clinical studies: diarrhea, headache, and altered taste. All reported 
events were mild in intensity and all subjects recovered from these events. 
Human dosimetry has been obtained in nine subjects. Generally, the radiotracer 
distribution was consistent among the subjects and showed rapid hepatobiliary clearance. 
There were three organs that received estimated doses higher than 0.05 mSv/MBq. The 
organ that received the largest estimated dose was the upper large intestinal wall (0.0962 
± 0. 0134 mSv/MBq), followed by the small intestine and the liver. The Effective Dose 
was 0.0241 ± 0.0016 mSv/MBq. This results in an estimated Effective Dose of 8.70 mSv 
for an anticipated 370 MBq (10 mCi) injection and is comparable to the effective dose of 
approved 18F-labeled compounds such as fluorodeoxyglucose (FDG) and florbetapir F 
18 injection.  
Evaluation of the PET images from completed studies demonstrates little focal cortical 
retention of 18F-AV-1451 in either young cognitively normal (YCN) or older cognitively 
normal (OCN) subjects known to be amyloid negative (florbetapir PET SUVR <1.10; 
Figure 1 Panels A and B). However, OCN subjects frequently demonstrated retention in 
the mesial temporal lobes and some OCN subjects also demonstrated retention in the 
brainstem or striatum (Figure 1 Panel B). In MCI and AD subjects, retention appeared to 
spread from mesial temporal lobes to isocortical areas (Figure 1 Panels C-F). The pattern 
of 18F-AV-1451 distribution seen on PET imaging, across subjects with various levels of 
impairment, paralleled the pattern reported in the classic autopsy series of older persons 
and subsequently used to define the Braak stage (Braak and Braak, 1991). Two clinically 
diagnosed AD subjects that were found to be amyloid negative on a florbetapir PET scan 
were the exception to this pattern, as their scans were similar to clinically normal elder 
controls and showed no cortical 18F-AV-1451 retention (Figure 1 Panel G).  
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Figure 1: 
Representative 18F-AV-1451 PET Scans 
 
 
B) Typical Aβ- Older Control
A) Typical young control subject
D) Aβ+ MCI subject (MMSE = 26)
C) Aβ+ MCI subject (MMSE = 26)
G) Aβ- AD subject (MMSE = 23)
E) Aβ+ AD subject (MMSE = 21)
F) Aβ+ AD subject (MMSE = 18)
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Comparison of tracer binding to aggregated protein with autopsy material is one means of 
validating a novel PET agent. Multiple studies have been completed comparing amyloid 
PET scans to histopathologic assessment of amyloid burden subjects for whom biopsy 
samples were available or who came to autopsy after receiving a PET amyloid scan. 
These studies support the relationship between PET amyloid imaging results and cortical 
neuritic plaque density (Clark et al., 2011, 2012; Leinonen et al., 2008; Sojkova et al., 
2011; Kantarci et al., 2011; Burack et al., 2010). The larger autopsy studies (Clark et al., 
2012; Curtis et al., 2015; Sabri et al., 2015) demonstrated a high sensitivity and 
specificity for amyloid 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). 
By contrast, systematic studies correlating imaging data from tau ligands with post-
mortem verification of AD pathology have not been completed. The goal of this protocol 
is to generate evidence to support the relationship between PET imaging with 18F-AV-
1451 PET imaging and AD neuropathology assessed at autopsy.  
2. 
TRIAL OBJECTIVES 
2.1. 
Primary Objective:  
This study is designed to test the relationship between ante-mortem 18F-AV-1451 PET 
imaging and tau neurofibrillary pathology associated with AD, as measured at autopsy. 
To accomplish this goal, two primary analyses will be performed:  
Primary Analysis 1 
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern 
of 18F-AV-1451 neocortical uptake that corresponds to NFT Score of B3 (Hyman et 
al., 2012; Montine et al., 2012) at autopsy will be evaluated; and if success criteria are 
met, 
Primary Analysis 2 
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern 
of 18F-AV-1451 neocortical uptake that corresponds to high levels of AD 
neuropathologic change as defined by NIA-AA criteria (Hyman et al., 2012) will be 
evaluated. For individuals with cognitive impairment, high levels of AD 
neuropathologic change are considered adequate to explain cognitive impairment or 
dementia symptoms. 
The trial will be considered successful if both co-primary endpoints are met according to 
the Statistical Analysis Plan.  
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2.2. 
Secondary Objective: 
To assess performance of independent, blinded readers of 18F-AV-1451 PET scans: 
Secondary Analysis 1: To assess diagnostic performance of ante-mortem 18F-AV-
1451 PET imaging, based on majority interpretation of 5 independent readers, for 
detection of a pattern of 18F-AV-1451 neocortical uptake that corresponds to 
Neurofibrillary Tangle (NFT) Score of B3 and for detection of a pattern of 18F-AV-
1451 neocortical uptake that corresponds to high levels of AD neuropathologic 
change as defined by National Institute on Aging - Alzheimer’s Association (NIA-
AA) criteria. 
Secondary Analysis 2: To assess agreement among readers of 18F-AV-1451 PET 
scans. 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER 
PARTICIPANTS 
The trial is sponsored by: 
 
Avid Radiopharmaceuticals 
 
The medical contact is: 
 
