Clinical trial NCT03901092
Conditions: Alzheimer Disease
Keywords: flortaucipir F 18 Positron Emission Tomography 18F-AV-1451 Diagnostic imaging Tau imaging
Sponsor: Avid Radiopharmaceuticals
Start date: 2019-03-26; Completion date: 2019-04-26
Enrollment: 242 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the performance of physician readers trained to read flortaucipir-PET (positron emission tomography) scans.

Detailed description:

Arms: arm 1: Scans previously acquired from Study A16 (NCT02516046) and A05 (NCT02016560) will be read by independent, blinded readers.
Interventions: intervention 1: flortaucipir F 18
Intervention descriptions: intervention 1: No study drug will be administered.

Protocol documents:
Prot_000.pdf: 
18F-AV-1451-FR01 Protocol Amendment 1 
 
A Reader Study to Assess Accuracy and Reliability of Flortaucipir F 18 PET Scan Interpretation 
 
NCT03901092 
Approval date: 21 Mar 2019


Protocol: 18F-AV-1451-FR01 Confidential 
 
Page 1 of 15 
Protocol Number:  
 
18F-AV-1451-FR01 
“A reader study to assess accuracy and reliability of flortaucipir F 18 PET scan interpretation.” 
 
 
Date and Version: 
21MAR2019 
Amendment 1 
Final  
 
Name of Compound: Flortaucipir F 18 (18F-AV-1451) 
 
Sponsor: 
Avid Radiopharmaceuticals, Inc. 
Philadelphia, Pennsylvania USA 
 
 
 
CONFIDENTIAL 
This material is the property of Avid Radiopharmaceuticals, Inc. (Avid).  The information is confidential and 
is to be used only in connection with matters authorized by Avid and no part of it is to be disclosed to others 
without prior written permission from Avid. 


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TABLE OF CONTENTS 
. 
1. 
Rationale/Introduction ......................................................................................................................... 3 
2. 
Study Objectives .................................................................................................................................. 4 
2.1. 
Primary Objectives ......................................................................................................................... 4 
2.2. 
Secondary Objectives ..................................................................................................................... 4 
3. 
Study Design ........................................................................................................................................ 5 
4. 
Procedures and Methods ...................................................................................................................... 6 
4.1. 
Selection and Number of Investigators (Readers) .......................................................................... 6 
4.2. 
Selection/Number of Images .......................................................................................................... 6 
4.3. 
Blinded Read Method ..................................................................................................................... 6 
4.4. 
Data Collection ............................................................................................................................... 7 
4.5. 
Good Clinical Practice and Monitoring .......................................................................................... 7 
5. 
Statistical Methods ............................................................................................................................... 8 
5.1. 
General Statistical Considerations .................................................................................................. 8 
5.2. 
Population for Analysis .................................................................................................................. 8 
5.2.1. 
Analysis Population for Scan Accuracy Assessment ............................................................ 8 
5.2.2. 
Analysis Population for Scan Interpretation Precision Assessment ...................................... 8 
5.3. 
Power Analysis ............................................................................................................................... 8 
5.4. 
Efficacy Analysis. .......................................................................................................................... 9 
5.4.1. 
Primary Analyses .................................................................................................................. 9 
5.4.1.1. 
Assessing the Accuracy of Flortaucipir F 18 PET Scan ................................................. 9 
5.4.1.2. 
Assessing the Precision of Flortaucipir F 18 PET Scan Reads ..................................... 11 
5.4.2. 
Secondary Analyses ............................................................................................................ 11 
5.4.2.1. 
Analyses for Secondary Objective 1 ............................................................................. 12 
5.4.2.2. 
Analysis for Secondary Objective 2.............................................................................. 13 
5.4.2.3. 
Analysis for Secondary Objective 3.............................................................................. 13 
5.4.2.4. 
Analysis for Secondary Objective 4.............................................................................. 13 
6. 
Study Documentation ........................................................................................................................ 14 
6.1. 
Investigators (Readers) ................................................................................................................. 14 
6.2. 
Use of Study Scan Data for Research Purposes ........................................................................... 14 
7. 
References .......................................................................................................................................... 15 
 


Protocol: 18F-AV-1451-FR01 Confidential 
 
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1. Rationale/Introduction 
In prior clinical studies supporting accuracy and reliability of flortaucipir F 18 positron emission 
tomography (PET) scans, interpretation has been shown to have acceptable performance when 
compared to the autopsy truth standard (TS).  
This study is designed to further evaluate the accuracy and reliability of multiple readers’ 
interpretations of flortaucipir F 18 PET scans, not only from those subjects who came to autopsy, 
but also in the intended population for clinical use.  