 
Approximately 30 centers in the United States and Australia will participate. 
4. 
TEST DRUG AND CONTROL AGENTS  
4.1. 
Descriptive Name: 18F-AV-1451 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole 
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MW = 262.27 amu 
4.2. 
Radioactive Labeling 
The compound is labeled with [18F] fluorine that decays by positron (β+) emission and 
has a half-life of 109.77 min. The principal photons useful for diagnostic imaging are the 
511 keV gamma photons, resulting from the interaction of the emitted positron with an 
electron. 
4.3. 
Decay Characteristics 
The time course of radioactive decay for Fluorine [18F] is shown below 
Min. 
Fraction Remaining 
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
Physical decay chart for Fluorine [18F]. Half-life = 109.77 min. 
4.4. 
Formulation and Dose 18F-AV-1451 Injection 
18F-AV-1451 Injection is a sterile, apyrogenic clear solution for intravenous bolus 
administration. 18F-AV-1451 Injection contains 18F-AV-1451 (drug substance) 
formulated in 10% (v/v) ethanol, USP in 0.9% sodium chloride injection, USP. 
The shelf-life of 18F-AV-1451 Injection is dependent on the strength or specific activity 
calculated at End-of-Synthesis (EOS) but is not more than 10 hours post EOS. The 18F-
AV-1451 Injection expiration time and date will be provided on the label on the 
secondary packaging of each vial or syringe.  
4.5. 
Packaging 18F-AV-1451 Injection 
18F-AV-1451 Injection is contained in a sterile, non-pyrogenic septum sealed Type I glass 
vial or a sterile apyrogenic syringe. Vials and syringes containing 18F-AV-1451 Injection 
are stored in an opaque shield (secondary packaging) which protects personnel from 
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radiation exposure. The shield may be packaged in a Type A shipping container for 
shipment to the imaging facility. 
4.6. 
 Storage and Handling 18F-AV-1451 Injection 
18F-AV-1451 Injection is stored at room temperature. 18F-AV-1451 Injection should be 
stored within the original container or equivalent radiation shielding.  
5.
INVESTIGATIONAL PLAN
5.1. 
Overall Design and Plan of Trial 
This study is a clinico-pathological study of the correspondence between 18F-AV-1451 
PET imaging and post-mortem assessment of tau pathology and associated NIA-AA 
pathological diagnosis. 
The screening and imaging procedures have been designed to be tolerable for eligible 
end-of-life patients. Individuals with terminal medical conditions with projected life 
expectancy of ≤ 6 months and/or their LAR will provide informed consent. The subject 
will then receive a PET scan with 18F-AV-1451 and will be followed to death. Subjects 
that have a historical brain MRI, acquired within 12 months of the 18F-AV-1451 PET 
imaging visit, may consent to have the scan made available to the designated imaging 
core lab. If death does not occur within nine months of the 18F-AV-1451 PET scan, the 
subject may be given the opportunity to undergo a second 18F-AV-1451 PET scan and 
continue in the protocol at the sponsor’s discretion (screening assessments will not need 
to be repeated). If the subject subsequently comes to autopsy, the second scan (nearest to 
time of death) will be used in the efficacy analyses.  
Approximately 200 subjects may be enrolled and imaged with 18F-AV-1451 PET. It is 
expected that approximately 80 individuals will undergo post-mortem autopsy (including 
the Primary Efficacy Cohort and 6 subjects in a Front-Runner Cohort). The Primary 
Efficacy Cohort will form the basis for the tests of diagnostic performance. The Primary 
Efficacy Cohort will include all subjects with a valid PET scan that come to autopsy 
before the sample size requirement/trial stopping criteria (Section 8.6) are met (subjects 
for whom autopsies are ongoing at the time the sample size requirement is met will also 
be included in the Primary Efficacy Population). In order to control for the potential 
progressive change in tau deposition over time, cognitively impaired subjects will not 
have an autopsy performed or be included in the Primary Efficacy Cohort if death does 
not occur within nine months of a valid imaging session.  However, because cortical tau 
deposition is expected to occur very slowly, if at all, in cognitively normal (unimpaired) 
subjects, cognitively normal subjects will not be required to undergo repeat scans. 
Cognitively normal subjects will remain eligible for autopsy, regardless of time from first 
scan or second scan to autopsy, and will be included in the primary efficacy cohort if the 
subject comes to autopsy any time before the trial stopping criteria are met. No new 
autopsies will begin once the sample size requirement and trial stopping criteria (Section 
8.6) are met.  However, some subjects may have died and had autopsy material removed 
at the time the sample size requirement is met. Histology analysis will be completed in 
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subjects for whom autopsies are ongoing at the time the sample size requirement is met 
and these subjects will also be included in the Primary Efficacy Population. 
Up to the first 6 subjects that come to autopsy will be considered front-runners. Results 
from the front-runners will be analyzed on a patient-by-patient basis and may be used to 
refine the PET or autopsy methods (e.g. pathology staining/quantitation methods). Upon 
completion of the final front-runner subject analysis, the final imaging and autopsy 
methods will be specified. No additional PET image reads or autopsy analyses will be 
performed until the PET image read and autopsy methods have been finalized. The 
primary efficacy analyses will be performed on those subjects with valid imaging data 
that come to autopsy after the front-runners (Primary Efficacy Cohort). The front-runners 
will not be included in the primary efficacy analyses, but additional analyses of combined 
primary plus front-runner cases may be performed. 
The first 30 PET scans collected will be reviewed by an independent DMB. The DMB 
will assess whether the scans can be evaluated in a manner consistent with methods 
developed in Phase II (18F-AV-1451-A05 Exploratory Phase Cohort) as determined by 
criteria outlined in the Data Monitoring Board Charter. The purpose of establishing these 
criteria for review by the DMB is to ensure that scans in the autopsy population do not 
appear significantly different than scans obtained in early phase studies, where subjects 
were not at end-of-life. The DMB will have the ability to recommend unblinding the 
Sponsor to all 30 cases if a pre-specified number of scans in the autopsy population have 
anomalies not present in the early phase studies. Study enrollment will continue during 
the DMB’s review. In the event the Sponsor proceeds with the DMB recommendation for 
unblinding, the unblinded subjects will be excluded from the Primary Efficacy Cohort 
(neither the scans nor any autopsies will be used in the primary analyses) or the study 
may be terminated. If unblinding occurs, it must be completed before the final image read 
and autopsy methods are specified. If clinically significant incidental findings are 
identified on a PET scan, the DMB will communicate the findings to Avid. This process 
will be described in the DMB Charter. 
Avid personnel will be blinded to the Primary Efficacy Cohort 18F-AV-1451 PET images. 
A single Avid member will perform periodic quality assurance (QA) by reviewing a 
listing of the PET image header data (not to exceed 20% unless issues identified that 
warrant additional review). These QA reviews will serve to ensure quality control 
processes at the imaging core laboratory are adequately performed. Avid staff performing 
the PET image data header QA assessment will not be aware of the clinical status for the 
subjects/images being reviewed. The independent blinded readers and DMB will be 
blinded to the subject clinical status and autopsy results. The pathology core lab(s) will 
be blinded to the subject clinical status, PET scan images, and read results. All other Avid 
personnel will be blinded to the Primary Efficacy Cohort 18F-AV-1451 read results and 
pathology data. 
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5.2. 
Planned Dosage and Duration of Treatment 
5.2.1. 
Dosage and Administration 
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 
mCi) of 18F-AV-1451 Injection. 
5.2.2. 
Rationale for Dosage  
This trial is designed to evaluate the brain tau protein imaging properties of 18F-AV-1451 
to be used in subjects near end-of-life. 18F-AV-1451 will be administered IV in a 
radioactive target dose of 370 MBq with a MHD limited to 20 µg of compound by mass. 
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.  
5.3. 
Selection of Subjects 
Subjects will be enrolled in the study with the intent of capturing a range of tau 
neurofibrillary pathology in AD. In order to accomplish this goal in living subjects, cases 
will be classified based on clinical features that are believed to be related to tau pathology 
such as cognitive status and age. Enrollment will not be formally stratified, but it is 
expected that at least 65% of the subjects enrolled will have dementia or MCI. The study 
sponsor will review enrollment on an ongoing basis to ensure that subjects that represent 
a broad range of age (including individuals aged > 80 years) and cognitive performance 
are enrolled. A limited number of subjects with end stage dementia may be enrolled at 
sponsor’s discretion both to ensure appropriate balance across the cognitive spectrum and 
because these subjects may have difficulty participating in the PET scan. This review will 
be performed based on clinical data only and the sponsor will remain blinded to PET scan 
results. 
5.3.1. 
Inclusion Criteria 
Only subjects who meet all of the following criteria will be reviewed and will be eligible 
to enroll in the study: 
1. Are males or females ≥ 50 years of age; 
2. Have a projected life expectancy of ≤ 6 months as determined by the principal 
investigator (terminal medical condition such as end-stage congestive heart 
failure, end-stage chronic obstructive pulmonary disease [COPD], end-stage renal 
disease, or end-stage cancer); 
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3. Can tolerate a 20 minute PET scan. The principal investigator will carefully 
assess each subject and use medical judgment to determine whether the subject 
can tolerate the PET scan procedure; and 
4. Give informed consent or have a legally authorized representative (LAR) to 
consent for study procedures and brain donation consistent with the legal 
requirements of the State in which they die. 
5.3.2. 
Exclusion Criteria 
Subjects will be excluded from enrollment if they: 
1. Are aggressively being treated with life sustaining measures (e.g., receiving 
chemotherapy, currently on respirator; palliative chemotherapy is allowed); 
2. Are known to have a structural brain lesion that would interfere either with PET 
imaging or pathological assessment. (Such lesions are typically > 2 cm at their 
greatest extent and may include stroke, primary or metastatic neoplasm, other 
tumors or cystic lesions. Subjects with a history of major stroke or other structural 
lesion as well as cases with a history of primary CNS neoplasm or known 
metastatic cancer must be discussed with the study sponsor prior to enrollment); 
3. Have a clinically significant infectious disease, such as Human Immunodeficiency 
Virus (HIV) infection, hepatitis or prion disease; 
4. Are currently receiving any investigational medications except with permission 
from the study sponsor; 
5. Have ever participated in an experimental study with an amyloid or tau targeting 
agent (e.g., immunotherapy, secretase inhibitor); 
6. Have suspected encephalopathy due to alcoholism or end-stage liver disease;  
7. Are females of childbearing potential who are pregnant or not using adequate 
contraception; 
8. Subjects who have a history of risk factors for Torsades de Pointes (TdP) (e.g., 
hypokalemia, family history of Long QT syndrome) or are taking drugs that are 
known to cause QT-prolongation (a list of prohibited and discouraged 
medications is provided by the Sponsor). 
5.4. 
Prior and Concomitant Therapy 
Except as noted in the exclusion criteria, all medications (prescription or over-the-
counter) that have been started prior to screening may be continued during the course of 
the trial. All medications that are continued from the start of the trial or that are started 
during the trial (other than the study medication) must be documented in the case record 
form on the Concomitant Medication Page of the electronic Case Report Form (eCRF).  
5.5. 
Removal of Subjects from Trial 
Subjects must be removed from the trial if: 
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1. Informed consent is withdrawn; or
2. The investigator or the sponsor believes it is in the best interest of the subject to
be removed from the trial.
Subjects may be withdrawn from the trial if a serious adverse event occurs. The date and 
reason for discontinuation should be noted on the eCRF. 
5.6. 
Premature Termination of Trial/Closure of Center 
The sponsor may discontinue the trial at any time. Reasons for discontinuation of the trial 
may include, but are not limited to, new information on safety or efficacy, requests from 
regulatory authorities, changes in business priorities, or study termination upon review of 
the recommendations/findings of the DMB. Additional reasons for center closure may 
include, but are not limited to, excessive protocol violations, inadequate regard for 
subject safety, failure to follow recommended procedures (e.g., documentation), failure 
or inability to accommodate Avid/Contract Research Organization (CRO) monitors or to 
provide required access to data and source documents, staff turnover or inadequate 
staffing, and inadequate enrollment. Except in cases affecting subject safety, the 
investigators will be given a minimum of 30 days to complete final study evaluations for 
ongoing subjects. In all cases of center or study termination, appropriate steps will be 
taken to ensure the safety of study subjects. 
6.
PRODUCT RISK ASSESSMENT
The most up-to-date and complete information regarding the use of 18F-AV-1451 
Injection can be found in the investigator's brochure.  
In brief, 18F-AV-1451 Injection is an experimental imaging agent that will be used at 
relatively low (tracer) doses. Because 18F-AV-1451 Injection is under clinical 
investigation, it is recommended that subjects receiving 18F-AV-1451 Injection be 
followed closely by means of adverse event reporting and vital signs. 
There are no data on the effects of 18F-AV-1451 Injection in human perinatal 
development. For this reason, females must avoid becoming pregnant. Both females and 
males must use adequate contraceptive methods for 24 hours after administration of 18F-
AV-1451 Injection. 18F-AV-1451 Injection must not be administered to females who are 
pregnant or lactating. Males with female partners who are pregnant or of childbearing 
potential must agree to refrain from sexual activity for 24 hours following administration 
of 18F-AV-1451 Injection.  Additionally, males must agree not to donate sperm for 24 
hours following administration of 18F-AV-1451 Injection. 
7.
PROCEDURES AND METHODS
7.1. 
Assessment Periods
See Section 11.2, Trial Flow Chart 
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7.1.1. 
Screening Visit: 
Screening may take place over several days and can occur at multiple locations (e.g. 
hospice, subject’s home, research office, or clinic). All screening assessments will 
preferably be performed within 45 days prior to the PET imaging session. Some 
screening assessments may be performed on the imaging day prior to injection with 
sponsor approval. Screening assessments will include:  
1. Informed consent (for clinical, imaging and autopsy procedures); 
2. Obtain historical brain MRI images if available;  
3. Demographics and baseline characteristics (e.g. birth year, gender, race, ethnicity, 
education); 
4. Medical history and concomitant medications; 
5. Brief physical and neurological exam;  
6. Neurologic disease history (if relevant: date or months since symptom onset, date 
or months since diagnosis, family history of neurologic disease); 
7. Mini-Mental Status Examination (MMSE) may be obtained if the subject is able 
to cooperate with the test; 
8. Caregiver or informant to complete IQCODE; 
9. Urine pregnancy test (for females of childbearing potential); 
10. Vital signs, including the most recent height and weight which will be collected 
from subject’s previous medical record; and 
11. A physician or appropriate designee evaluation and summary of current medical 
status. 
7.1.2. 
18F-AV-1451 PET Imaging Visit(s): 
1. The subject will be seen by a physician prior to dose administration who will 
assess their ability to safely tolerate the imaging procedure; 
2. Females of childbearing potential will have a urine (or serum if required by local 
IRB) pregnancy test prior to injection (the result must be negative for the subject 
to be administered 18F-AV-1451); 
3. A target dose of 370 MBq (10 mCi) of 18F-AV-1451 will be administered 
intravenously and a 20-minute continuous brain PET imaging will begin 80 
minutes post injection; 
4. Images will be reconstructed and reviewed immediately after completion of the 
scan;  
5. Vital signs will be taken immediately prior to administration of 18F-AV-1451, and 
after completion of imaging, prior to discharge; 
6. Subjects will be observed continuously for signs of adverse events (AE) or serious 
adverse events (SAE). All AEs and SAEs will be followed until resolution; 
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7. The injection site will be observed for excessive inflammation or damage to the
surrounding tissue where the dose was injected; and
8. A physician will see the subject prior to discharge to evaluate the subject’s
readiness for discharge.
Follow-Up Phone Call: 
A follow-up phone call to the subject, (or caregiver/informant if 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. End of study for the purpose of adverse event reporting is 
defined as the completion of the follow-up phone call.  
7.1.3. 
Death and Autopsy: 
1. The responsible family member or caregiver/informant will be contacted
immediately after the time of death to obtain a description of events leading up to
death;
2. Subjects will not have an autopsy performed or be included in the primary
analyses if death does not occur within nine months of the most recent imaging
session or if tissue has not been acquired before the required number of autopsies
for the study has been completed.
3. If subject and/or LAR consented, additional research and genetic testing will be
performed on brain tissue.
Detailed autopsy procedures are described in the Technical Autopsy Manual.  
7.1.4. 
Additional PET Imaging 
If death does not occur within nine months of the 18F-AV-1451 PET scan, the subject 
may be given the opportunity to undergo a second 18F-AV-1451 PET scan and continue 
in the protocol at the sponsor’s discretion. In order to obtain a second scan before the 
nine month expiry date, it is recommended the second scan be performed any time 
between six and nine months after the first scan. If the subject agrees to a second 18F-AV- 
1451 PET scan, screening assessments will not be repeated. The procedures in Section 
7.1.2 will be performed and updated medical history /concurrent medications and an 
updated neurological disease diagnosis (according to best available information) will be 
collected. If the subject subsequently comes to autopsy, the second scan (nearest to time 
of death) will be used in the efficacy analyses. Because cortical tau deposition is expected 
to occur very slowly, if at all, in cognitively normal (unimpaired) subjects, cognitively 
normal subjects will not be required to undergo repeat scans. Cognitively normal subjects 
will remain eligible for autopsy, regardless of time from first scan or second scan to 
autopsy, and will be included in the primary efficacy cohort if the subject comes to 
autopsy any time before the trial stopping criteria are met. Subjects of other cognitive 
status that do not consent to a second 18F-AV-1451 PET scan will not be included in the 
primary analyses unless death occurs within nine months of the initial scan.  
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7.2. 
Observations and Measurements 
Informed Consent 
Potential subjects and LARs, if applicable, will be allowed to read a written informed 
consent form. The principal investigator or designee will explain all study procedures, 
risks, and alternative therapies to the subject and LAR, if applicable. The subject and 
LAR will have an opportunity to have all questions answered. The appropriate parties 
will then sign and date the informed consent form, indicating willingness to participate 
in the study and brain donation (see Section 7.5). A copy of the signed informed consent 
will be given to the subject and/or LAR.  
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB) prior to use. 
IQCODE – Short Version 
Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE; Jorm 1994) is a 
tool used to assess cognitive impairment in older people. IQCODE will be administered 
to the subject’s caregiver/informant.  
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. The MMSE will be 
administered at screening to subjects that are able to cooperate with testing. 
Medical History, Neurologic Disease History 
The investigator or designee will obtain a case history at the screening visit. Whenever 
possible, the medical history will be confirmed by medical records. 
•
Relevant demographic information (e.g. birth year, gender, race, ethnicity,
education);
•
Social history/baseline characteristics (e.g. history of alcohol, drug use, and
smoking, prior CSF or genetic testing results);
•
Medical and surgical history;
•
Concurrent medications;
•
Neurologic Disease history (if relevant: date or months since symptom onset,
date or months since diagnosis, family history of neurologic disease);
After the 48 hour follow-up phone call has been completed, additional medical history 
and concurrent medications will not be collected until death or unless the subject 
consents to a second 18F-AV-1451 PET scan.  
Documentation of the events leading up to death will be collected. 
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Physical Examination  
A brief physical examination will be conducted by a medically qualified study team 
member at the screening visit. Clinically significant changes from screening will be 
recorded as adverse events for the relevant study period. 
Neurological Examination  
A brief neurological examination will be performed by a medically qualified study team 
member at the screening visit to evaluate cranial nerves, gait, sensory, and motor 
function, coordination and tendon reflexes. 
MRI 
Historical brain MRIs that have been obtained within 12 months of the 18F-AV-1451 PET 
imaging visit and are available electronically will be sent to the designated imaging core 
lab if the subject provides consent. 
Vital Signs  
Vital signs (pulse rate, respiratory rate, blood pressure) will be taken in the supine 
position at the following time points: 
• Screening Visit 
• 
18F-AV-1451 Imaging Visit  
− Immediately prior to the administration of 18F-AV-1451 Injection; 
− After the completion of imaging prior to discharge. 
Height and Weight 
At the screening visit the most recent body weight and height will be collected from the 
subject’s medical record.  
Optional Brain Tissue Research/Genetic Testing  
Additional research and genetic testing is optional, and may be performed on brain tissue 
and will be outlined in the Neuropathology Analysis Plan or other vendor manual. Where 
local regulations allow, samples will be stored and analysis may be performed on genetic 
variants thought to play a role in dementia or related diseases. Samples will only be used 
for investigations related to disease and drug or class of drugs under study in the context 
of this clinical program. They will not be used for broad exploratory unspecified disease 
or population genetic analysis.  
Samples will be identified by the subject number and stored for up to 15 years after the 
last subject visit for the study at a facility selected by the sponsor. The sample and any 
data generated from it can only be linked back to the subject by investigator-site 
personnel. The results of this testing will not be shared with the principal investigator or 
subjects’ families. 
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Pregnancy Testing  
A urine beta-hCG test will be performed at screening and at the 18F-AV-1451 imaging 
visit(s) prior to injection for females of childbearing potential (defined as pre-
menopausal, less than 2 years post-menopausal or not surgically sterile). A serum 
pregnancy test may also be obtained prior to injection at the 18F-AV-1451 imaging 
visit(s) if required by the local site. 
Physician Visit 
At screening, a physician or designee must see the subject to evaluate their current 
medical status. 
A physician must see the subject prior to drug administration and prior to discharge from 
the 18F-AV-1451 imaging session. At this time, the physician should review all safety 
data and briefly examine/query the subject regarding potential adverse events or other 
treatment issues. 
Brain Autopsy 
For those subjects who come to autopsy, brain harvesting will be performed locally by 
the site in accordance with the Technical Autopsy Manual and tissue will be sent to a 
pathology core lab(s) for neuropathological examination according to the 
Neuropathology Analysis Plan, which will be written prior to the first subject 
neuropathology analysis in this study. Autopsies will not be performed on subjects that 
live longer than nine months after the 18F-AV-1451 PET scan. 
Brain tissue will be under custody of Avid Radiopharmaceuticals for up to 15 years for 
research purposes. During this time Avid may choose to transfer the brain tissue to 
another laboratory for additional study related research, or to a long term storage facility, 
or back to the clinical site or brain bank at which the subject was previously enrolled. 
Autopsy reports will be sent to the principal investigators to share with the subjects’ 
families after the study has been completed. 
7.3. 
Protocol for Image Collection 
The designated imaging core lab will prepare and distribute a PET Technical Operations 
Manual for 18F-AV-1451. Historical brain MRI transmission procedures will be outlined 
in a separate document. 
7.4. 
Good Clinical Practice and Monitoring 
All clinical studies performed under the direction of Avid/CRO will be conducted in 
accordance with applicable regulatory requirements and International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) and Avid/CRO Standard Operating 
Procedures (SOP).  
This includes: 
1. IRB approval: An investigation will be initiated at a study site only after the IRB 
for that study site has given their written approval of the protocol and informed 
consent; 
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2. Informed Consent: Study procedures will not be initiated until the subject and/or
their legally authorized representative (as appropriate) signs the informed consent
form;
3. Recording and monitoring of adverse events as outlined in Section 7.7.3 including
the notification of study site clinical investigators, local IRBs and the FDA
regarding serious adverse event;
4. Avid RP’s obligation to monitor the participating center on a regular basis; and
5. The termination of a center or the trial if conditions apply, as outlined in Section
5.6. 
7.5. 
Informed Consent and Subject Information 
Potential subjects, or their LAR (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 LAR 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 and 
brain donation. 
End-of-life, as well as, AD subjects are potentially a vulnerable population with 
compromised mental capacity. Investigators should take extra care to evaluate a subject’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. If the subject is not 
capable of giving consent, consent may be given by a LAR, consistent with the 
requirements of the State where the subject resides and local IRB guidance. Subjects with 
the capacity to understand that they are engaging in a research study should affirm that 
they do not object to participating. Subjects lacking the capacity to assent and/or dissent 
will not be precluded from participation.  
All informed consent forms must be approved by Avid or designee, and by the 
appropriate 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 subject and/or their legally authorized 
representative for their records. 
7.6. 
Documentation 
18F-AV-1451 PET scans, as well as historical MRI scans, will be saved in an appropriate 
electronic format as specified in the imaging manuals. A copy of all scans will be saved 
at the site/imaging center and a copy of each will be forwarded to the designated imaging 
core lab as described in the imaging manuals. All other data required by the protocol will 
be recorded in the eCRF. All data in the eCRF will be substantiated by “source 
documents,” which consist of the subject’s medical files, etc. All source documentation 
must be made available to Avid and designees. Completed source documents and eCRFs 
may need to be made available and complete for an inspection by the FDA, other 
international regulatory authorities, or Avid at any time. A ballpoint pen should be used 
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to ensure that all copies are legible. eCRFs and all other records must be filed in 
accordance with applicable laws and regulations (see Section 10.6). 
7.7. 
Adverse Events (AE) 
Avid’s standards for recording and reporting adverse events (AEs) are to be followed 
regardless of applicable regulatory requirements that may be less stringent. All AEs must 
be fully recorded on the Adverse Event Page of the eCRF. Investigators will be instructed 
to report to Avid or its designee their assessment of the potential relatedness of each AE 
to investigational product or protocol procedure via electronic data entry. If a subject’s 
treatment is discontinued as a result of an AE, study site personnel must clearly report to 
Avid or its designee via electronic data entry the circumstances and data leading to any 
such discontinuation of treatment. In cases where the investigator notices an 
unanticipated benefit to the subject, 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 investigational product, action taken, and 
outcome). Additionally, any clinically significant findings from vital sign measurements 
or other study procedures including those that result in a diagnosis should be reported as 
an AE to Avid or its designee.  
7.7.1. 
Adverse Event Monitoring 
Each subject must be carefully monitored for adverse events. An assessment must be 
made of the severity/intensity and relationship to the administration of the investigational 
product. 
7.7.2. 
Adverse Event Definitions 
Adverse Events 
For reporting purposes, Avid will distinguish among pre-existing conditions, treatment -
emergent adverse events and trial-emergent adverse events. Pre-existing conditions (i.e., 
undesirable experiences, signs or symptoms that begin prior to the Screening Visit) will 
be recorded on the medical history and/or physical exam eCRF pages. Signs and 
symptoms that are believed to be due to the pre-existing condition (started prior to dose 
of investigational product) do not have to be recorded in the AEs section of the eCRF, 
unless there is an increase in frequency or severity. Additionally, signs or symptoms or 
changes in pre-existing conditions that occur outside the trial-defined adverse event 
reporting will be recorded in medical history. 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. For the purposes of this study, untoward 
medical occurrences will be considered associated with the use of 18F-AV-1451, and thus 
be reported as treatment-emergent adverse events, if they occur within 48 hours after 18F-
AV-1451 administration.  
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In the context of this study, adverse experiences including hospitalizations, medical 
complications and death are expected, since terminal illness is a requirement for entry 
into the study. Thus, if the investigator becomes aware of such events that occur after 
administration of the drug but outside the 48 hour reporting window, these will only be 
reported as adverse events if the investigator believes they are attributable to the 
investigational product or protocol procedure. 
In order to capture possible adverse effects of trial participation, any untoward medical 
occurrences occurring after the informed consent until the administration of 18F-AV-1451 
will be recorded in the CRF for reporting as trial-emergent adverse events. If the subject 
consents to a second 18F-AV-1451 PET scan, trial-emergent adverse events will be 
collected in a similar period, from either date of additional consent (if applicable) or the 
date the dose request for the second scan is submitted to Avid, up to the second 
administration of 18F-AV-1451. 
Serious Adverse Event (SAE) 
An SAE is an AE that results in one of the following outcomes or constitutes one of the 
following events: 
• Death; 
• Initial or prolonged inpatient hospitalization (other than that required by 
protocol; “social hospitalization” or any hospitalization for non-medical 
reasons does not constitute an SAE); 
• A life-threatening experience (that is, immediate risk of dying); 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect; 
• Considered significant by the investigator for any other reason. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
Unexpected Adverse Event 
An unexpected adverse event is an adverse event not previously reported or an adverse 
event that occurs with specificity, severity or frequency that is not consistent with the 
current investigator’s brochure. 
Relationship to Investigational Product 
Investigators will be instructed to report their assessment of the potential relatedness of 
each adverse event to protocol procedure and/or investigational product. The assessment 
of the relationship of an adverse event to the administration of the investigational product 
is a clinical decision based on all available information at the time of the completion of 
the eCRF. 
Intensity/Severity of an Adverse Event 
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In addition to assessing the relationship of the administration of the investigational 
product to adverse events, an assessment is required of the intensity (severity) of the 
event.  
The following classifications should be used: 
Mild: 
A mild adverse event is an adverse event, usually transient in nature and generally not 
interfering with normal activities. 
 