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2. Study Objectives 
2.1. Primary Objectives  
• Test the relationship between ante-mortem flortaucipir F 18 PET imaging and tau 
neurofibrillary pathology associated with Alzheimer’s disease (AD), as measured at autopsy.  
• Assess inter-reader reliability.  
2.2. Secondary Objectives  
• Test the relationship between ante-mortem flortaucipir F 18 PET imaging of an AD pattern 
with uptake beyond the temporal/occipital regions (i.e., τAD++; see Table 1) and tau 
neurofibrillary pathology associated with AD, as measured at autopsy. 
• Assess inter-reader reliability for scans with an AD pattern that is beyond the 
temporal/occipital regions (i.e., τAD++; see Table 1). 
• Assess agreement among readers of flortaucipir F 18 PET scans in subjects known to be from 
the intended population (interpretation of scans from Avid Study 18F-AV-1451-A05 [A05]). 
• Assess intra-reader reliability for scans read twice by each reader. 


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3. Study Design 
All training and reads will be conducted by an imaging contract research organization (CRO) as 
described in the imaging review charter (IRC).  Five readers will be trained in-person on the 
flortaucipir F 18 PET scan read methodology using the previously developed read method.  The 
training will consist of teaching the readers the steps of interpretation, followed by a practice 
session using a set of demonstration and practice cases. After the training phase is complete, 
readers will then independently read 262 scans; 83 from Study 18F-AV-1451-A16 (A16) and 159 
from Study A05.  
The study population for Study A16 (18F-AV-1451-A16:  A clinico-pathological study of the 
correspondence between 18F-AV-1451 PET imaging and post-mortem assessment of tau 
pathology) consisted of subjects at the end of life, who were imaged with flortaucipir F 18 and 
came to autopsy.  Subjects were enrolled in the study with the intent of capturing a range of tau 
neurofibrillary pathology in AD.  
The study population for Study A05 confirmatory cohort (18F-AV-1451-A05:  An open label, 
multicenter study, evaluating the safety and imaging characteristics of 18F-AV-1451 in 
cognitively healthy volunteers, subjects with mild cognitive impairment, and subjects with 
Alzheimer’s disease) consisted of subjects with cognitive impairment who had mild cognitive 
impairment (MCI) or dementia with a suspected neurodegenerative cause, and a Mini Mental 
State Examination (MMSE) score of 20-27, inclusive. Subjects were imaged with flortaucipir 
F 18 and followed longitudinally for 18 months to assess the subsequent rate of cognitive 
decline.  
 
 


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4. Procedures and Methods 
4.1. Selection and Number of Investigators (Readers)  
Five qualified physicians will perform the blinded reads.  Readers will be selected using the 
following criteria: 
• Board Certified in radiology or nuclear medicine 
• Experience interpreting PET scans 
• Have not received training on the Avid flortaucipir F 18 read methodology   
4.2. Selection/Number of Images  
Two hundred and forty-two unique scans will be read for this study, comprised of the following: 
• All 83 subjects from Study A16 (primary and supplemental) who have a valid scan and 
autopsy 
• All 159 subjects from the Study A05 confirmatory cohort who have a valid scan 
• In addition, a sub-set of 20 randomly selected cases  will be used for intra-reader 
reliability purposes for a total of 262 scan reads  
4.3. Blinded Read Method  
Readers will be blinded to all demographic and clinical data.  All readers will be trained in-
person on the steps of image interpretation, using a set of demonstration and practice cases, prior 
to starting their independent reads.  A copy of the training materials will be provided to each 
reader for reference.  The read methodology is briefly outlined below. 
After scaling images to the cerebellar reference region and selecting an appropriate color scale, 
regions of the neocortex (the posterolateral temporal [PLT], occipital, parietal, and frontal 
regions) are evaluated for increased tracer uptake; and scans are interpreted as either not 
consistent (τAD-), consistent with an AD pattern (τAD+), or consistent with an AD pattern and 
likely to progress (τAD++) using the criteria shown in Table 1.  
 
 
 


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Table 1. 
Clinical Read Method Criteria  
Read Outcome 
Objective Image Features 
Not consistent with AD pattern 
(τAD-) 
No increased neocortical activity, or increased neocortical 
activity  isolated to the mesial temporal, anterolateral temporal, 
and/or frontal regions. 
AD pattern (τAD) 
τAD+ 
In either hemisphere, increased neocortical activity in the 
posterolateral temporal (PLT) or occipital region(s).  
τAD++ 
In either hemisphere, increased neocortical activity in the 
parietal/precuneus region(s), or frontal region(s) with increased 
uptake in the PLT, parietal, or occipital region(s).  
4.4. Data Collection  
Data will be collected using electronic case report forms (eCRFs).   
4.5. 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, Good 
Clinical Practice, and Avid/CRO Standard Operating Procedures.  Monitoring of study data will 
be performed by the Imaging CRO and will be performed in accordance with their standard 
operating procedures. 


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5. Statistical Methods 
5.1. General Statistical Considerations  
All statistical analyses will be performed using SAS® version 9.0 or higher.  The specific 
analyses to address the objectives will be described in the Statistical Analysis Plan. 
5.2. Population for Analysis  
Five readers will independently interpret the flortaucipir F 18 PET scans collected from 
2 completed Avid Studies, A16 and A05.  No new subjects will be enrolled for purposes of this 
study.  All 83 autopsy scans were collected from Study A16 (67 from main study and 16 from 
supplementary autopsy cohort (SAC)).  All 159 scans from Study A05 confirmatory cohort will 
be included.  
Valid images will be considered unevaluable only if 3 out of 5 independent readers declare the 
image unevaluable for the same reason.  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 IRC.  
5.2.1. Analysis Population for Scan Accuracy Assessment  
Flortaucipir F 18 scan accuracy (sensitivity and specificity) will be assessed using all 83 cases 
from Study A16 that had an autopsy diagnosis by pathologist panel, including: 
• 3 front-runners 
• 64 main study autopsy cases 
• 16 autopsy cases collected under SAC 
5.2.2. Analysis Population for Scan Interpretation Precision 
Assessment  
The precision of flortaucipir F 18 PET scan interpretation will be assessed in 2 ways:  inter-
reader (i.e., reader-to-reader) reliability, and intra-reader reliability (i.e., agreement between the 
repeated reads on same scan from same reader).  The inter-reader reliability will be assessed 
using all 242 scans included for this study (83 Study A16 scans and 159 Study A05 scans).  The 
inter-reader reliability will also be assessed separately on the 159 Study A05 scans (i.e., the 
targeted population for clinical usage), and on the 83 Study A16 scans.  Twenty scans will be 
randomly selected and will be read twice by the 5 readers in a randomized sequence, along with 
all the other scans.  The repeated reads on these 20 scans will be used to assess the intra-reader 
reliability.   
5.3. Power Analysis   
Assuming 80% sensitivity and 80% specificity, 14 TS positive or TS negative cases will be 
needed to show the lower bounds of 95% confidence interval (CI; 2-sided) greater than 50%, for 


Protocol: 18F-AV-1451-FR01 Confidential 
 
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either sensitivity or specificity, with a Wilson score method to calculate the 95% CI.  Out of the 
83 Study A16 cases with autopsy results, 47 were neurofibrillary tangle (NFT) stage B3 per 
pathologist’s panel diagnosis (TS positive for primary analysis 1), and 36 were NFT stage B2 or 
lower (TS negative for primary analysis 1); 41 were high AD neuropathologic change (ADNC) 
according to panel diagnosis (TS positive for primary analysis 2), and 42 were low to 
intermediate  ADNC  (TS negative for primary analysis 2).  Therefore, this sample size provides 
adequate power to assess the accuracy of flortaucipir F 18 PET scan in detecting underlying 
pathological changes. 
Fleiss’ Kappa will be used to assess the reader-to-reader consistency in flortaucipir F 18 scan 
visual interpretation.  Five independent qualified physicians will read 242 unique scans 
(83 autopsy scans from Study A16 and 159 scans from Study A05).  Assuming the Fleiss’ Kappa 
is expected to be 0.7, this sample size provides over 90% power in detecting a kappa value 
greater than 0.6, under a two-sided type I error rate of 0.05. 
5.4. Efficacy Analysis. 
5.4.1. Primary Analyses  
The primary objectives for this study are to assess both the accuracy and precision of flortaucipir 
F 18 PET imaging to detect tau neurofibrillary pathology associated with (AD).  
5.4.1.1. Assessing the Accuracy of Flortaucipir F 18 PET Scan  
Analyses for Primary Objective 1: 
For the first primary objective, 2 analyses will be planned to assess the accuracy of flortaucipir 
F 18 PET imaging in detecting tau pathology, as measured at autopsy. 
Primary Analysis 1  
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ interpretations of 
ante-mortem flortaucipir F 18 PET imaging for detection of a pattern of flortaucipir F 18 
neocortical uptake that corresponds to NFT Score of B3 (Hyman et al. 2012; Montine et al. 
2012) at autopsy will be evaluated; and 
Primary Analysis 2  
The diagnostic performance (sensitivity/specificity) of 5 independent readers’ interpretations of 
ante-mortem flortaucipir F 18 PET imaging for detection of a pattern of flortaucipir F 18 
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.  
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 
flortaucipir F 18 PET reading results will be ≥50%.  As detailed in Section 5.4.1, Table 2, 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.  Flortaucipir F 18 PET imaging will be classified by each reader 