Moderate: 
A moderate adverse event is an adverse event that is sufficiently discomforting to 
interfere with normal activities. 
Severe: 
A severe adverse event is an adverse event that incapacitates the subject and prevents 
normal activities. Note that a severe event is not necessarily a serious event. Nor must a 
serious event necessarily be severe. 
7.7.3. 
Adverse Event Documentation 
All adverse events must be fully recorded on the Adverse Event Page via the Electronic 
Data Capture (EDC) system. Documentation must be supported by an entry in the subject 
file. AEs 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 Eli Lilly or its designee of any SAE within 24 hours of 
their awareness of the event via a sponsor-approved method. Alerts issued via telephone 
are to be immediately followed with official notification on study-specific SAE forms.  
Serious adverse events occurring after a subject receives a dose of investigational product 
will be collected until 48 hours after the dosing of the investigational product, regardless 
of the investigator’s opinion of causation. Therefore, SAEs that occur later than 48 hours 
after the dosing of the investigational product are not required to be reported unless the 
investigator feels the events were related to either investigational product or a protocol 
procedure. 
If a subject experiences an SAE after signing informed consent(s), but prior to receiving 
investigational product, the event will be reported on the eCRF and to Eli Lilly or its 
designee. Previously planned (prior to signing the ICF) surgeries should not be reported 
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as SAEs unless the underlying medical condition has worsened during the course of the 
study. 
8. 
STATISTICAL ANALYSIS  
8.1. 
General Statistical Considerations 
All statistical analyses will be performed using SAS® version 8.2 or higher. The specific 
analyses to address the objectives will be described in the Statistical Analysis Plan (SAP). 
 
8.2. 
Populations for Analysis 
Invalid Data  
Subject specimens for which technical errors result in invalid or uninterpretable autopsy 
specimens (e.g. lost tissue, tissue processed improperly by the site or tissue irretrievably 
missing key identifying information), as determined by the pathology core lab(s), in 
accordance with criteria set in the Technical Autopsy Manual and Neuropathology 
Analysis Plan will be excluded from primary analyses.  
Subjects with invalid or unevaluable PET data will be excluded from analyses. Criteria 
for declaring an image invalid or not evaluable will be specified in advance in the Image 
Review Charter. If an image is considered invalid by the designated imaging core lab, the 
subject will not be followed to autopsy. Valid images will be considered unevaluable 
only if 3 out of 5 independent readers declare the image unevaluable for the same reason. 
Subjects with unevaluable images will be excluded from the Primary Efficacy 
Population.  
8.2.1. 
Primary Objective Analyses 
This study is designed to test the relationship between ante-mortem 18F-AV-1451 PET 
imaging and tau neurofibrillary pathology associated with AD, as measured at autopsy. 
To accomplish this goal, two primary analyses will be performed:  
Primary Analysis 1 
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern 
of 18F-AV-1451 neocortical uptake that corresponds to NFT Score of B3 (Hyman et 
al., 2012; Montine et al., 2012) at autopsy will be evaluated; and if success criteria are 
met, 
Primary Analysis 2 
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ 
interpretations of ante-mortem 18F-AV-1451 PET imaging for detection of a pattern 
of 18F-AV-1451 neocortical uptake that corresponds to high levels of AD 
neuropathologic change as defined by NIA-AA criteria (Hyman et al., 2012) will be 
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evaluated. For individuals with cognitive impairment, high levels of AD 
neuropathologic change are considered adequate to explain cognitive impairment or 
dementia symptoms. 
The trial will be considered successful if both co-primary endpoints are met according to 
the Statistical Analysis Plan.  
For Primary Analysis 1, the hypothesis to be tested is that for the same 3 out of 5 
independent readers, the lower bound of the two-sided 95% CI for both sensitivity and 
the specificity of 18F-AV-1451 PET reading results will be ≥ 50%. As detailed in Section 
8.5 Table 7, NFT scores for autopsy cases will be categorized as either B0/B1/B2 or B3 
level and will serve as the NFT Score TS for this analysis. 18F-AV-1451 PET imaging 
will be classified as either neocortical uptake not consistent with AD (AD-) or neocortical 
uptake consistent with AD (AD+) and consistent with AD and likely to progress (AD++) 
by each reader. Sensitivity and specificity will be calculated for each reader as the 
proportions of TP and TN cases correctly identified as such, according to Table 5 below: 
Table 5: 
Primary Analysis 1: Diagnostic Performance Calculations for AV-
1451 PET Scan Reader Interpretation vs. Autopsy NFT Score TS 
Autopsy NFT Score TS 
Physician Reader 
Interpretation 
NFT Score B3 
[Truth Positive] 
NFT Score B0–B2 
[Truth Negative] 
AV-1451 Neocortical uptake; 
AD pattern (AD+/AD++) 
True Positive (TP) 
False Positive (FP) 
AV-1451 neocortical uptake 
not consistent with AD (AD-) 
False Negative 
(FN) 
True Negative (TN) 
Two-sided 95% CIs for sensitivity and specificity will be calculated using the Wilson 
score method. The first primary endpoint is considered to be met if for the same 3 out of 
5 readers, the lower bound of the 95% CIs for both sensitivity and specificity are ≥ 50% 
(i.e., statistically significant at two-sided significance level of 0.05).  
Like Primary Analysis 1, the hypothesis to be tested for Primary Analysis 2 is that for the 
same 3 out of 5 readers, the lower bound of the 95% CIs for both sensitivity and the 
specificity will be ≥ 50%. For Primary Analysis 2, autopsy cases will be categorized as 
either [not, low, or intermediate] vs. [high] level of AD neuropathologic change 
according to NIA-AA criteria, considering Braak stage, Thal plaque score, and CERAD 
amyloid neuritic plaque score, and this level of AD neuropathologic change will be used 
as the NIA-AA Autopsy Diagnosis TS as detailed in Section 8.5 Table 8.  
18F-AV-1451 PET images will be interpreted by visual examination as either AD- or 
AD+/AD++ as for Primary Analysis 1. Sensitivity and specificity will then be calculated 
for each reader as the proportions of TP and TN cases correctly identified as such, 
according to Table 6 below: 
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Table 6: 
Primary Analysis 2: Diagnostic Performance Calculations for 
AV-1451 PET Scan Reader Interpretation vs. NIA-AA Autopsy 
Diagnosis TS 
 
 
 
NIA-AA Autopsy Diagnosis TS 
Physician Reader 
Interpretation 
High AD 
Neuropathologic 
Change 
[Truth Positive] 
Not, Low, or 
Intermediate AD 
Neuropathologic 
Change 
[Truth Negative] 
AV-1451 Neocortical uptake; 
AD pattern (AD+, AD++) 
 
True Positive (TP) 
False Positive (FP) 
AV-1451 Neocortical uptake; 
Inconsistent with AD pattern  
(AD-) 
 
False Negative 
(FN) 
True Negative (TN) 
 
Two-sided 95% CIs will be calculated using the Wilson score method. The second 
primary endpoint is met if for the same 3 out of 5 readers, the lower bounds of the 95% 
CIs for both sensitivity and specificity are ≥ 50%. 
8.2.2. 
Secondary Objective Analyses 
Secondary Analysis 1:  To assess diagnostic performance of ante-mortem 18F-AV-1451 
PET imaging, based on majority interpretation of 5 independent readers, for detection of 
a pattern of 18F-AV-1451 neocortical uptake that corresponds to Neurofibrillary Tangle 
(NFT) Score of B3 and for detection of a pattern of 18F-AV-1451 neocortical uptake that 
corresponds to high levels of AD neuropathologic change as defined by National Institute 
on Aging - Alzheimer’s Association (NIA-AA) criteria: 
Majority scan interpretation will be derived using individual readers’ scan interpretation 
results. Diagnostic performance of this majority scan interpretation will be assessed 
relative to the Autopsy NFT score TS as per Primary Analysis 1 and again relative to the 
NIA-AA Autopsy Diagnosis TS as per Primary Analysis 2. In each case (image), a 
majority reading result will be derived using each individual reader’s scan interpretations 
results. Sensitivity and specificity, and two-sided 95% CI thereof, will be calculated for 
the majority interpretation results relative to the appropriate TS. The hypotheses to be 
tested are: 
1a: the majority reading result will have the lower bounds of two-sided 95% CI ≥ 
55% for both sensitivity and specificity for detection of tau neurofibrillary pathology 
that corresponds to NFT Score of B3, and  
1b: the majority reading results will have the lower bounds of two-sided 95% CI ≥ 
55% for both sensitivity and specificity for detection of a pattern of 18F-AV-1451 
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neocortical uptake that corresponds to high levels of AD neuropathologic change as 
defined by NIA-AA criteria. 
Secondary Analysis 2: Assess agreement among readers of 18F-AV-1451 PET scans: 
Fleiss’ Kappa statistics will be used to assess inter-reader agreement for the diagnostic 
decisions associated with Primary Analyses 1 and 2. For evaluation of agreement in the 
context of Primary Analysis 1, kappa will be calculated according to the reader 
interpretation classification in Table 5. If Primary Analysis 1 is successful, a second 
kappa will be performed using the reader interpretation classification in Table 6 . The 
hypothesis to test is the observed kappa values are ≥ 0.64 and the lower bound of the two-
sided CIs for this assessment are ≥ 0.55.  
8.3. 
Safety Analysis 
Safety vital signs measurements will be summarized by subject and by evaluation time 
point. Change from baseline (pre-dose time point) values will be determined and 
summarized.  
Adverse events including injection site reactions will be summarized in terms of number 
and percentage of subjects experiencing an AE. The summary will be further broken 
down by system organ class (SOC) and preferred term using Medical Dictionary for 
Regulatory Activities (MedDRA) terms. Adverse events will also be presented by 
severity, relationship to treatment and seriousness. All subjects who experience SAEs or 
who discontinue due to AEs will be summarized. 
Discontinuation  
All subjects who discontinued participation prior to completing the study will be listed 
and their discontinuation reasons will be tabulated. 
Vital Signs 
Changes in vital signs from baseline will be summarized. 
8.4. 
18F-AV-1451 Image Analysis 
18F-AV-1451 retention on PET images from subjects with valid autopsy data will be 
interpreted by visual examination as either  
• Neocortical Uptake Not Consistent with an AD Pattern (AD-: no increased 
neocortical activity in any region or increased activity is isolated to the mesial 
temporal, anterolateral temporal or frontal region(s); 
• Neocortical Uptake Consistent with an AD Pattern (AD+: increased neocortical tracer 
activity in the posterolateral temporal (PLT), parietal (including precuneus), or 
occipital region(s)); or 
• Neocortical Uptake Consistent with an AD Pattern and with Likelihood of Disease 
Progression (AD++, which is a subset of AD+ (Neocortical uptake consistent with an 
AD pattern) where increased tracer activity is found in the parietal (including 
precuneus) region(s) regardless of uptake elsewhere, or in the frontal region in 
addition to PLT, occipital, or parietal region(s)). 
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For the purpose of testing the primary analyses, a scan interpretation will be considered 
positive (hypothesized to correspond to a B3 neuropathology score in Primary Analysis 1 
and  an NIA-AA score of high AD pathology in Primary Analysis 2) if the scan is 
interpreted as at least consistent with an AD pattern (AD+ or AD++). 
Details of the visual PET image review methods will be provided in the Blinded Read 
Manual. 
Images will also be assessed quantitatively (semi-automated computerized measurement 
of SUVRs) for exploratory analysis purposes. Details of the analysis methods will be 
provided in the Quantitative Methodology Document.  
The 18F-AV-1451 PET imaging results will not be shared with the investigator sites or 
subjects and their families prior to the end of the study. 
8.5. 
Neuropathology Analysis 
All neuropathological measurements on brain tissue in this trial will be evaluated in a 
standardized and blinded (with respect to PET image results and subject 
identifying/clinical information) fashion in a qualified laboratory. A Technical Autopsy 
Manual and Neuropathology Analysis Plan will be developed for this study containing all 
methods and measurement procedures. Neuropathological assessment will be derived 
from the NIA-AA guidelines (Hyman et al., 2012; Montine et al., 2012). Sections from 
brain regions recommended for pathological assessment of AD, as well as additional, pre-
specified neocortical regions will be sampled. Staining will follow the procedures 
recommended in the NIA-AA practical approach guidelines. NFT extent will be assessed 
using standard procedures and NFT scores (B0-B3) will be recorded (Hyman et al., 2012; 
Montine et al., 2012). The TS for Primary Analysis 1 will be constructed from NFT 
scores as shown in Table 7. 
Table 7: 
Autopsy NFT Score Truth Standard (Primary Analysis 1) 
Braak 
Stage 
NFT Scorea 
Truth 
Standard 
(TS) 
0 (no NFTs) 
B0  
Negative 
 
I-II 
B1 
III-IV 
B2 
V-VI 
B3 
Positive 
a adapted from Hyman et al., 2012 
 
Amyloid pathology will be evaluated using Thal and CERAD rating systems. 
Distribution of amyloid (Thal plaque score A0-A3; Montine et al., 2012) will be 
recorded. The frequency of neuritic amyloid plaques will be evaluated semi-
quantitatively (CERAD score: none, sparse, moderate or frequent). Potential alternative 
neuropathologies contributing to cognitive impairment will also be considered as 
recommended by Montine et al., 2012, and level of AD neuropathologic change will be 
recorded as none, low, intermediate or high per NIA-AA guidelines (Hyman et al., 2012; 
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Montine et al., 2012). The TS for Primary Analysis 2 will be constructed from levels of 
AD neuropathologic change as shown in Table 8. 
Table 8: 
NIA-AA Autopsy Diagnosis Level of AD Neuropathologic Change 
Truth Standard (Primary Analysis 2) 
Level of AD 
Neuropathologic Change 
Presenta 
Truth Standard 
(TS) 
Not 
Negative 
 