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as either neocortical uptake not consistent with AD (τAD-), or neocortical uptake consistent with 
AD (τAD+) or neocortical uptake consistent with AD and likely to progress (τAD++).  
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 2 below: 
Table 2. 
Primary Objective 1 Analysis 1:  Diagnostic Performance 
Calculations for flortaucipir F 18 PET Scan Reader Interpretation 
vs. Autopsy NFT Score Truth Standard  
 
Autopsy NFT Score TS 
Physician Reader Interpretation 
NFT Score B3 
[Truth Positive] 
NFT Score B0–B2 
[Truth Negative] 
Flortaucipir F 18 neocortical uptake; AD 
pattern (τAD+/τAD++) 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18 neocortical uptake not 
consistent with AD (τAD-) 
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 versus high level of AD neuropathologic change according to NIA-AA criteria, 
considering Braak stage, Thal plaque score, and Consortium to Establish a Registry for 
Alzheimer’s Disease (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 
5.4.1 Table 3.  Flortaucipir F 18 PET images will be interpreted by visual examination as either 
τAD- or τAD+/τAD++ 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 3 below: 
 
 
 


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Table 3. 
Primary Objective 1 Analysis 2:  Diagnostic Performance 
Calculations for Flortaucipir F 18 PET Scan Reader Interpretation 
vs. NIA-AA Autopsy Diagnosis Truth Standard  
 
NIA-AA Autopsy Diagnosis TS 
Physician Reader Interpretation 
High 
AD Neuropathologic 
Change 
[Truth Positive] 
Not, Low, or Intermediate 
AD Neuropathologic Change 
[Truth Negative] 
Flortaucipir F 18  neocortical uptake; 
AD pattern (τAD+, τAD++) 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18  neocortical uptake; 
not consistent with AD pattern (τAD-) 
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 pathological diagnosis (for both NFT score TS and NIA-AA autopsy diagnosis TS) for 
Study A16 SAC cases were based on tissue samplings from 1 side of brain.  Therefore, the reads 
from the corresponding hemisphere upon which the pathological diagnosis was based on will be 
used for primary analyses 1 and 2. 
5.4.1.2. Assessing the Precision of Flortaucipir F 18 PET Scan Reads  
The second primary objective will assess inter-reader reliability. 
Primary Objective Analysis 2 
The inter-reader reliability of flortaucipir F 18 PET scan visual interpretation will be assessed 
using kappa statistics. Fleiss’ Kappa and the associated 95% CI will be calculated based on 
5 readers’ visual interpretations on the 242 scans (comprised of 83 scans from Study A16 
autopsy cases, and 159 cases from Study A05).  The p-value will be calculated using normal 
approximation method.  The lower bound of the 95% CI for Fleiss’ Kappa must be greater than 
or equal to 0.6 to meet the inter-reader reliability criterion.  If the scan is selected (by random) to 
be read twice for the intra-reader reliability assessment, the first read will be used for the second 
primary objective analysis; for Study A16 SAC cases; the overall reads (using both hemispheres) 
from each reader will be used for the second primary objective analysis. 
5.4.2. Secondary Analyses  
Four secondary objectives/analyses will further evaluate the precision of flortaucipir PET scan 
results.   


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5.4.2.1. Analyses for Secondary Objective 1 
With the same TS as used in primary analyses 1 and 2, these secondary analyses will assess the 
diagnostic performance (sensitivity/specificity) of a τAD++ pattern found on flortaucipir PET 
scan interpretation as below: 
Table 4. 
Secondary Objective 1 Analysis 1:  Diagnostic Performance 
Calculations for Flortaucipir F 18 PET Scan Reader Interpretation 
vs. Autopsy NFT Score Truth Standard  
 
Autopsy NFT Score TS 
Physician Reader Interpretation 
NFT Score B3 
[Truth Positive] 
NFT Score B0–B2 
[Truth Negative] 
Flortaucipir F 18  neocortical uptake; 
τAD++ pattern 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18  neocortical uptake; non-
τAD++ pattern (τAD- or τAD+) 
False Negative (FN) 
True Negative (TN) 
 