Low 
Intermediate 
High 
Positive 
8.6. 
Sample Size Calculation and Trial Stopping Criteria 
Assuming sensitivity/specificity of approximately 80%, a minimum of 14 autopsy cases 
in each of the truth standard groups (pathological positive or negative) is required for the 
lower bound of the two-sided 95% CI to be > 50% for each individual reader.  The 
sponsor is blinded to the pathology results (truth standard) until after the study is 
completed and the database is locked.  Therefore, in order to ensure that an adequate 
number of subjects are recruited and come to autopsy for each truth standard group, the 
sponsor will assume that subjects diagnosed on clinical grounds as having dementia due 
to AD will be truth standard positive, subjects diagnosed as having no cognitive 
impairment (cognitively normal) will be truth standard negative.  Based on these 
assumptions, the study sample size requirement and trial stopping criteria will be deemed 
to have been met when  
• the number of subjects diagnosed as having impairment due to AD that have come to 
autopsy, is greater than or equal to 14, AND 
• the number of subjects diagnosed as having no cognitive impairment that have come 
to autopsy is greater than or equal to 14 
The sponsor recognizes that there may be some errors in clinical diagnosis such that some 
patients diagnosed clinically as having impairment due to AD may have a nonAD 
pathology, or limited amounts of AD tau pathology, and thus be truth standard negative, 
and, less often, subjects considered clinically normal may have AD pathology and be 
truth standard positive.  However, given the excess frequency of cases with AD 
diagnoses relative to clinically normal subjects already recruited in this trial population, 
any diagnostic errors will likely help ensure a minimum of 14 truth standard negative 
subjects without jeopardizing the criterion for truth standard positive subjects. 
In addition to the above subjects diagnosed as clinically normal or AD patients, it is 
expected that approximately 10-15 subjects with nonAD impairments will be enrolled 
and come to autopsy in this trial.  However, the proportion of these that will have truth 
standard positive/negative AD tau pathology is very difficult to predict and will depend 
on the precise cases enrolled. Thus, it is not expected that these cases will be useful in 
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estimating when a sufficient number of cases have occurred in each truth standard group 
and are not employed in the stopping criteria.  
No new autopsies will begin once the sample size requirement/trial stopping criteria are 
met.  However, some subjects may have died and had autopsy material removed at the 
time the sample size requirement is met. Histology analysis will be completed in subjects 
for whom autopsies are ongoing at the time the sample size requirement is met and these 
subjects will also be included in the Primary Efficacy Population. 
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 analyses will include data from all centers. A 
multicenter publication, reporting the primary analyses data set, with authorship from all 
contributing centers, should precede any other publications. 
10.
INVESTIGATOR’S REGULATORY OBLIGATIONS
All clinical work conducted under this protocol is subject to Good Clinical Practice 
regulations; this may include an inspection by Avid and/or Health Authority 
representatives (FDA, EMA or international regulatory authorities) at any time. 
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10.1. 
Institutional Review Board (IRB) 
The intent of the research program, the trial protocol, the subject information/informed 
consent form and any advertising material used to recruit subjects must be submitted to 
the clinical investigator’s local IRB and its approval must be obtained prior to its use. A 
copy of the approval must be forwarded to Avid. When necessary, an extension or 
renewal of IRB approval must be obtained and also forwarded to Avid. 
10.2. 
 Informed Consent 
A signed, written informed consent for study procedures and brain donation must be 
obtained from each subject and/or LAR. A copy of the signed informed consent should 
be given to the subject and/or LAR for their records. A copy of the local IRB’s approved 
version of the informed consent form must be forwarded to Avid or designee for review 
prior to being used to obtain subject consent. 
10.3. 
 Protocol Adherence 
The protocol must be read thoroughly and the instructions must be followed exactly. 
Where a deviation occurs, it must be documented, the sponsor/monitor informed, and a 
course of action agreed upon. 
10.4. 
 Documents Necessary for Initiation of the Trial 
Avid must be provided with the following documents prior to the enrollment of any 
subjects: 
• Original signed and dated Statement of Agreement page; 
• Copy of the IRB and radiation safety committee approval (if applicable); 
• Copy of the IRB stamped approved consent form; 
• Name and location of the laboratory utilized for laboratory assays, and other 
facilities conducting tests, including laboratory certification number and date 
of certification if available. Avid may be responsible for supplying these to 
the investigator if a central laboratory is used;  
• List of reference range laboratory values. Avid may be responsible for this if a 
central laboratory is used; and 
• Any additional licenses required in order to order to use 18F-AV-1451. 
10.5. 
Investigational Product Control 
The receipt of clinical supplies must be documented at the site. 
All drug supplies for this trial should be retained in a safe and secure place at all times 
during the trial. 18F-AV-1451 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 
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accounted for. After completion of the trial, all remaining clinical supplies must be 
returned to the sponsor or their representative. 
10.6. 
Data Collection 
Electronic case report forms (eCRFs) will be used for this trial. Individual subject files 
should include appropriate source documents, including but not limited to subject’s 
medical records. 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 the designated 
imaging core lab as specified in the PET Technical Operations Manual. 
Each subject’s source file should include an original signed informed consent form. 
When the trial is completed, the informed consent form should be kept on file with other 
trial related records. 
The eCRFs must be kept in order and up-to-date so that they always reflect the latest 
observations on the subjects that are enrolled in the trial. The eCRFs must be completed 
for each subject enrolled in the trial and signed by the investigator. A monitor will verify 
the source data for all information on the eCRF. 
10.7. 
Adverse Events 
All adverse events encountered during the clinical trial must be documented on the eCRF, 
whether or not considered drug-related. 
Eli Lilly must be notified immediately (as soon as possible, and in all cases within 24 
hours) of a drug experience, condition, development, or event, which is considered 
serious. Eli Lilly must be notified immediately of any findings with the use of the drug 
that may suggest significant hazards, contraindications, adverse drug reactions (ADRs) 
and precautions pertinent to the safety of the drug. The investigator will be requested to 
complete a separate report form in addition to the information on the CRF. See section 
7.7.4 for reporting serious adverse events. 
If an SAE is determined to be unexpected (not previously reported or described by Avid), 
and study drug-related, Eli Lilly will notify the investigator in writing. The investigator 
should forward this notification to the IRB within 24 hours of receipt. 
10.8. 
Records Retention 
All correspondence (e.g., with Avid, IRB, etc.) relating to this clinical trial should be kept 
in appropriate file folders. Records of subjects, source documents, and drug inventory 
sheets pertaining to the trial must be kept on file. Records must be retained until the date 
a marketing application (NDA) is approved for the drug for the indication for which it is 
being investigated, or until 3 years following the date of clinical trial termination or 
completion, whichever is later. If no application is to be filed or if the application is not 
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approved for such indication, records should be kept until 3 years following the date of 
clinical trial termination or completion. 
If an investigator moves, withdraws from an investigation, or retires, the responsibility 
for maintaining the records may be transferred to another person who will accept the 
responsibility. Notice of transfer must be made to and agreed upon by Avid. 
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11.
APPENDICES
11.1. 
References 
Braak, H. and Braak, E. “Demonstration of Amyloid Deposits and Neurofibrillary 
Changes in Whole Brain Section.” Brain Pathology. 1991; 1(3):213-216.  
Burack, M.A., Hartlein, J., Flores, H.P., Taylor-Reinwald, L., Perlmutter, J.S., Cairns, 
N.J. “In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia”. 
Neurology. 2010;74(1):77-84. 
Chien, D.T., Bahri, S., Szardenings, A.K., Walsh, J.C., Mu, F., Su, M.Y., Shankle, W.R., 
Elizarov, A., Kolb, H.C., “Early clinical PET imaging results with the novel PHF-tau 
radioligand [18F]-T807.” J Alzheimers Dis. 2013; 34(2):457-68. 
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. 
Curtis, C., et al. “Phase 3 Trial of Flutemetamol Labeled with Radioactive Fluorine 18 
Imaging and Neuritic Plaque Density”. JAMA Neurology, 2015 Mar; 72(3): 287-94. 
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. 
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. 
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Jorm, A. F. (1994). A short form of the Informant Questionnaire on Cognitive Decline in 
the Elderly (IQCODE): Development and cross-validation. Psychological Medicine, 24, 
145-153. 
Kantarci, K., Lowe, V.J., Boeve, B.F., Weigand, S.D., Senjem, M.L., Przybelski, S.A., et 
al. “Multimodality imaging characteristics of dementia with Lewy bodies”. Neurobiol 
Aging 2011: Oct 20. [Epub ahead of print]. 
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. 
Montine, Thomas J., et al. "National Institute on Aging–Alzheimer’s Association 
guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical 
approach." Acta neuropathologica 123.1 (2012): 1-11. 
Nelson, P.T., et al. “Correlation of Alzheimer Disease Neuropathologic Changes with 
Cognitive Status: A Review of the Literature”. J Neuropathol. 71(5), 362-381, 2012. 
Sabri, O., et al. “Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer 
disease: Phase 3 study”. Alzheimer’s & Dementia: The Journal of the Alzheimer’s 
Association, 1-11, 2015. 
Serrano, G.E., Sabbagh, M.N., Sue, L.I., Hidalgo, J.A., Schneider, J.A., Bedell, B.J., Van 
Deerlin, V.M., Akiyama, H., Joshi, A.D., Pontecorvo, M.J., Mintun, M.A., Beach T.G. 
Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic 
Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions. 
Journal of Alzheimer’s Disease, 2014, 42: 814-821. 
Siderowf, A. Pontecorvo, M.J., Shill,H.A., Mintun, M.A., Arora, A., JoshiA.D., Lu, M., 
Adler, C.H., Galasko, D., Liebsack, C., Skovronsky, D.M., Sabbagh, M.N. PET Imaging 
of Amyloid with Florbetapir F 18 and PET Imaging of Dopamine Degeneration With 18F-
AV-133 (Florbenazine) in Patients with Alzheimer’s Disease and Lewy Body Disorders. 
BMC Neurology, 2014, 14: 79-87. 
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. 
Wong, D.F., Rosenberg, P.B., Zhou, Y., et al. “In vivo imaging of amyloid deposition in 
Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)”. J 
Nucl Med. 2010;51(6):913-920. 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent for 
Alzheimer’s disease,” Alzheimers Dement. 2013, 1-11.
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11.2. 
Trial Flow Chart 
Evaluations 
Screening 
Visit 
Pre-Dose 
18F-AV-1451 
Dose 
PET 
Imaging 
(20 minutes) 
End of 
Imaging 
Follow-Up 
Phone Call 
Autopsy 
Signed Consente 
X 
 
 
 
 
 
 
Demographics and baseline 
characteristics 
X 
 
 
 
 
 
 
Medical History/Neurologic 
Disease History 
X 
 
 
 
 
 
Xc 
Concomitant Medication 
X 
 
 
 
 
 
Xc 
Physical Exam/ 
Neurological Exam 
X 
 
 
 
 
 
 
Vital Signsa  
X 
X 
 
 
X 
 
 
IQCODE 
X 
 
 
 
 
 
 
Urine Pregnancy test 
X 
Xb 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
 
18F-AV-1451 Injection 
 
 
X 
 
 
 
 
PET Imaging 
 
 
 
X 
 
 
 
Evaluation by a physician  
Xd 
X 
 
 
X 
 
 
Adverse Events  
X  
X 
X 
X 
X 
X 
 
Serious Adverse Events 
 X 
X 
X 
X 
X 
X 
 
Death  
 
 
 
 
 
 
X 
a Vital signs will be performed in the supine position. Height and weight will be collected from subject’s medical records.  
b A urine or serum pregnancy test is acceptable on imaging day. 
c Documentation of the events leading up to death will be collected including concomitant medications, significant medical events, and cause(s) of death. 
d Evaluation by physician or designee at screening. 
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e Subjects may consent to a second 18F-AV-1451 PET scan 6 months after the initial scan. Cognitively normal subjects will not be required to undergo repeat scans. Cognitively normal subjects will 
remain eligible for autopsy, regardless of time from first scan or second scan to autopsy. 
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Page 
INVESTIGATOR’S AGREEMENT TO PROTOCOL 
Protocol: A Clinico-Pathological Study of the Correspondence Between 18F-AV-1451 
PET Imaging and Post-Mortem Assessment of Tau Pathology 
Date and Version: 18Dec2017 – Amendment 2 
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 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 1 of 41 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
18 F-AV-1451-A16 
A Clinico-Pathological Study of the Correspondence Between 18F-AV-
1451 PET Imaging and Post-Mortem Assessment of Tau Pathology 
 
 
 
AUTHOR:
VERSION NUMBER AND DATE: FINAL, V1.0, 15AUG2018 
 
 
 
 


@Avid 
Avid Radiopharmaceuticals, Inc. / &:w t
._....,CAL ANAI.YSlS PLAN: PROTOCOL Slf.AV-14S1-Al 6 
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Page 2 of41 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
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that the content Is acceptable for the reporting of this study. 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 3 of 41 
 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
Final, v1.0 
15Aug2018 
Not Applicable – First Version 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 4 of 41 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION 
8 
2. 
STUDY OBJECTIVES 
8 
2.1. 
Primary Objective ....................................................................................................................................... 8 
2.2. 
Secondary Objectives ................................................................................................................................. 8 
3. 
STUDY DESIGN 
9 
3.1. 
General Description .................................................................................................................................... 9 
3.2. 
Evaluation of 18F-AV-1451 PET images ...................................................................................................... 13 
3.3. 
Neuropathological Evaluation .................................................................................................................. 13 
3.4. 
Blinding .................................................................................................................................................... 14 
3.5. 
Changes to Analysis from Protocol ........................................................................................................... 15 
4. 
PLANNED STATISTICAL ANALYSES 
15 
5. 
ANALYSIS SETS 
16 
5.1. 
All Subjects Enrolled Set ........................................................................................................................... 16 
5.2. 
Safety Analysis Set ................................................................................................................................... 16 
5.3. 
Modified Intent-to-Treat Analysis Set ...................................................................................................... 16 
5.4. 
Full Analysis Set ........................................................................................................................................ 16 
5.4.1. 
Full Analysis Set #1 
17 
5.4.2. 
Full Analysis Set #2 
17 
5.5. 
Efficacy Analysis Set ................................................................................................................................. 17 
5.5.1. 
Efficacy Analysis Set #1 
17 
5.5.2. 
Efficacy Analysis Set #2 
18 
5.6. 
Sensitivity Analysis Set ............................................................................................................................. 18 
6. 
GENERAL CONSIDERATIONS 
19 
6.1. 
Reference Start Date and Study Day ......................................................................................................... 19 


 
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Page 5 of 41 
6.2. 
Baseline .................................................................................................................................................... 19 
6.3. 
Repeats, Unscheduled Visits and Early Termination Data ......................................................................... 19 
6.4. 
Windowing Conventions .......................................................................................................................... 20 
6.5. 
Software Version ...................................................................................................................................... 20 
7. 
STATISTICAL CONSIDERATIONS 
20 
7.1. 
Sample Size Justification and Trial Stopping Criteria ................................................................................. 20 
7.2. 
Multicenter Studies .................................................................................................................................. 21 
7.3. 
Missing data ............................................................................................................................................. 21 
7.4. 
Hypotheses Testing and Multiple Comparisons/ Multiplicity ................................................................... 22 
7.5. 
Statistical Models ..................................................................................................................................... 22 
7.5.1. 
Sensitivity, Specificity, Positive and Negative Predictive Values, and Likelihood Ratios 
22 
7.5.2. 
Simple Kappa Coefficient 
23 
7.5.3. 
Fleiss’ Kappa 
24 
7.6. 
Examination of Subgroups ........................................................................................................................ 24 
8. 
OUTPUT PRESENTATIONS 
24 
9. 
DISPOSITION AND WITHDRAWALS 
24 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
25 
10.1. Derivations ............................................................................................................................................... 26 
11. 
MEDICAL HISTORY 
26 
11.1. Derivations ............................................................................................................................................... 27 
12. 
MEDICATIONS 
27 
13. 
IQCODE AND MMSE 
28 
14. 
EXPOSURE TO 18F-AV-1451 
28 
15. 
EFFICACY OUTCOMES 
29 
15.1. Primary Efficacy ........................................................................................................................................ 29 
15.1.1. 
Primary Efficacy Analysis #1 
29 


 
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Page 6 of 41 
15.1.2. 
Primary Efficacy Analysis #2 
29 
15.1.3. 
Supportive Analysis to Primary Efficacy Analyses 
30 
15.1.4. 
Subgroup Analyses to Primary Efficacy Analyses 
30 
15.2. Secondary Efficacy .................................................................................................................................... 31 
15.2.1. 
Diagnostic Performance of Ante-Mortem 18F-AV-1451 PET Imaging Based on Majority Interpretation of 
5 Independent Readers 
31 
15.2.2. 
Inter-Rater Agreement Among Readers of 18F-AV-1451 PET Imaging Interpretation 
31 
15.2.3. 
Supportive Analysis to Secondary Efficacy Analyses 
31 
15.2.4. 
Subgroup Analyses to Secondary Efficacy Analyses 
32 
15.3. Exploratory Efficacy .................................................................................................................................. 32 
15.3.1. 
Supportive Analysis to Exploratory Efficacy Analyses 
32 
15.3.2. 
Subgroup Analyses to Exploratory Efficacy Analyses 
33 
15.4. Other Efficacy ........................................................................................................................................... 33 
15.4.1. 
Supportive Analysis to Other Efficacy Analysis 
33 
15.4.2. 
Subgroup Analyses to Other Efficacy Analysis 
33 
16. 
SAFETY OUTCOMES 
33 
16.1. Adverse Events ......................................................................................................................................... 33 
16.1.1. 
All TEAEs 
34 
16.1.1.1. 
Severity 
34 
16.1.1.2. 
Relationship to Study Medication 
34 
16.1.1.3. 
Relationship to Study Procedures 
34 
16.1.2. 
Injection Site Reactions 
34 
16.1.3. 
Adverse Events with an Outcome of Death 
34 
16.1.4. 
Serious Adverse Events 
35 
16.1.5. 
TEAEs Leading to Discontinuation of Study 
35 
16.2. Laboratory Evaluations ............................................................................................................................. 35 
16.3. ECG Evaluations ........................................................................................................................................ 35 
16.4. Vital Signs ................................................................................................................................................. 35 
16.4.1. 
Potentially Clinically Significant Abnormal Vital Signs Criteria 
35 
16.5. Physical and Neurological Examinations ................................................................................................... 36 
17. 
REFERENCES 
37 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
38 
Output Conventions ............................................................................................................................................ 38 
Dates & Times ...................................................................................................................................................... 38 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 7 of 41 
Spelling Format .................................................................................................................................................... 38 
Outputs Presentation .......................................................................................................................................... 38 
Listings ................................................................................................................................................................. 39 
APPENDIX 2. PARTIAL DATE AND/OR TIME CONVENTIONS 
40 
Algorithm for Prior / Concomitant Medications ................................................................................................... 40 
Algorithm for Treatment Emergence of Adverse Events ...................................................................................... 40 
 
 
LIST OF TABLES 
Table 1 
Schedule of Events ............................................................................................................................ 12 
Table 2 
Autopsy NFT Score Truth Standard ................................................................................................... 14 
Table 3 
NIA-AA Autopsy Diagnosis Level of AD Neuropathological Change Truth Standard .......................... 14 
Table 4 
Potentially Clinically Significant Abnormal Vital Signs Criteria .......................................................... 36 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 8 of 41 
1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of safety 
and efficacy for Avid Radiopharmaceuticals protocol 18F-AV-1451-A16 final analysis.  It described the data 
to be summarized and analyzed, including specifics of the statistical anlayses to be performed. 
 
This statistical analysis plan (SAP) is based on final protocol amendment 3, dated 03-Apr-2018. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
This study is designed to test the relationship between ante-mortem 18F-AV-1451 Positron Emission 
Tomography (PET) imaging and tau neurofibrillary pathology associated with Alzheimer’s disease (AD), as 
measured at autopsy.  To accomplish this goal, two primary analyses will be performed: 
1. The diagnostic performance (sensitivity/specificity) of 5 independent readers’ interpretations of 
ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 neocortical 
uptake that corresponds to Neurofibrillary Tangle (NFT) scores of B3 (Hyman et al., 2012; Montine 
et al., 2012) as measured at autopsy will be evaluated; and if success criteria are met, 
2. The diagnostic performance (sensitivity/ specificity) of 5 independent readers’s interpretation of 
ante-mortem 18F-AV-1451 PET imaging for detection of a pattern of 18F-AV-1451 neocortical 
uptake that corresponds to high levels of AD neuropathologic change as defined by National 
Institute on Aging Alzheimer’s Association (NIA-AA) criteria (Hyman et al., 2012) as measured at 
autopsy will be evaluated.  For individuals with cognitive impairement, high levels of AD 
neuropathologic change are considered adequate to explain cognitive impairement or dementia 
symptoms. 
The trial will be considered a success if both primary analyses are met. 
2.2. SECONDARY OBJECTIVES 
The secondary objectives are: 
 
To assess diagnostic performance of ante-mortem 18F-AV-1451 PET imaging, based on majority of 
interpretation of 5 independent readers, for detection pattern of 18F-AV-1451 neocortical uptake 
that corresponds to NFT scores of B3 at autopsy and for detection of a pattern of 18F-AV-1451 
neocortical uptake that corresponds to high levels of AD neuropathologic change as defined by 
NIA-AA crieria at autopsy. 
 