Table 5. 
Secondary Objective 1 Analysis 2:  Diagnostic Performance 
Calculations for Flortaucipir F 18 PET Scan Reader Interpretation 
vs. NIA-AA Autopsy Diagnosis Truth Standard 
 
NIA-AA Autopsy Diagnosis TS 
Physician Reader Interpretation 
High 
AD Neuropathologic 
Change 
[Truth Positive] 
Not, Low, or Intermediate 
AD Neuropathologic 
Change 
[Truth Negative] 
Flortaucipir F 18  neocortical uptake; 
τAD++ pattern 
True Positive (TP) 
False Positive (FP) 
Flortaucipir F 18  neocortical uptake; 
non-τAD++ pattern (τAD- or τAD+) 
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 pathological diagnosis (for both NFT score TS and NIA-AA autopsy diagnosis TS) for 
Study A16 SAC cases were based on tissue samplings from 1 side of the brain.  Therefore, the 


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reads from the corresponding hemisphere upon which the pathological diagnosis was based on 
will be used for secondary objective 1, analyses 1 and 2. 
For both analyses as listed above, the hypotheses for testing are 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%. 
5.4.2.2. Analysis for Secondary Objective 2 
Like the analysis for primary objective 2, kappa statistics will be used to assess inter-reader 
reliability of flortaucipir F 18 PET scan visual interpretation with a τAD++ pattern.  Fleiss’ 
Kappa and the associated 95% CI will be calculated based on 5 readers’ visual interpretations on 
the 242 scans (comprised of 83 scans from Study A16 autopsy cases, and 159 cases from Study 
A05). The p-value will be calculated using a normal approximation method.  The lower bound of 
the 95% CI for Fleiss’ Kappa must be greater than or equal to 0.6 to meet the inter-reader 
reliability criterion.  If the scan is selected (by random) to be read twice for the intra-reader 
reliability assessment, the first read will be used for this analysis; for Study A16 SAC cases, the 
overall reads (using both hemispheres) from each reader will be used for this analysis. 
5.4.2.3. Analysis for Secondary Objective 3  
For this objective, inter-reader reliability of flortaucipir F 18 PET scan visual interpretation in 
the Study A05 scans, a population similar to the intended population for clinical use will be 
assessed similar to the second primary objective analysis except that the Fleiss’ Kappa will be 
calculated based on 5 readers’ visual interpretations on the 159 scans from Study A05.  If any of 
the scans are selected (by random) to be read twice for the intra-reader reliability assessment, the 
first read will be used for this analysis. As an exploratory analysis, a similar analysis will be 
conducted using Study A16 scans. 
5.4.2.4. Analysis for Secondary Objective 4 
Twenty scans will be randomly selected for this analysis, and the 5 readers will read them in 
random sequence along with other scans.  Cohen’s Kappa will be calculated for each of these 5 
readers, based on these 20 scans read repeatedly to assess the intra-reader reliability of 
flortaucipir F 18 PET scan visual interpretation.  The 95% CI as well as p-values will be 
calculated using normal approximation method.  


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6. Study Documentation  
Avid will be responsible for the submission of the protocol to the Instututional Review 
Board/Independent Ethics Committee for regulatory approval prior to start of the study.  
All data required by the protocol will be recorded in the eCRF.  Completed eCRFs may need to 
be made available for an audit by the United States Food and Drug Administration or other 
international regulatory authorities at any time. The eCRFs and all other records will be filed in 
accordance with applicable laws and regulations.  
6.1. Investigators (Readers)  
Readers must supply Avid with the following documentation prior to performing any tasks 
associated with this protocol: 
• Signed and dated 1572 
• Signed and dated curriculum vitae  
• Medical license  
• Financial disclosure form  
In order to ensure blinding, readers will not be provided a copy of the protocol for review; 
therefore, a Protocol Signature Page will not be collected as part of the trial master file.  
6.2. Use of Study Scan Data for Research Purposes  
Patients who participated in the parent Studies A16 and A05 consented to the use of their data 
(including scans) for future research purposes.  All data (scans) will be anonymized and 
confidential for the purposes of this study.  Additional details around the process for 
anonymizing scans can be found in the IRC.  


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7. References 
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts 
C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski 
JQ, Vinters HV, Montine TJ. National Institute on Aging-Alzheimer's Association guidelines 
for the neuropathologic assessment of alzheimer's disease. Alzheimers Dement. 
2012;8(1):1-13. 
Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch 
MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, 
Hyman BT; National Institute on Aging; Alzheimer’s Association.. National Institute on 
Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of alzheimer’s 
disease: a practical approach. Acta Neuropathol. 2012;123(1):1-11. 
 

SAP_001.pdf: 
18F-AV-1451-FR01 SAP Amendment 2 
 
A Reader Study to Assess Accuracy and Reliability of Flortaucipir F 18 PET Scan Interpretation 
 
NCT03901092 
Approval date: 26 Apr 2019


Statistical Analysis Plan for 18F-AV-1451-FR01
1
STATISTICAL ANALYSISPLAN
DATE OF PLAN:
26-April-2019
STUDY DRUG:
Flortaucipir 18F (18F-AV-1451)
PROTOCOL NUMBER:
18F-AV-1451-FR01Amendment 1 
STUDY TITLE:
A READER STUDY TO ASSESS ACCURACY AND RELIABILITY OF 
FLORTAUCIPIR F 18 PET SCAN INTERPRETATION
SPONSOR:
Avid Radiopharmaceuticals, Inc.
Approval Date: 30-Apr-2019 GMT
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents.


Statistical Analysis Plan for 18F-AV-1451-FR01
2
SIGNATURE PAGE
This document has been prepared and/or reviewed by:
Sgnature
Date
This document has been reviewed and accepted by:
Signature
Signature


Statistical Analysis Plan for 18F-AV-1451-FR01
3
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS...................................................................................5
2.
INTRODUCTION....................................................................................................6
3.
STUDY OBJECTIVES.............................................................................................7
3.1.
Primary Objective.....................................................................................................7
3.2.
Secondary Objective.................................................................................................7
4.
STUDY DESIGN.....................................................................................................8
5.
SAMPLE SIZE JUSTIFICATION............................................................................9
6.
FLORTAUCIPIR PET SCAN SELECTION...........................................................10
7. 
DEFINITIONS AND CONVENTIONS.................................................................11
7.1.
General Summary Table and Individual Patient Data Listing Considerations..........11
7.2.
Analysis Populations..............................................................................................11
7.2.1.
Efficacy Analysis Population for Accuracy Evaluation (EFFA)..............................11
7.2.2.
Efficacy Analysis Population for Precision Evaluation (EFFP)...............................11
8.
DATA PRESENTATIONS AND DATA MANAGEMENT...................................13
8.1.
Data Presentations..................................................................................................13
8.2.
Data Management...................................................................................................13
8.3.
General Post Text Summary...................................................................................13
8.3.1.
Table and Individual Patient Data Listing Format Considerations...........................13
9.
BASELINE PATIENT DATA AND EFFICACY ENDPOINT...............................14
9.1.
Demographic, PET Scan, and Autopsy Data...........................................................14
9.2.
Neuropathological Evaluation.................................................................................14
9.3.
Flortaucipir F 18 PET Imaging Evaluation..............................................................15
10.
EFFICACY ANALYSIS........................................................................................16
10.1.
General Considerations...........................................................................................16
10.2.
Multiple comparisons/multiplicity of hypotheses testing.........................................16
10.3.
Analyses of the Primary Objectives........................................................................16
10.3.1.
Primary Objective #1 Efficacy Analysis 1: Accuracy of Flortaucipir F 18 
PET Scan Interpreted as AD Pattern in Detecting NFT Tau Stage...........................16
10.3.2.
Primary Objective #1 Efficacy Analysis #2: Accuracy of Flortaucipir F 18 
PET Scan Interpreted as AD Pattern in Detecting AD Neuropathological 
Change...................................................................................................................17
10.3.3.
Primary Objective #2 Efficacy Analysis: Inter-Reader Agreement of 
Flortaucipir F 18 PET Scan Interpreted as AD Pattern............................................18