To assess agreement among readers of 18F-AV-1451 PET scans. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 9 of 41 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This study is a clinico-pathological study of the correspondence between ante-mortem 18F-AV-1451 PET 
imaging and post-mortem assessment of tau pathology and associated NIA-AA pathological diagnosis. 
 
Approximately 200 subjects with terminal medical conditions and projected life expectancy of ≤ 6 months 
were to be enrolled and imaged with 18F-AV-1451 in order to obtain post-mortem histological data on 
approximately 80 subjects (including up to 6 subjects in a Front-Runner Cohort and up to 74 subjects in 
the Primary Efficacy Analysis Cohort; see below for more details).  Enrollment was not formally stratified, 
but an effort was made to enroll subjects with cognitive status ranging from normal cognition to mild 
cognitive impairment (MCI) and dementia to achieve a full range of tau pathology.  It was expected that 
at least 65% of the subjects enrolled will have MCI or dementia. 
 
The screening and imaging procedures were desgined to be tolerable for eligible end-of-life subjects.  
Individuals with terminal medical conditions with projected life expectancy of ≤ 6 months and/or their 
legally authorized representative (LAR) provided informed consent.  The subject then received a PET scan 
with 18F-AV-1451 and was followed to death. 
 
In order to control for the potential progressive change in tau deposition over time, cognitively impaired 
subjects for who death did not occur within nine months of the 18F-AV-1451 PET scan were given the 
opportunity to undergo a second 18F-AV-1451 PET scan and continue in the protocol at the Sponsor’s 
discretion.  In order to obtain a second PET scan before the nine month expiry date, it was recommended 
that the second scan be performed any time between six and nine months after the first scan.  If the 
subject agreed to a second 18F-AV-1451 PET scan, screening asssessments were not repeated with 
exception of any updates to the medical history/concurrent medications and an updated neurological 
disease diagnosis (according to best available information) which were collected at the time of the second 
18F-AV-1451 PET imaging visit.  If the subject subsequently came to autopsy, the data (neurological disease 
diagnosis and 18F-AV-1451 PET scan) from the second 18F-AV-1451 PET imaging visit (nearest to time of 
death) will be used in the analyses.  Cognitively normal (unimpaired) subjects were not required to 
undergo repeat scans, even if death occurred more then nine months after the 18F-AV-1451 PET scan, 
because cortical tau deposition was expected to occur very slowly, if at all, in such subjects.  That is, 
cognitively normal subjects remained eligible for autopsy, regardless of time from first or second scan to 
autopsy, and will be included in the Primary Efficacy Analysis Cohort if the subject came to autopsy at any 
time before the trial stopping criteria were met (refer to Section 7.1). 
 
Up to the first 6 subjects that come to autopsy were to be considered as ‘front-runners’.  Avid were not 
blinded to the front-runner imaging and pathology results.  These results were analyzed on a patient-by-
patient basis and were used to refine the PET or autopsy methods (e.g., pathology staining, quantitation 
methods, etc.).  Upon completion of the final front-runner subjects analysis, the final imaging and autopsy 
methods were specified.  No additional PET image reads or autopsy analyses were performed until the 
PET image read and autopsy methods were finalized.  The front-runners will not be included in the Primary 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 10 of 41 
Efficacy Analysis Cohort, but additional analyses of combined Primary Efficacy Analysis plus Front-Runner 
Cohorts will be performed.  It is to be noted that the first three subjects who came to autopsy were 
considered as front runners.  That is, all subjects who came to autopsy starting with the the fourth subject 
who came to autopsy were elligible to be part of the Primary Efficacy Analysis Cohort. 
 
The Primary Efficacy Analysis Cohort includes all subjects with valid autopsy after the Front-Runner Cohort 
was completed, but before the sample size requirement/trial stopped criteria were met (refer to Section 
7.1).  Subjects for whom autopsies were ongoing at the time of the sample size requirement/trial stopped 
criteria were met are also included in the Primary Efficacy Analysis Cohort. 
 
Each subject had a screening visit, up to two 18F-AV-1451 PET scan imaging visits1, and a follow-up phone 
call after each imagining visit.  Prior to each 18F-AV-1451 PET scan, all subjects received a single 
intravenous (IV) bolus administration target dose of 370 MBq (10 mCi) of 18F-AV-1451 injection.  Subjects 
who came to autopsy during study received a post-mortem evaluation.  Specific details of assessments 
that were performed at each visit can be found in Table 1. 
 
The first 30 PET scans collected (including front-runner subjects) were to be reviewed by an independent 
Data Monitoring Board (DMB) to assess whether the scans could be evaluated in a manner consistent with 
methods developed in Phase II (18F-AV-1451 Exploratory Phase Cohort) as determined by criteria outlined 
in the DMB Charter.  The DMB had the ability to recommend unblinding of the Sponsor to all 30 cases if a 
pre-specified number of scans in the autopsy population had anomalies not present in the early phase 
studies.  Study enrollment continued during the DMB’s review.  In the event the Sponsor proceeded with 
a DMB recommendation for unblinding, the unblinded subjects were to be excluded from the Primary 
Efficacy Analysis Cohort (neither scans nor any autopsies were to be used in the primary analyses) or the 
study might have been terminated.  If unblinding was to occur, it should have been completed before the 
final image read and autopsy methods were specified.  It is to be noted that, as planned, the DMB 
reviewed scans from the first 30 cases in a pre-specified manner.  The DMB did not recommend 
unblinding.  Therefore, the first 30 cases (with the exception of the front-runners) are eligible to be 
included in the Primary Efficacy Analysis Cohort. 
 
In addition, the Sponsor was aware of a number of cases who received 18F-AV-1451 and came to autopsy 
in studies conducted by independent investigators outside of this protocol.  The Sponsor identified all 
investigators/institutions known to have collected at least one case that was reasonably likely to be truth 
standard (TS) negative at autopsy (refer to Section 3.3 for TS negative definition).  The Sponsor then 
worked with the investigators to obtain 18F-AV-1451 images and autopsy tissue from all cases that have 
come to autopsy at that institution (both TS positive and negative cases).  Although not recruited and 
imaged under protocol A16, these cases would have been used to expand the main efficacy analysis set 
i.e., the Efficacy Analysis Set (EFF; refer to Section 5.5), should the minimum number of cognitively normal 
                                                          
1 Should a 18F-AV-1451 PET image obtained during a subject first 18F-AV-1451 PET scan imaging visit be deemed  
invalid (refer to Section 3.2), then this first imaging visit could have been repeated in order to obtain a valid 18F-
AV-1451 PET image.  Similarly, should a subject for who death did not occur within nine months of the first valid 
18F-AV-1451 PET image agreed to come to another 18F-AV-1451 PET scan imaging visit and should the 18F-AV-
1451 PET scan image obtained at that imaging visit be deemed as invalid, this second 18F-AV-1451 PET scan 
imaging could have been repeated in order to obtain a second valid 18F-AV-1451 PET image. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 11 of 41 
subjects required by the sample size would not have been reached among the subjects enrolled under 
this protocol.  It is to be noted that, as mentioned in the protocol (Section 8.6), an independent statistician 
who is not an employee of the Sponsor and who is not involved in the conduct and analysis of the study 
examined the pathology consensus data after the third consensus panel meeting and notified the Sponsor 
that the stopping criteria had been met (i.e., at least 14 cases in each of the TS positive and negative 
categories came to autopsy; refer to Section 7.1).  Hence, the cases recruited by independent investigators 
outside of this protocol will not be included in the EFF, but supportive analyses with these cases will be 
performed.  These supportive analyses will be detailed in a separate SAP. 
 
 


 
 
 
 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 12 of 41 
Table 1 Schedule of Events 
Evaluations 
Screening Visit 
Pre-Dose 
18F-AV-1451 
Dose 
PET Imaging 
(20 minutes) End of Imaging 
Follow-Up 
Phone Call 
Autopsy 
Signed ConsentA 
X 
 
 
 
 
 
 
Demographics and Baseline 
Characteristics 
X 
 
 
 
 
 
 
Medical History/Neurologic 
Disease History 
X 
 
 
 
 
 
XB 
Concomitant Medication 
X 
 
 
 
 
 
XB 
Physical Exam/ Neurological 
Exam 
X 
 
 
 
 
 
 
Vital SignsC 
X 
X 
 
 
X 
 
 
IQCODE 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
XD 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
 
18F-AV-1451 Injection 
 
 
X 
 
 
 
 
PET Imaging 
 
 
 
X 
 
 
 
Evaluation by a physician 
XE 
X 
 
 
X 
 
 
Adverse Events  
X 
X 
X 
X 
X 
X 
 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
 
Death  
 
 
 
 
 
 
X 
A Subjects might have consented to a second 18F-AV-1451 PET scan 6 to 9 months after the initial scan.  Cognitively normal subjects were not 
required to undergo repeat scans and remained eligible for autopsy, regardless of time from first or second scan to autopsy. 
B Documentation of the events leading up to death was collected including concomitant medications, significant medical events, and cause(s) of 
death. 
C Vital signs were performed in the supine position. Height and weight were collected from subject’s medical records. 
D A urine or serum pregnancy test was acceptable on imaging day. 
E Evaluation by physician or designee at screening. 


 
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Page 13 of 41 
3.2. EVALUATION OF 18F-AV-1451 PET IMAGES 
Criteria for declaring an image invalid or not evaluable were specified in advance in the Image Review 
Charter.  In this SAP, valid images will be considered as unevaluable only if at least 3 out of 5 independent 
readers declare the image unevaluable for the same reason(s). 
 
18F-AV-1451 retention of PET images were interpreted by visual examination as either 
 
AD-: neocortical uptake not consistent with an AD pattern i.e., no increased neocortical activity 
in any region or increased activity is isolated to the mesial temporal, anterolateral temporal or 
frontal region(s);  
 
AD+: neocortical uptake consistent with an AD pattern i.e., increased neocortical tracer activity 
in the posterolateral temporal (PLT), parietal (including precuneus) or occipital region(s); or 
 
AD++: neocortical uptake consistent with an AD pattern and with likelihood of disease 
progression i.e., increased neocortical tracer activity is found in the parietal (including percuneus) 
region(s) regardeless of uptake elsewhere (subset of AD+) or in the frontal region in addition to 
PLT, occipital or parietal region(s). 
 
For the purpose of testing the primary analyses, a scan interpretation will be considered positive 
(hypothesized to correspond to a B3 NFT score for the first primary efficacy analysis and an NIA-AA score 
of high AD pathology for the second primary efficacy analysis) if the scan was interperted as at least 
consistent with an AD pattern (AD+ or AD++). 
 
Images were also assessed quantitatively (computerized measurement of Standard Uptake Value Ratios 
[SUVRs]) for exploratory analysis purposes.  
 
The 18F-AV1451 PET imaging results will not be shared with the investigator sites or subjects and their 
families prior to the end of the study. 
3.3. NEUROPATHOLOGICAL EVALUATION 
All neuropathological measurements on brain tissue in this trial were evaluated in a standardized fashion 
in a qualified laboratory.  In this SAP, subject autospy specimens for which technical errors resulted in 
invalid or uninterpretable autospy specimens (as determined by the pathology core laboratory in 
accordance with criteria set in the Technical Autopsy Manual and Neuropathology Analysis Plan) will be 
considered as being invalid and/or uninterpretable if the specimens were assessed as being ‘not 
evaluable’ for both hemispheres in the Braak Stage or NIA-AA autopsy diagnosis by the consensus panel, 
as appropriate for the primary efficacy endpoint #1 (refer to Section 15.1.1) and primary efficacy endpoint 
#2 (refer to Section 15.1.2). 
 
Neuropathological assessment was derived from the NIA-AA guidelines (Hyman et al., 2012).  Sections 
from brain regions recommended for pathological assessment of AD, as well as additional, pre-specified 


 
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Page 14 of 41 
neocortical regions were sampled.  Staining followed the procedures recommended in the NIA-AA 
practical approach guidelines.  NFT extent was assessed using standard procedures and NFT score (B0-B3) 
was recorded (Hyman et al., 2012; Montine et al., 2012).  The TS for the first primary efficacy analysis was 
constructed from NFT scores at autopsy as shown in Table 2. 
Table 2 Autopsy NFT Score Truth Standard 
Braak Stage 
NFT ScoreA 
Truth Standard 
0 (no NFTs) 
B0 
Negative 
I-II 
B1 
III-IV 
B2 
V-VI 
B3 
Positive 
A Adapted from Hyman et al., 2012. 
 
Amyloid pathology was evaluated using Thal and CERAD rating systems.  Distribution of amyloid (Thal 
plaque score A0-A3; Montine et al., 2012) was recorded.  The frequency of neuritic amyloid plaques was 
evaluated semi-quantitatively (CERAD score: none, sparse, moderate or frequent).  Potential alternative 
neuropathologies contributing to cognitive impairment were also considered, as recommended by 
Montine et al., 2012, and level of AD neuropathologic change was recorded as none, low, intermediate or 
high as per NIA-AA guidelines (Hyman et al., 2012; Montine et al., 2012).  The TS for the second primary 
efficacy analysis was constructed from levels of AD neuropathological change as shown in Table 3. 
Table 3 NIA-AA Autopsy Diagnosis Level of AD Neuropathological Change Truth Standard 
Level of AD Neuropathological Change PresentA 
Truth Standard 
None 
Negative 
Low 
Intermediate 
High 
Positive 
A Adapted from Hyman et al., 2012. 
3.4. BLINDING 
A single Avid member performed periodic quality assurance (QA) by reviewing a listing of the PET image 
header data throughout the course fo the study.  These QA reviews served to ensure image quality control 
processes at the imaging core laboratory was adequately performed.  Avid staff performing PET image 
data QA assessment was not aware of the clinical status for the subjects/images being reviewed and 
pathology data.  After the independent visual reads was completed, PET scan images were transferred to 
Avid for SUVr analysis which was done blinded to visual read results and pathology data.  Only designated 
Avid personnel responsible for image QC and SUVr analysis had access to the image data.  All other Avid 
personnel are blinded to the Primary Efficacy Analysis Cohort 18F-AV-1451 PET images and visual read 
results as well as to the pathology data until database lock (DBL). 
 
The independent visual readers and DMB were blinded to the subject clinical status and pathology data. 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 15 of 41 
The pathological core laboratory was blinded to the subject clinical status, PET scan image(s), and visual 
read results. 
 
IQVIA Biostatistical team (including statistical programmers) are blinded to the Primary Efficacy Analysis 
Cohort 18F-AV-1451 PET scan images, visual read results, and pathology data until DBL. 
 
For additional details about blinding and unblinding, refer to the PET imaging read manual, pathological 
analysis manual, and Biostatistics Unblinding Plan, as appropriate.  
 
Finally, an independent statistician who is not an employee of the Sponsor and who is not involved in the 
conduct and analysis of the study reviewed the pathology consensus data in an unblinded fashion after 
the third consensus panel meeting in order to determined if the sample size requirement/trial stopped 
criteria were met (i.e., at least 14 cases in each of the TS positive and negative categories have came to 
autopsy; refer to Section 7.1).  The independent statistician was blinded to the PET scan images and visual 
read results 
3.5. CHANGES TO ANALYSIS FROM PROTOCOL 
As per protocol Section 8.4, only 18F-AV-1451 PET images from subjects with valid autopsy data were to 
be interpreted by visual examination.  However, all collected 18F-AV-1451 PET images of subjects who 
were still active in the study (i.e., who could potentially come to autopsy) at the time the visual reads were 
conducted, were interpreted by visual examination, regardless of the validity of the autopsy data. 
 
During the study, it was identified that the imaging core laboratory (InVicro) included ~10% randomly 
selected scans for a second read by each imaging reader. This was a violation of the protocol.  That is, 
rereads were not planned for this protocol because 1) the expected sample size for reads was small and 
2) an intra-reader reliability has already been performed in a larger, target population-like sample 
population in study A05.  Therefore, the second read data from this study will not be used for any analyses 
exception of an intra-reader consistency evaluation (refer to Section 15.4). 
4. PLANNED STATISTICAL ANALYSES 
No interim analysis (IA) or analysis for a Data Safety Monitoring Board (DSMB) committee were 
performed.  That is, the only statistical analysis that will be performed for this study is the final analysis.  
This analysis will be performed by IQVIA Biostatistics following Sponsor authorization of this SAP, DBL, and 
study unblinding.  Considering that the definition of each analysis set defined in this SAP (refer to Section 
5) does not include any subjective criterion, Sponsor approval of this SAP will stand for the Sponsor 
approval of the inclusion/exclusion of each subject in/from each analysis set. 


 
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Page 16 of 41 
5. ANALYSIS SETS 
5.1. ALL SUBJECTS ENROLLED SET 
The all subjects enrolled analysis set (ENR) will contain all subjects who provided informed consent and 
received at least one 18F-AV-1451 injection.  Subjects who provided informed consent, completed 
screening evaluation but did not receive any 18F AV-1451 injection will be treated as screen failures and 
will not be analyzed.  
 
This analysis set will be used to summarize subjects’ disposition, major protocol devations, and analysis 
sets data (refer to Section 9).  Summaries will be presented overall and by most recent neurological 
disease diagnosis i.e., normal, mild cognitive impairment, and dementia. 
5.2. SAFETY ANALYSIS SET 
The safety analysis set (SAF) will be the same as ENR i.e., include all subjects who provided informed 
consent and received at least one 18F-AV-1451 injection. 
 
This analysis set will be used to summarize demographic and other baseline characteristics (refer to 
Section 10), medical/surgical history, concurrent medical conditions/diseases, family neurological disease 
history, and subjects neurological disease history (refer to Section 11), concomitant medications (refer to 
Section 12), cognition assessments at screening (refer to Section 13), exposure to 18F-AV-1451 (refer to 
Section 14), and all safety data (refer to Section 16).  Summaries will be presented overall and by most 
recent neurological disease diagnosis. 
5.3. MODIFIED INTENT-TO-TREAT ANALYSIS SET 
The modified Intent-to-Treat analysis set (mITT) will include all SAF subjects (refer to Section 5.2) recruited 
under this protocol with available PET Scan visual interpretation data (regardless of PET Scan image 
validity and evaluability) 
 
This analysis set will be used to conduct the secondary efficacy analysis for the inter-reader agreement 
among readers (refer to Section 15.2.2).  Summaries will be presented according to the individual reader’s 
interpretation of the 18F-AV-1451 PET image (see Section 3.2 and APPENDIX 1). 
5.4. FULL ANALYSIS SET 
Two full analysis set (FAS) will be defined for this study, one for each primary efficacy analysis (refer to 
Section 15.1). 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 17 of 41 
5.4.1. FULL ANALYSIS SET #1 
The FAS #1 (FAS1) will include all SAF subjects (refer to Section 5.2) recruited under this protocol that: 
 
came to autopsy, including the Front-Runner Cohort (i.e., including the first three subjects who 
came to autopsy), 
 
had valid and evaluable PET data (refer to Section 3.2), and 
 
had valid and interpretable autopsy specimens (refer to Section 3.3), where interpretability will 
be assessed for the Braak Stage. 
 
This analysis set will be used to summarize the consensus panel’s assessment of each TS (refer to Section 
15.1), conduct supportive analyses to the first primary efficacy analysis (refer to Section 15.1.1) and 
secondary analysis of majority of readers versus the NFT Score TS (15.2.1) as well as to conduct the 
exploratory efficacy analysis exception of the logistic regression model for the NIA-AA autospy diagnosis 
TS (refer to Section 15.3).  Data will be presented according to the individual reader’s interpretation of 
the 18F-AV-1451 PET image (see Section 3.2 and APPENDIX 1), majority of readers’ interpretation of the 
18F-AV-1451 PET image (see Section 3.2 and APPENDIX 1) or by most recent neurological disease diagnosis, 
as appropriate. 
5.4.2. FULL ANALYSIS SET #2 
The FAS #2 (FAS2) will include all SAF subjects (refer to Section 5.2) recruited under this protocol that: 
 
came to autopsy, including the Front-Runner Cohort (i.e., including the first three subjects who 
came to autopsy), 
 
had valid and evaluable PET data (refer to Section 3.2), and 
 
had valid and interpretable autopsy specimens (refer to Section 3.3), where interpretability will 
be assessed for the NIA-AA autopsy diagnosis. 
 
This analysis set will be used to conduct supportive analyses to the second primary efficacy analysis (refer 
to Section 15.1.2) and majority of readers secondary analysis for the NIA-AA autopsy TS (refer to Section 
15.2.1) as well as to conduct the logistic regression model exploratory efficacy analysis for the NIA-AA 
autospy diagnosis TS (refer to Section 15.3).  Data will be presented according to the individual reader’s 
or majority of readers’ interpretation of the 18F-AV-1451 PET image (see Section 3.2 and APPENDIX 1), as 
appropriate. 
5.5. EFFICACY ANALYSIS SET 
Two EFF will be defined for this study, one for each primary efficacy analysis (refer to Section 15.1) 
5.5.1. EFFICACY ANALYSIS SET #1 
The EFF #1 (EFF1) will include all SAF subjects (refer to Section 5.2) recruited under this protocol that: 
 
 came to autopsy after the Front-Runner Cohort (i.e., excluding the first three subjects who came 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 18 of 41 
to autopsy), 
 
had valid and evaluable PET data (refer to Section 3.2), and 
 
had valid and interpretable autopsy specimens (refer to Section 3.3) , where interpretability will 
be assessed for the Braak Stage. 
 
This analysis set will be used to summarize demographic and other baseline characteristics (refer to 
Section 10), medical/surgical history, concurrent medical conditions/diseases, family neurological disease 
history, and subjects neurological disease history (refer to Section 11), concomitant medications (refer to 
Section 12), cognition assessments at screening (refer to Section 13), exposure to 18F-AV-1451 (refer to 
Section 14), and other efficacy endpoint (refer to Section 15.4) as well as to conduct the first primary 
efficacy analysis (refer to Section 15.1.1) and majority of readers secondary efficacy for the NFT Score TS 
(refer to Section 15.2.1).  Summaries will be presented according to the individual reader’s interpretation 
of the 18F-AV-1451 PET image (see Section 3.2 and APPENDIX 1), majority of readers’ interpretation of the 
18F-AV-1451 PET image (see Section 3.2 and APPENDIX 1) or by most recent neurological disease diagnosis, 
as appropriate. 
5.5.2. EFFICACY ANALYSIS SET #2 
The EFF #2 (EFF2) will include all SAF subjects (refer to Section 5.2) recruited under this protocol that: 
 
 came to autopsy after the Front-Runner Cohort (i.e., excluding the first three subjects who came 
to autopsy), 
 
had valid and evaluable PET data (refer to Section 3.2), and 
 
had valid and interpretable autopsy specimens (refer to Section 3.3) , where interpretability will 
be assessed for the NIA-AA autopsy diagnosis. 
 
This analysis set will be used to conduct the second primary efficacy analysis (refer to Section 15.1.2) and 
majority of readers secondary efficacy analysis for the NIA-AA autopsy diagnosis (refer to Section 15.2.1).  
Summaries will be presented according to the individual reader’s or majority of readers’ interpretation of 
the 18F-AV-1451 PET image (see Section 3.2 and APPENDIX 1), as appropriate. 
5.6. SENSITIVITY ANALYSIS SET 
The sensitivity analysis set (SENS) will include all SAF subjects (refer to Section 5.2) recruited under this 
procotol that came to autopsy after the Front-Runner Cohort (i.e., excluding the first three subjects who 
came to autopsy) with an available PET Scan visual interpretation (regardless of PET Scan image validity 
and evaluability; refer to Section 3.2) and available pathological diagnosis (regardless of its 
interpretability; refer to Section 3.3). 
 
This analysis set will be used to conduct supportive analysis to the primary and secondary efficacy analyses 
exception of the inter-reader agreement among readers (refer to Sections 15.1 and 15.2).  Data will be 
presented according to the individual reader’s or majority of readers’ interpretation of the 18F-AV-1451 
PET image (see Section 3.2 and APPENDIX 1), as appropriate. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 19 of 41 
6. GENERAL CONSIDERATIONS 
Categorical data will be summarized by the number and percentage of subjects in each category.  
Continuous data will be summarized by descriptive statistics including n (number of subjects with available 
data), mean, standard deviation (SD), median, minimum, and maximum values. 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day of 
assessments and events. 
 
Reference start date is defined as the date of the first 18F-AV-1451 injection (Study Day 1 is the day of the 
first injection). 
 
If the date of the event/assessment is on or after the reference start date, then:  
Study Day = (date of event/assessment – reference start date) + 1. 
 
If the date of the event/assessment is prior to the reference start date, then:  
 
Study Day = (date of event/assessment – reference start date). 
In the situation where the event/assessment date is partial or missing, Study Day and any corresponding 
durations will be missing. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
reference start date and time, i.e. date and time of first 18F-AV-1451 injection, including unscheduled 
assessments.  In case where the last non-missing measurement and the reference start date and time 
coincide, that measurement will be considered as pre-baseline, with the exception of the adverse events 
(AEs) and medications.  AEs/medications commencing on the reference start date and time will be 
considered as post-baseline (i.e. treatment-emergent/concomitant). 
6.3. REPEATS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In order to control for the potential progressive change in tau deposition over time, cognitively impaired 
subjects for whom death did not occur within nine months of the 18F-AV-1451 PET scan were given the 
opportunity to undergo a second 18F-AV-1451 PET scan and continue in the protocol at the Sponsor’s 
discretion.  If the subject agreed to a second 18F-AV-1451 PET scan, screening asssessments were not 
repeated with exception of any updates to the medical history/concurrent medications and an updated 
neurological disease diagnosis (according to best available information) which were collected at the time 
of the second 18F-AV-1451 PET imaging visit.  If the subject subsequently came to autopsy, the data 
(neurological disease diagnosis and 18F-AV-1451 PET scan) from the second 18F-AV-1451 PET imaging visit 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 20 of 41 
(nearest to time of death) will be used in the analyses.  Cognitively normal (unimpaired) subjects were not 
required to undergo repeat scans, even if death occurred more then nine months after the 18F-AV-1451 
PET scan, because cortical tau deposition is expected to occur very slowly, if at all, in such subjects.  That 
is, cognitively normal subjects remained eligible for autopsy, regardless of time from first or second scan 
to autopsy.  The safety analyses will include data from all scans. 
 
This study does not accommodate unscheduled visits and no data will be collected at the time of an early 
termination beside the date and reason for discontinuation. 
 
Listings will include scheduled, repeat, and early discontinuation data. 
6.4. WINDOWING CONVENTIONS 
No visit windowing will be performed for this study. 
6.5. SOFTWARE VERSION 
All analyses will be conducted using SAS® version 9.4 or higher. 
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE JUSTIFICATION AND TRIAL STOPPING CRITERIA 
Assuming sensitivity/specificity of approximately 80%, a minimum of 14 autopsy cases in each of the TS 
groups (pathological positive or negative as defined in Table 2 and Table 3) is required for the lower bound 
of the two-sided 95% confidence interval (CI) to be > 50% for each individual reader. 
 
The Sponsor is blinded to the pathological results (TS) until after the study is completed and the database 
is locked.  Therefore, in order to ensure that an adequate number of subjects were recruited and came to 
autopsy for each TS group, the Sponsor assumed that subjects diagnosed on clinical grounds as having 
dementia due to AD are TS positive and subjects diagnosed as having no cognitive impairment (cognitively 
normal) are TS negative.  Based on these assumptions, the study sample size requirement and trial 
stopping criteria were to be deemed as having been met when: 
 
the number of subjects diagnosed as having impairment due to AD that came to autopsy was 
greater than or equal to 14, AND 
 
the number of subjects diagnosed as having no cognitive impairment that came to autopsy was 
greater than or equal to 14 
The Sponsor recognizes that there might have been some error in clinical diagnosis such that some 
subjects diagnosed clinically as having impairment due to AD may have non-AD pathology, or limited 
amounts of AD tau pathology, and thus be TS negative, and less often, subjects considered clinically 


 
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Page 21 of 41 
normal may have AD pathology and thus be TS positive.  However, given the excess frequency of cases 
with AD diagnoses relative to clinically normal subjects recruited in this trial population, any diagnosis 
errors will likely help ensure a minimum of 14 TS negative subjects without jeopardizing the criterion for 
TS positive subjects. 
 
In addition to the above subjects diagnosed as clinically normal or AD patients, it was expected that 
approximately 10-15 subjects with non-AD impairment would be enrolled and came to autopsy in this 
trial.  However, the proportion of these subjects that will have TS positive/negative AD tau pathology is 
very difficult to predict and will depend on the precise cases enrolled.  Thus, it was not expected that the 
clinical profile of these cases would be useful in estimating when a sufficient number of cases had occurred 
in each TS group. 
 
In accordance with protocol amendment 2, the actual number of cases that met the TS positive and TS 
negative criteria at autopsy were determined in an unblinded fashion using the neuropathology consensus 
panel results by an independent statistician who is not an employee of the Sponsor and who is not 
involved in the conduct and analysis of the study.  Because the number of cases in this study were too 
large to review in a single session, this panel met periodically during the course of the trial and reviewed 
the cases in batches.  After the third consensus panel meeting (held in May 2018), the independent 
statistician reviewed the consensus panel data and notified the Sponsor that the stopping criteria were 
met (i.e., at least 14 cases in each of the TS positive and negative categories had come to autopsy). 
 
By the time the independent statistician notified the sponsor that the stopping criteria were met, more 
than 14 subjects diagnosed as having no cognitive impairment and more than 14 subjects diagnosed as 
having impairment due to AD had come to autopsy.  Hence, both set of stopping criteria were met after 
the third consensus panel meeting that was held in May 2018. 
7.2. MULTICENTER STUDIES 
This study was conducted by multiple investigators at multiple centers.  However, there are no plans to 
perform a formal analysis of homogeneity across centers. 
7.3. MISSING DATA 
Missing efficacy and safety data will not be imputed with the exception of missing AE severity and missing 
AE relationship to study medication/procedure (refer to Sections 16.1.1.1, 16.1.1.2, and 16.1.1.3, 
respectively).  Missing or partial AEs and medications dates and/or time will be handle as described in 
APPENDIX 2. 
 
It is possible that for some cases, only half of the brain tissues was avaible for pathological analysis while 
the whole brain 18F-AV1451 PET scan images were available for visual reads. For these cases, only the 
visual reads from corresponding side of brain will be used for efficacy analyses.  


 
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Page 22 of 41 
7.4. HYPOTHESES TESTING AND MULTIPLE COMPARISONS/ MULTIPLICITY 
For the primary analysis of the first primary efficacy endpoint (refer to Section 15.1.1), the hypothesis to 
be tested is that for at least the same 3 out of 5 independent readers, the lower bound of the two-sided 
95% CI for both sensitivity and specificity of 18F-AV-1451 PET reading interpretations will be ≥ 50%. 
 
For the primary analysis of the second primary efficacy endpoint (refer to Section 15.1.2), the hypothesis 
to be tested is also that for at least the same 3 out of 5 independent readers, the lower bound of the two-
sided 95% CI for both sensitivity and specificity of 18F-AV-1451 PET reading interpretations will be ≥ 50%. 
 
This trial will be considered as successful if both primary efficacy analyses reach statistical significance at 
a two-sided significance level of 0.05. 
 
All other efficacy endpoints (refer Sections 15.2.1, 15.2.2, and 15.3) will be tested without multiplicity 
adjustments and nominal p-values will be provided.  Although nominal p-values will be provided for the 
secondary efficacy endpoints, the hypothesis to be tested for these endpoints are: 
 
The majority read results will have the lower bound of the two-sided 95% CI ≥ 55% for both 
sensitivity and specificity for detection of tau neurofibrillary pathology that corresponds to NFT 
score of B3,  
 
The majority read results will have the lower bound of the two-sided 95% CI ≥ 55% for both 
sensitivity and specificity for detection of a pattern of 18F-AV-1451 neocortical uptake that 
corresponds to a high levels of AD neuropathologic change as defined by NIA-AA criteria, and 
 
The observed kappa values are ≥ 0.64 and the lower bound of the two-sided 95% CIs are ≥ 0.55 
for the inter-reader agreement among readers. 
 
No statistical testing will be carried out for disposition and withdrawal (refer to Section 9), demographic 
or other baseline characteristics (refer to Section 10), medical/surgical history (refer to Section 11), 
concurrent diseases/conditions (refer to Section 11), prior and concomitant medications (refer to Section 
12), exposure to 18F-AV-1451 (refer to Section 14), other efficacy endpoint (refer to Section 15.4), and all 
safety outcomes (refer to Section 16). 
7.5. STATISTICAL MODELS 
The following general statistical models will be used in the analysis of the primary, secondary, and 
exploratory efficacy endpoints. 
7.5.1. SENSITIVITY, SPECIFICITY, POSITIVE AND NEGATIVE PREDICTIVE VALUES, AND LIKELIHOOD 
RATIOS 
The following table contains terms used to define sensitivity, specificity, accuracy, positive predictive 
value (PPV), negative predictive value (NPV), likelihood ratio positive (LR+) and likelihood ratio negative 
(LR-): 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 23 of 41 
 
Diagnostic Test: 18F-AV-1451 PET  
Scan Read Result 
Truth Standard 
Positive 
Negative 
Positive 
True Positive (TP) 
False Positive (FP) 
Negative 
False Negative (FN) 
True Negative (TN) 
 
The sensitivity, which evaluates how good a test is at detecting a positive disease, will be calculated as: 
100×
𝑇𝑃
𝑇𝑃 +  𝐹𝑁 
 
The specificity, which estimates how likely subjects without the disease can be correctly ruled out, will 
be calculated as:  
100×
𝑇𝑁
𝐹𝑃 + 𝑇𝑁 
 
The accuracy, which evaluates the overall proportion of observed agreement, will be calculated as: 
100×
𝑇𝑃 +  𝑇𝑁
𝑇𝑃 +  𝐹𝑁 +  𝐹𝑃 +  𝑇𝑁 
 
The PPV, which is the proportion of positive test results that are true positives, will be calculated as: 
100×
𝑇𝑃
 𝑇𝑃 +   𝐹𝑃 
 
The NPV, which is the proportion of subjects with a negative test result who are correctly diagnosed, will 
be calculated as: 
100×
 𝑇𝑁
 𝐹𝑁 +   𝑇𝑁 
 
The 95% CIs provided for specificity, sensitivity, accuracy, PPV and NPV will be based on the Wilson score 
method (Wilson 1927; Newcombe 1998). 
 