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10.4.
Analysis of Secondary Objectives...........................................................................18
10.4.1.
Test theRelationship Between Ante-mortem Flortaucipir F 18 PET Imaging 
of an AD Pattern with Uptake Beyond the Temporal/Occipital Regions 
(τAD++) and Tau Neurofibrillary Pathology Associated with AD, as 
Measured at Autopsy..............................................................................................18
10.4.2.
Inter-Reader Reliability of Flortaucipir F 18 PET Scan Interpreted as τAD++ 
Pattern....................................................................................................................19
10.4.3.
Inter-Reader Agreement of Flortaucipir F 18 PET Scan Interpreted as AD 
Pattern  for Intended Clinical Use Population..........................................................19
10.4.4.
Intra-Reader Agreement of Flortaucipir F 18 PET Scan Visual Interpretation 
Interpreted as AD Pattern........................................................................................19
10.5.
Other Efficacy Analyses.........................................................................................20
10.5.1.
Accuracy of FlortaucipirF 18 Scan in Detecting Tau Neurofibrillary 
Pathology Associated with Alzheimer’s Disease (AD), Based on Majority 
Scan Interpretations................................................................................................20
10.5.2.
Inter-Reader Agreement of Flortaucipir F 18 PET Scan  Interpreted as AD 
Pattern   for Autopsy Population.............................................................................20
10.5.3.
Additional Visual Interpretation Reliability Assessment of Flortaucipir F 18 
Scan Interpreted as τAD++ Pattern.........................................................................20
10.5.4.
Diagnostic Performance Calculation for Flortaucipir F 18 PET Scan Reader 
Interpretation vs. Modified Autopsy NFT Score TS (B0/1 vs. B2/3).......................21
11.
SENSITIVITY ANALYSIS....................................................................................22
12.
SAFETY ASSESSMENT.......................................................................................23
13.
REFERENCES.......................................................................................................24
LIST OF TABLES
Table1:
List of Abbreviations................................................................................................5
Table 2.
Autopsy NFT Score Truth Standard........................................................................14
Table 3.
NIA-AA Autopsy Diagnosis Level of AD Neuropathological Change Truth 
Standard.................................................................................................................14


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1.
LIST OF ABBREVIATIONS
Table1:
List of Abbreviations
AD
Alzheimer’s Disease
CN
Cognitively Normal
TS
Truth Standard
MCI
Mild Cognitive Impairment
SAP
Statistical Analysis Plan
CRO
Contract Research Organization
ODD
Other Dementia Disorder
τAD-
Not consistent with AD pattern
τAD
AD pattern
CRF/eCRF
Case Report Form/ Electronic Case Report Form
SAS
SAS®software
ADNC
AD Neuropathological  Change
EFFA
Efficacy Analysis Population for Accuracy Evaluation 
EFFP
Efficacy Analysis Population for Precision Evaluation 
SAC
Supplementary Academic Cohort
PET
Positron Emission Tomography
PPV
Positive Predictive Value
NPV
Negative Predictive Value
LR+
Likelihood Ratio Positive
LR-
Likelihood Ratio Negative
FN
False Negative
TN
True Negative
FP
False Positive
TP
True Positive


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2.
INTRODUCTION
In prior clinical studies supporting accuracy and reliability of flortaucipir F 18positron emission 
tomography (PET) scans, interpretation has been shown to have acceptable performance when 
compared to the autopsy truth standard(TS). 
This study is designed to further evaluate the accuracy and reliability of multiple readers’ 
interpretations of flortaucipir F 18PET scans not only from those subjects who came to autopsy, 
but also in the intended population for clinical use. 
The purpose of this statistical analysis plan (SAP) is to describe thestatistical analyses for this 
study. The SAP should be read in conjunction with the protocol. 


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3.
STUDY OBJECTIVES
3.1.
Primary Objective
There are two co-primary objectives for this study:
Test the relationship between ante-mortem flortaucipir F 18 PET imaging and tau 
neurofibrillary pathology associated with Alzheimer’s disease (AD), as measured at autopsy. 
Assess inter-reader reliability
3.2.
Secondary Objective
There are foursecondary objectives for this study:
Test the relationship between ante-mortem flortaucipir F 18 PET imaging of an AD 
pattern with uptake beyond the temporal/occipital regions (i.e., τAD++; refer to Protocol 
Table 1) and tau neurofibrillary pathology associated with Alzheimer’s disease (AD), as 
measured at autopsy
Assess inter-reader reliability for scans with an AD pattern that is beyond the 
temporal/occipital regions (i.e., τAD++; refer to Protocol Table 1)
Assess agreement among readers of flortaucipir F 18PET scans in subjects known to be 
from the intended population (interpretation of scans from Avid study 
18F-AV-1451-A05 
[Study A05])
Assess intra-reader reliability for scans read twice by each reader