The LR+, which is true positive rate divided by the false positive rate, will be calculated as: 
 
𝑠𝑒𝑛𝑠𝑖𝑡𝑖𝑣𝑖𝑡𝑦
1 −𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐𝑖𝑡𝑦 
 
The LR-, which is the false negative rate divided by the true negative rate, will be calculated as: 
 1 − 𝑠𝑒𝑛𝑠𝑖𝑡𝑖𝑣𝑖𝑡𝑦
𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐𝑖𝑡𝑦
 
7.5.2. SIMPLE KAPPA COEFFICIENT 
The agreement between two readers will be calculated using the simple kappa coefficient, i.e. Cohen’s 
kappa.  The simple kappa coefficient along with its 95% CI can be obtained by using the FREQ procedure 
from SAS®. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
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7.5.3. FLEISS’ KAPPA 
The agreement between the five readers will be calculated using Fleiss’ kappa along with its 95% CI (Fleiss 
1981). 
7.6. EXAMINATION OF SUBGROUPS 
The following subgroups will be investigated for the primary efficacy endpoints: 
 
Age group i.e.,  <65, ≥65 to <75, and ≥ 75 years 
 
Birth gender i.e., male and female 
 
Most recent neurological disease diagnosis i.e., normal, mild cognitive impairment, and dementia 
 
Atypical tau pathology status i.e., atypical AD tau pathology present in both sides of the brain , 
atypical AD tau pathology present from either side of the brain, and absent from both side of 
brain. “Not evaluable” cases will be excluded from this analysis 
If the data are too sparse for at least one age subgroup (i.e. less than 5 subjects), the concerned age 
subgroup will be pooled with another age subgroup, as appropriate.  For example, should the <65 years 
age subgroup has less than 5 subjects, it will be pooled with the ≥65 to <75 years age subgroup yielding 
to the following two age subgroups: <75 years and ≥75 years. 
If the data are too sparse for one of the birth gender, one of the most recent neurological disease diagnosis  
or one of the atypical tau pathology status subgroup, only descriptive statistics will be provided for that 
subgroup.  That is no statistical inference will be performed. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
 
The shells that will be provided with this SAP will describe the presentations for this study and therefore, 
the format and content of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent, meet all inclusion/exclusion criteria and have received at least 
one 18F-AV-1451 injection will be accounted for in this study. 
 
The numbers and percentages of subjects enrolled, who received at least one 18F-AV-1451 injection, 
completed the study, and discontinued early from the study as well as the reason for early discontinuation 
will be summarized based on the ENR overall and by most recent neurological disease diagnosis.  For the 
analysis purpose, study completion will be defined as subjects who died within nine months of their most 
recent 18F-AV-1451 PET scan and had an autopsy performed. 


 
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The numbers and percentages of subjects with any critical and/or major protocol deviation (as defined by 
the clinical team during the course of the study and finalized before database lock) will be summarized 
based on the ENR overall and by most recent neurological disease diagnosis.  The number and percentages 
of subjects with at least one protocol deviation in each type of protocol deviation will be summarized 
similarly by severity (critical/major), where type of protocol deviations are: 
 
Administrative criteria 
 
Compliance with investigational product 
 
Concomitant medication criteria 
 
Eligibility and entry criteria 
 
Informed consent 
 
Laboratory assessment criteria 
 
Other criteria 
 
Serious adverse event criteria 
 
Source document criteria 
 
Study procedures criteria 
 
Visit schedule criteria 
 
Summaries will be presented in decreasing order of type of protocol deviation within each severity 
(critical/major).  Minor protocol deviations which will be presented in subjects data listing only. 
 
The numbers and percentages of subjects included in/excluded from each analysis set and reasons for 
exclusion from each analysis set will be summarized based on the ENR overall and by most recent 
neurological disease diagnosis. 
 
The primary and secondary cause of death as well as clincial events leading up to death with potential to 
affect autopsy findings (i.e., stroke, brain infection, and other) will be summarized based on the SAF 
overall and by most recent neurological disease diagnosis. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics will be summarized for the SAF overall and by most recent 
neurological disease diagnosis.  A similar summary will be also presented for the EFF1. 
 
The following demographic and other baseline characteristics will be reported for this study: 
 
Age (years) – calculated relative to the date of the signed informed consent 
 
Age group (<65, ≥65 to <75, and ≥ 75 years) 


 
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Page 26 of 41 
 
Birth gender 
 
Race 
 
Ethnicity 
 
Highest level of education completed 
 
Subject handedness 
 
Weight (kg) 
 
Height (cm) 
 
Body mass index (BMI) (kg/m2) 
 
Childbearing potential 
 
Alcohol, tobacco, and recreational drug use 
Asian sub-race, country of birth and number of years patients lived in the country of birth will be 
presented in the subjects data listing only. 
10.1. 
DERIVATIONS 
 
Age (years)= (year of signed informed consent – year of birth) + 1 
 
BMI (kg/m2)= weight (kg)/ height (m)2 
11. MEDICAL HISTORY 
Medical history (including surgical history) and concurrent condition/disease information collected at 
screening, repeat 18F-AV-1451 PET scan visit(s) (if any), and autopsy will be classified according to the 
following categories and coded to system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 18.1: 
 
Medical history finding are defined as any findings that stopped prior to the first 18F-AV-1451 
injection; 
 
Concurrent medical conditions/diseases are defined as any findings that were still present at or 
started after the first 18F-AV-1451 injection. 
 
Incidence of medical history findings, surgeries, and concurrent medical conditions/diseases will be 
presented separately by SOC and PT for the SAF overall and by most recent neurological disease diagnosis.  
Summaries will be presented by alphabetical order of SOC and decreasing order of total frequency of PT.   
Subjects with multiple occurrences of the same SOC/ PT will only be counted once per SOC/ PT in the 
tables. 
 
Family history of Parkinson’s disease, Alzheimer’s disease, dementia with Lewy bodies (DLB), stroke, and 


 
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Page 27 of 41 
other dementing or movement disorder will be summarized by family relationship for the SAF overall and 
by most recent neurological disease diagnosis. 
 
Number of months since neurological disease symptom onset and number of months since neurological 
disease diagnosis will be summarized for the SAF overall and by most recent neurological disease 
diagnosis.  Number and percentage of subjects in each etiology category for the ‘mild cognitive 
impairment’ and ‘dementia’ most recent neurological disease diagnosis will be summarized for the SAF 
overall.  Number and percentage of subjects who had a previous CSF test (including the A and Tau levels, 
when available) as well as the number and percentage of subjects who had a previous ApoE test, are ApoE 
4 carrier (including the genotype, when available) will be provided for the SAF overall and by most recent 
neurological disease diagnosis. 
 
All these summaries will be also similarly presented for the EFF1. 
11.1. 
DERIVATIONS 
For subjects who will provide the date of neurological symptom onset and/or the date of neurological 
disease diagnosis instead of the number of months since neurological symptom onset/neurological 
disease diagnosis will be computed as follows: 
 
Number of months since neurological disease symptom onset= [(date of signed informed 
consent – onset date of neurological disease symptom) + 1]/ (30.4375 days/month) 
 
Number of months since neurological disease diagnosis= [(date of signed informed consent –
date of neurological disease diagnosis) + 1]/ (30.4375 days/month) 
12. MEDICATIONS 
Medications will be classified according to the following categories: 
 
‘Prior’ medications are defined as any medications which started and stopped prior to the first 
18F-AV-1451 injection. 
 
‘Concomitant’ medications are defined as any medications taken on or after the first 18F-AV-
1451 injection. 
 
APPENDIX 2 describes the handling of partial dates for medications.  In the case where it is not possible 
to determine if a medication is prior or concomitant, the medication will be classified by the worst case; 
i.e. concomitant. 
 
Medications will be coded to the anatomical therapeutic chemical (ATC) level 3 and preferred drug name 
using the World Health Organization Drug Dictionary (WHO-DD), version September 2015 C. 
 
Concomitant medications will be summarized by ATC level 3 and preferred drug name for the SAF overall 
by most recent neurological disease diagnosis.  Summaries will be presented by alphabetical order of ATC 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 28 of 41 
level 3 and decreasing order of total frequency of preferred drug name .  Subjects with multiple 
occurrences of the same ATC/preferred drug name will only be counted once per ATC/ preferred drug 
name in the tables.  A similar summary will be also presented for the EFF1. 
 
Prior medications will be provided in subjects data listing only. 
13. IQCODE AND MMSE 
Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE; Jorm 1994) is a short questionnaire 
designed to assess cognitive decline and dementia in elderly people.   The questionnaire is filled out by a 
relative or friend who has known the elderly person for 10 years or more.  To score the IQCODE, the score 
of each question will be added up and divided by the number of questions i.e., 16.  The result is a score 
that ranges from 0 to 5.  A score of 3 means that the subject is rated on average as ‘no change’. A score 
of 4 means an average of ‘a bit worse’ and a score of 5, an average of ‘much worse’.  Should the score of 
at least one question be missing, the IQCODE score will be set to missing.  It will be administered to the 
subject’s caregiver/informant at screening.  The IQCODE score will be summarized using descriptive 
statistics based on the SAF overall and by most recent neurological disease diagnosis 
 
The Mini-Mental State Examination (MMSE; Folstein et al. 1975) is a brief instrument used to assess 
cognitive function in elderly patients.  The instrument is divided into two 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 MMSE total score is the 
sum of the score of each section and hence, ranges from 0 to 30.  It wil be administered at screening to 
subjects that are able to cooperate with testing.  Only the MMSE total score will be captured into the 
eCRF.  Descriptive statistics will be provided for the MMSE total score for the SAF overall and by most 
recent neurological disease diagnosis. 
 
Similar summaries will be presented for the EFF1. 
14. EXPOSURE TO 18F-AV-1451 
There is only one scheduled IV bolus injection of 18F-AV-1541 in this study, unless the subject meets the 
requirements to undergo a second 18F-AV-1451 PET (see Section 3.1).  For each injection, the net activity 
administered (mCi) as determined by the PET imaging core laboratory(ies) will be summarized using 
descriptive statistics for the SAF overall and by most recent neurological disease diagnosis.  A similar 
summary will be presented for the EFF1. 
 
The injection site will be presented in subjects data listing only. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 29 of 41 
15. EFFICACY OUTCOMES 
All efficacy analyses will be peformed using the EFF1 or EFF2, as appropriate, unless otherwise indicated. 
15.1. 
PRIMARY EFFICACY 
15.1.1. PRIMARY EFFICACY ANALYSIS #1 
For the primary efficacy analysis #1, the diagnosis performance (sensitivity/specificity) of 5 independent 
readers’ interpretation of ante-mortem 18F-AV-1451 PET scan images (AD+/AD++ or AD-; refer to Section 
3.2) for detection of a pattern of 18F-AV-1451 PET neocortical uptake that corresponds to NFT score B3 
(Hyman et al., 2012; Montine et al., 2012; refer to Section 3.3) at autopsy will be evaluated. 
 
18F-AV-1451 PET Scan Read Result 
Autopsy NFT Score TS 
NFT Score B3 
(True Positive) 
NFT Score B0, B1 or B2 
(True Negative) 
AD+/AD++: 18F-AV-1451 Neocortical 
Uptake Consistent with AD Pattern 
TP 
FP 
AD-: 18F-AV-1451 Neocortical Uptake 
Not Consistent with AD Pattern 
FN 
TN 
 
The sensitivity and specificity along with their two-sided 95% CI (based on the Wilson score method) will 
be calculated for each of the five readers.  The first primary efficacy analysis will be considered to be met 
if for at least the same 3 out of 5 readers, the lower bound of the 95% CI for both sensitivity and specificity 
are ≥ 50% (i.e., statistically significant at two-sided significance level of 0.05). 
 
The accuracy, PPV, NPV, LR+ and LR- of the 18F-AV-1451 PET imaging classification for each of the five 
readers relative to the autopsy NFT score TS will be also calculated.  Two-sided 95% CIs (based on the 
Wilson score method)will be provided for the accuracy, the PPV and NPV. 
 
Addtionnally, the number and percentage of subjects for each Braak stage and NFT stage will be provided 
for each hemisphere overall and by most recent neurological disease diagnosis.  The number and 
percentage of subjects in each highest hemisphere/stain NFT score and autopsy NFT score TS will be 
summarized overall and by most recent neurological disease diagnosis.  A listing of subjects who are 
autopsy NFT score TS positive and TS negative will be provided including the same information as well as 
the readers’interpretation of the 18F-AV-1451 PET scan image(s). 
15.1.2. PRIMARY EFFICACY ANALYSIS #2 
For the primary efficacy analysis #2, the diagnosis performance (sensitivity/specificity) of 5 independent 
readers’ interpretation of ante-mortem 18F-AV-1451 PET scan images (AD+/AD++ or AD-; refer to Section 


 
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Page 30 of 41 
3.2) for detection of a pattern of 18F-AV-1451 neocortical uptake that corresponds to high levels of AD 
neuropathologic change as defined by NIA-AA criteria (Hyman et al., 2012; refer to Section 3.3) at autopsy 
will be evaluated statistically, if and only if the primary efficacy analysis #1 is a success.  For individuals 
with cognitive impairment, high levels of AD neuropathologic change are considered adequate to explain 
cognitive impairment or dementia symptoms. 
 
18F-AV-1451 PET Scan Read Result  
NIA-AA Autopsy Diagnosis TS 
High AD Neuropathologic 
Change 
(True Positive) 
No, Low or intermediate AD 
Neuropathologic Change 
(True Negative) 
AD+/AD++: 18F-AV-1451 Neocortical 
Uptake Consistent with AD Pattern 
TP 
FP 
AD-: 18F-AV-1451 Neocortical Uptake 
Not Consistent with AD Pattern 
FN 
TN 
 
The sensitivity and specificity along with their two-sided 95% CI (based on the Wilson score method) will 
be calculated for each of the five readers. The second primary efficacy analysis will be considered to be 
met if for at least the same 3 out of 5 readers, the lower bound of the 95% CI for both sensitivity and 
specificity are ≥ 50% (i.e., statistically significant at two-sided significance level of 0.05). 
 
The accuracy, PPV, NPV, LR+ and LR- of the 18F-AV-1451 PET imaging classification for each of the five 
readers relative to the NIA-AA autopsy diagnosis TS will be also calculated.  Two-sided 95% CIs (based on 
the Wilson score method) will be provided for the accuracy, the PPV and NPV. 
 
Addtionnally, the number and percentage of subjects for each Thal phase, Aβ plaque score, atypical tau 
pathology status, neuritic plaque score (modified from CERAD), and NIA-AA AD neuropathological change 
will be provided for each hemisphere overall and by most recent neurological disease diagnosis.  A listing 
of subjects who are NIA-AA autopsy diagnosis TS positive and TS negative will be provided including the 
same information as well as the readers’interpretation of the 18F-AV-1451 PET scan image(s). 
15.1.3. SUPPORTIVE ANALYSIS TO PRIMARY EFFICACY ANALYSES 
Primary efficacy analyses #1 and #2 will be repeated based the FAS1/FAS2, as appropriate, and SENS set. 
15.1.4. SUBGROUP ANALYSES TO PRIMARY EFFICACY ANALYSES 
Primary efficacy analyses #1 and #2 will be repeated for each subgroup specified in Section 7.6. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 31 of 41 
15.2. 
SECONDARY EFFICACY 
15.2.1. DIAGNOSTIC PERFORMANCE OF ANTE-MORTEM 18F-AV-1451 PET IMAGING BASED ON 
MAJORITY INTERPRETATION OF 5 INDEPENDENT READERS 
For each image, the majority interpretation of 5 independent readers will be derived using individual 
readers’ interpretation results.  Diagnostic performance of this majority interpretation wil be assessed 
relative to the autopsy NFT score TS as per primary efficacy analysis #1 (refer to Section 15.1.1) and again 
relative to the NIA-AA autopsy diagnosis TS as per primary efficacy analysis #2 (refer to Section 15.1.2). 
 
The sensitivity and specificity along with their two-sided 95% CIs (based on the Wilson score method) will 
be calculated for the majority interpretation of 5 independent readers relative to the appropriate TS. 
 
The accuracy, PPV, NPV, LR+ and LR- of the 18F-AV-1451 PET imaging classification for the majority 
interpretation of 5 independent readers relative to the appropriate TS will be also calculated.  Two-sided 
95% CIs (based on the Wilson score method) will be provided for the accuracy, the PPV and NPV. 
15.2.2. INTER-RATER AGREEMENT AMONG READERS OF 18F-AV-1451 PET IMAGING INTERPRETATION 
Fleiss’ Kappa statistics will be used to assess inter-reader agreement for the diagnostic decision associated 
with the primary efficacy analysis #1 and #2.  For evaluation of agreement in the context of primary 
efficacy analysis #1, Fleiss’ Kappa statistic will be calculated according to the readers’ interpretation 
classification as specified in Section 15.1.1 along with its two-sided 95% CI and associated p-value.  A 
second Fleiss’ Kappa statistic will be calculated using the readers’ interpretation classfication as specifed 
in Section 15.1.2 along with its two-sided 95% CI and associated p-value.  Percentage of agreement will 
also be provided i.e., number of images for which a pair of readers in agreement divided by the total 
number of images evaluated by any pair of readers multiplied by 100%. 
 
In addition, the agreement between each pair of readers (reader 1 vs. readers 2, 3, 4, and 5 separately; 
reader 2 vs. readers 3, 4, and 5 separately; reader 3 vs. readers 4, and 5 separately; and reader 4 vs. reader 
5) will be assessed for each diagnostic decision using the simple kappa coefficient, its two-sided 95% CI, 
and associated p-value.  Percentage of agreement will also be provided for each pair of reader i.e., number 
images for which the pair of readers are in agreement divided by the total number of images evaluated 
by the pair of readers multiplied by 100%. 
15.2.3. SUPPORTIVE ANALYSIS TO SECONDARY EFFICACY ANALYSES 
The diagnosis performance of ante-mortem 18F-AV-1451 PET imaging based on majority interpretation of 
5 independent readers analysis will be repeated based on the FAS1/FAS2, as appropriate, and SENS. 
 
The inter-reader agreement among 5 readers of 18F-AV-1451 PET imaging interpretation analysis will be 
repeated based on the FAS1 and SENS. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 32 of 41 
15.2.4. SUBGROUP ANALYSES TO SECONDARY EFFICACY ANALYSES 
No subgroup analyses will be performed for the secondary efficacy analyses. 
15.3. 
EXPLORATORY EFFICACY 
Descriptive statistics will be presented for the quantitative analysis result of 18F-AV-1451 PET scan (i.e., 
SUVr) by most recent neurological disease diagnosis based on the FAS.  The reference region for SUVr 
values will be a selected white matter region derived using a parametric estimation of signal intensity 
(PERSI) method.  The global SUVr assessment will be computed using a data driven target region using 
multi-block baryercentric discriminant analysis (MUBADA) method.  The target region for regional SUVr 
are based on automated anatomical labeling (AAL) atlas.  
 
The objective of exploratory analysis is to find a cut-off value for MUBADA SUVr for each pathological 
truth standard as defined in Section 3.2 and 3.3 respectively, to define a positve (corresponding to 
patholodical positive) and negative (corresponding to patholoical negative) scan using MUBADA SUVr 
values.  For each pathological truth standard, a logisitical regression model will be applied using 
pathological truth standard as the dependent variable and MUBADA SUVr value as independent variable.  
Receiver operating curves (ROC) will be generated and a Youden’s Index method will be used to select the 
best cut-off values.  The ROC figure and area under the Curve (AUC) of the ROC will be provided as well as 
its p-value and the SUVr cut-off value.   
 
Additionnally, the number and percentage of accurate classification for the TS positive, negative, and both 
combined will be provided where an accurate classifcation is defined as follows for TS positive 
 
 
Number of TS positive subjects with global SUVr value on or above the cut-off value x 100% 
Total number of TS positive subjects 
 
Similarly, accurate classfication for TS negative is defined as follows: 
 
 
Number of TS negative subjects with global SUVr value below the cut-off value 
x 100% 
Total number of TS negative subjects 
 
Finally, accurate classification for TS postive/negative combined is defined as follows: 
 
 
[(Number of TS postive subjects with global SUVr value on or above the cut-off value)  
 
+ (Number of TS negative subjects with global SUVr value below the cut-off value)] x 100% 
 
Total number of TS positive/negative subjects 
15.3.1. SUPPORTIVE ANALYSIS TO EXPLORATORY EFFICACY ANALYSES 
No supportive analyses will be performed for the exploratory efficacy endpoints. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 33 of 41 
15.3.2. SUBGROUP ANALYSES TO EXPLORATORY EFFICACY ANALYSES 
No subgroup analyses will be performed for the exploratory efficacy endpoints. 
15.4. 
OTHER EFFICACY 
To evaluate the intra-rater reliability of the 18F-AV-1451 PET scan interpretation, eleven images were 
randomly selected to be reviewed twice by each of the 5 readers.  Given the limited number of images 
that were reviewed twice by each reader and that no stratification on the most recent neurological disease 
diagnosis was performed (to ensure balanced potentially TS negative cognitively normal and potentially 
TS positive dementia cases), no statistical inferences will be presented.  That is, only frequencies will be 
provided for the intra-rater reliability. 
15.4.1. SUPPORTIVE ANALYSIS TO OTHER EFFICACY ANALYSIS 
No supportive analyses will be performed for the other efficacy endpoint. 
15.4.2. SUBGROUP ANALYSES TO OTHER EFFICACY ANALYSIS 
No subgroup analyses will be performed for the other efficacy endpoint. 
16. SAFETY OUTCOMES 
All outputs for safety outcomes will be summarized overall and by most recent neurological disease 
diagnosis based on the SAF. 
16.1. 
ADVERSE EVENTS 
AEs will be coded to the SOC and PT using the MedDRA central coding dictionary, version 18.1. 
 
TEAEs are defined as AEs that started or worsened in intensity or frequency on or after an 18F-AV-1451 
injection and up to 48 hours after the 18F-AV-1451 injection.  APPENDIX 1 describes the handling of partial 
dates and/or times for AEs.  In case it is not possible to determine if an AE is treatment emergent or not, 
the AE will be classified by the worst case; i.e. treatment emergent.  
 
An overall summary of number and percentage of subjects within each of the categories described in the 
sub-sections below will be provided. 
 
Listings will include all AEs. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 34 of 41 
16.1.1. ALL TEAES  
Incidence (frequencies and percentages) of TEAEs will be presented by SOC and PT, and also broken down 
further by maximum severity, relationship to study medication, and relationship to study procedures.  In 
addition, incidence of TEAEs will be presented by PT only (i.e., not broken down by SOC).  Subjects with 
multiple occurrences of a SOC/ PT will only be counted once for that SOC/PT in the tables.  Summaries will 
be presented by alphabetical order of SOC and decreasing order of total frequency of PT. 
16.1.1.1. 
Severity 
Severity will be classified as mild, moderate or severe.  TEAEs with a missing severity will be classified as 
severe.  If a subject reports a TEAE more than once within a SOC/PT, the AE with the worst case severity 
will be used in the corresponding severity summaries. 
16.1.1.2. 
Relationship to Study Medication 
Relationship to study medication, as indicated by the Investigator on the eCRF, will be classified as related 
or not related to study medication.  TEAEs with a missing relationship to study medication will be regarded 
as related to 18F-AV-1451.  If a subject reports the same AE more than once within a SOC/ PT, the TEAE 
with the worst case relationship to 18F-AV-1451 will be used in the corresponding relationship summaries. 
16.1.1.3. 
Relationship to Study Procedures 
Relationship to study procedures, as indicated by the Investigator on the eCRF, will be classified as related 
or not related to study procedures.  TEAEs with a missing relationship to study procedures will be regarded 
as related to study procedures.  If a subject reports the same AE more than once within a SOC/ PT, the 
TEAE with the worst case relationship to study procedures will be used in the corresponding relationship 
summaries. 
16.1.2. INJECTION SITE REACTIONS 
Injection site reactions are those events that will be classified under the ‘Injection site reactions’ MedDRA 
High Level Term (HLT).  Incidence of injection site reactions will be presented by PT.  A listing containing 
all injection site reactions will also be prepared. 
16.1.3. ADVERSE EVENTS WITH AN OUTCOME OF DEATH 
AEs with an outcome of death are those events which have a resolution recorded as “Fatal” on the AEs 
page of the eCRF.  Incidence of AEs with an outcome of death will be presented by SOC and PT.  A listing 
containing all AEs with an outcome of death will also be prepared. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 35 of 41 
16.1.4. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the AEs page of the eCRF.  
Incidence of SAEs will be presented by SOC and PT.  A listing containing all SAEs will also be prepared. 
16.1.5. TEAES LEADING TO DISCONTINUATION OF STUDY 
TEAEs leading to discontinuation from study are those events with an action taken recorded as 
“permanently discontinued” on the AEs page of the eCRF.  Incidence of TEAEs leading to discontinuation 
from study will be presented by SOC and PT.  A listing containing all TEAEs leading to discontinuation from 
study will also be prepared. 
16.2. 
LABORATORY EVALUATIONS 
Not applicable. 
16.3. 
ECG EVALUATIONS 
Not applicable. 
16.4. 
VITAL SIGNS 
Vital sign measurements (pulse rate, respiratory rate, and blood pressure) will be taken in the supine 
position at screening, immediately prior to the 18F-AV-1451 injection, and after completion of the imaging 
prior to discharge. 
 
The change in vital sign measurements from baseline to completion of imaging prior to discharge will be 
computed as the value collected after the completion of the imaging prior to discharge minus the baseline 
value.  Observed and change from baseline values will be summarized through use of descriptive statistics 
for the each 18F-AV-1451 injection. 
 
Incidence of potentially clinically significant abnormal values will also be provided for each 18F-AV-1451 
injection and a listing of subjects with potentially clinically significant abnormal values will be prepared. 
16.4.1. POTENTIALLY CLINICALLY SIGNIFICANT ABNORMAL VITAL SIGNS CRITERIA 
Potentally clinically significant abnormal vital sign measurements will be identified in accordance with the 
following criteria: 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 36 of 41 
Table 4 Potentially Clinically Significant Abnormal Vital Signs Criteria 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg AND  
change from baseline 
≤ -20 mmHg 
≥ 180 mmHg AND 
change from baseline ≥ 20 mmHg 
DBP 
mmHg 
≤ 50 mmHg AND 
change from baseline 
≤ -15 mmHg 
≥ 105 mmHg AND 
change from baseline ≥ 15 mmHg 
Pulse rate 
bpm 
≤ 50 bpm  
 
≥ 110 bpm AND 
change from baseline ≥ 20 bpm 
Respiratory 
rate 
breaths/ 
min 
≤ 10 breaths/min  
 
NA 
16.5. 
PHYSICAL AND NEUROLOGICAL EXAMINATIONS 
A brief medical examination will be conducted by a medically qualified study team member at the 
screening visit.  Clinically significant changes from screening will be recorded as AEs. 
 
A brief neurological examination will also be performed by a medically qualified study team member at 
the screening visit to evaluate cranial nerves, gait, sensory, motor function, coordination, and tendon 
reflexes.  Clinically significant changes from screening will be recorded as AEs. 
 
Incidence of physical and neurological abnormalities at screening will be provided. 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 37 of 41 
17. REFERENCES 
 
Fleiss JL. (1981). Statistical Methods for Rates and Proportions. New York, NY: John Wiley & 
Sons. 
 
Folstein MR, Folstein SE, and McHugh PR. (1975). Mini Mental State: A Practical Method for 
Grading the Cognitive Status of Patients for the Clinician.  Journal of Psychiatric Research; 12: 
189-198. 
 
Hyman BT, Phelps CH, Beach TG at al. (2012). National Institute on Aging-Alzheimer’s 
Association Guidelines for the Neuropathologic Assessment of Alzheimer’s Disease.  Alzheimers 
Dement.; 8(1): 1-13. 
 
Jorm AF. (1994).  A Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly 
(IQCODE): Development and Cross-validation. Psyschological Medicine; 24: 145-153 
 
Mackinnon AJ and Mulligan R. (1998). Combining Cognitive Testing and Informant Report to 
Increase Accuracy in Screening for Dementia.  American Journal of Psychiatry; 155: 1529-1535. 
 
Montine TJ et al. (2012). National Institute on Aging-Alzheimer’s Association Guidelines for the 
Neuropathologic Assessment of Alzheimer’s Disease: A Practical Approach. Acta 
Neuropathologica; 123.1: 1-11 
 
Newcombe RG.. (1998). Two-Sided Confidence Intervals for the Single Proportion: Comparison of 
Seven Methods.  Statist. Med.; 17: 857-872. 
 
Wilson EB. (1927). Probable inference, the law of succession, and statistical inference. Journal of 
the American Statistical Association; 22: 209-212 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 38 of 41 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
PAPER SIZE, ORIENTATION AND MARGINS 
 
The size of paper will be letter for the United States.  The page orientation should be landscape.  Margins 
should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless of the 
paper size. 
 
FONTS 
 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8.  The 
font color should be black.  No bolding, underlining, italics or subscripting should be permitted.  Super-
scripts will be avoided, unless absolutely necessary. Single spacing should be used for all text. 
 
SDTM TERMINOLOGY 
 
When possible, SDTM controlled terminology (e.g., race) will be used in the tables, listings and figures 
outputs. 
DATES & TIMES 
Depending on data available, dates and times will take the form YYYY-MM-DD HH:MM. 
SPELLING FORMAT 
English US.  
OUTPUTS PRESENTATION 
For outputs presented by most recent neurological disease diagnosis category will be represented as 
follows and in that order: 
 
Most recent neurological disease diagnosis 
Order for Tables and Listings 
Normal 
1 
Mild Cognitive Impairment 
2 
Dementia 
3 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 39 of 41 
For outputs presented by autopsy NFT score TS, NIA-AA autopsy diagnosis levels of AD neuropathologic 
change TS, individual reader’s interpretation of the 18F-AV-1451 PET image or majority of readers’ 
interpretation of the 18F-AV-1451 PET image, groups will be represented as follows and in that order: 
 
Autopsy NFT score TS 
Order for Tables and Listings 
B3 
1 
B0, B1 or B3 
2 
 
NIA-AA Autopsy Diagnosis Levels of AD 
Neuropathologic Change TS 
 
Order for Tables and Listings 
High Levels of AD Neuropathologic Change 
1 
No, Low or Intermediate Levels of AD 
Neuropathologic Change 
2 
 
Individual or Majority of Reader’s Interpretation  Order for Tables and Listings 
AD+/AD++ 
1 
AD- 
2 
 
Inter-reader Agreement  
Order for Tables and Listings 
AD+/AD++ 
1 
AD- 
2 
LISTINGS 
All data collected on the eCRF will be presented in data listings.  The listings will be ordered by the 
following (unless otherwise indicated in the shells): most recent neurological disease diagnosis, subject 
number, date, and time (where applicable). 
 
 
 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 40 of 41 
APPENDIX 2. PARTIAL DATE AND/OR TIME CONVENTIONS 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS 
START DATE 
STOP DATE 
ACTION 
Known/ 
Partial/ 
Missing 
Known/ 
Ongoing 
If stop date < 18F-AV-1451 injection date, assign as prior 
If stop date ≥ 18F-AV-1451 injection date or medication is ongoing, assign as 
concomitant. 
Partial 
If known components of stop date show that: 
 Stop date < 18F-AV-1451 injection date, assign as prior  
 Stop date ≥ 18F-AV-1451 injection date, assign as concomitant. 
Missing 
Assign as concomitant 
 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
START  
DATE/TIME 
STOP 
DATE/TIME 
 
ACTION 
Known 
Known, 
Partial, 
Missing 
If start date/time < 18F-AV-1451 injection date/time, then not TEAE 
If 18F-AV-1451 injection date/time ≤ start date/time ≤ 18F-AV-1451 
injection date/time + 48 hours, then TEAE 
If start date/time > 18F-AV-1451 injection date/time + 48 hours, 
then not TEAE 
 
 
 
Partial, but known 
components show 
that it cannot be on or 
after 18F-AV-1451 
injection date/time 
and within 48 hours 
post-injection 
Known, 
Partial, 
Missing 
Not TEAE 
 
 
 
Partial and known 
components show 
that it could be on or 
after 18F-AV-1451 
injection date/time 
and within 48 hours 
post-injection 
Known, 
Partial, 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date/time < 18F-AV-1451 injection date/time, then not TEAE 
If stop date/time ≥ 18F-AV-1451 injection date/time, then TEAE 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 18F-AV-1451-A16 
Page 41 of 41 
START  
DATE/TIME 
STOP 
DATE/TIME 
 
ACTION 
Partial 
If known components of stop date/time show that: 
 Stop date/time  < 18F-AV-1451 injection date/time, then not TEAE 
 Stop date/time ≥ 18F-AV-1451 injection date/time, then TEAE 
Missing 
Assumed TEAE 
 
 
 


 
 
 
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