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4.
STUDY DESIGN
All training and reads will be conducted by an imaging contract research organization (CRO)as 
described in the imaging review charter (IRC). Five readers will be trained in-person on the 
flortaucipir F 18PET scan read methodology using the previously developed read method. The 
training will consist of teaching the readers the steps of interpretation, followed by a practice 
session using a set of demonstration and practice cases. After the training phase is complete, 
readers will then independently read 262scans; 83 from Study 
18F-AV-1451-A16(A16)and 159 
from Study A05.
The study population for the A16 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”) consisted of subjects at the end of life, who were imaged with flortaucipir F 18and 
came to autopsy. Subjects were enrolled in the study with the intent of capturing a range of tau 
neurofibrillary pathology in AD.
The study population for the A05 Study Confirmatory Cohort (
18F-AV-1451-A05 “An open 
label, multicenter study, evaluating the safety and imaging characteristics of 
18F-AV-1451 in 
cognitively healthy volunteers, subjects with Mild Cognitive Impairment, and subjects with 
Alzheimer’s disease”) consisted of subjects with cognitive impairment who had Mild Cognitive 
Impairment (MCI) or dementia with a suspected neurodegenerative cause, and a Mini Mental 
State Examination (MMSE) score of 20-27, inclusive. Subjects were imaged with flortaucipir F 
18 and followed longitudinally for 18 months to assess the subsequent rate of cognitive decline. 


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5.
SAMPLE SIZE JUSTIFICATION
Assuming 80% sensitivity and 80% specificity, 14 truth standard (TS) positive or TS negative 
cases will be needed to show the lower bounds of 95% confidence interval (CI; 2-sided) greater 
than 50%, for either sensitivity or specificity, with a Wilson score method to calculate the 95% 
CI. Out of the 83 A16 cases with autopsy results, 47 were neurofibrillary tangle (NFT)stage B3 
per pathologist’s panel diagnosis (TS positivefor primaryobjective #1efficacy analysis #1), and 
36 were NFT stage B2 or lower (TS negative for primary objective #1 efficacy analysis #1); 41 
were high AD neuropathologic change(ADNC)according to panel diagnosis (TS positive for 
primaryobjective #1 efficacyanalysis #2), and 42 were low to intermediate ADNC (TS negative 
for primaryobjective #1 efficacyanalysis #2). Therefore, this sample size provides adequate 
power toassess the accuracy of flortaucipir F 18PET scan in detecting underlying pathological 
changes.
Fleiss’ Kappa will be used to assess the inter-reader reliabilityin flortaucipir F 18scan visual 
interpretation. Five independent qualified physicians will read 242unique scans (83 autopsy 
scans from study A16 and 159scans from study A05). Assumingthe Fleiss’ kappa is expected to 
be 0.7, this sample size provides over 90% power in detectinga kappa value greater than or 
equal to 0.60, under a two-sided type I error rate of 0.05.


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6.
FLORTAUCIPIRPET SCANSELECTION
Flortaucipir F18 PETscans were selected from subjects enrolled in previous studies18F-AV-
1451-A16and 
18F-AV-1451-A05. The following images will be used for this study:
All 83 subjects from Study A16 (primary and supplemental) who have a valid scan and 
autopsy.This includes:
3 front-runners
64 main study autopsy cases
16 autopsy cases collected under SAC
All 159 subjects from the study 
18F-AV-1451-A05who have a valid scan, representing 
the intended population for clinical use. 
20 scans will be randomly selected (by simple random selection method) from studies
A16 and A05, to be read twice independently by each of the 5 readers for intra-reader 
reading reliabilityevaluationpurposes.
The majority read results from A05 and A16 both showed a ~56% scan positive (τAD+/τAD++) 
rate. Similarly, it is expected that the 20 scans randomly selected for intra-reader reliability
evaluation will have a similar scan positive rate. If by chance the randomly selected 20 cases
have a skewed positive or negativerate, to avoid possible interpretation bias from a sample 
population of primarily positive or negative scans,the random samplingprocesswill be repeated 
to ensure a relativelybalanced positive/negative rate from the selected samples(scan positive 
rate by majority reads from corresponding study is in the range of 30% -70%).
An external CRO will randomize all scans into a randomized sequence forvisualreading.        


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7.
DEFINITIONS AND CONVENTIONS
7.1.
General Summary Table and Individual Patient Data Listing 
Considerations
Summary tables and listings will be prepared according to ICH Guideline E3 that will include a 
footer providing the following notes:
1. Date of output generation.
2. SAS program name that generates the output.
3. Reference to the data listings that the summary table based on. 
4. Any other output specific details that require further elaboration.
7.2.
Analysis Populations
Since there will be no flortaucipir F 18dose in this study, there will be no safety evaluation 
planned thus the analysis population will be for efficacy analyses only.
Efficacy analysis population will include all valid scan reading results from 5 readers on 242
cases. Valid images will be considered unevaluable only if 3 out of 5 independent readers declare 
the image unevaluable for the same reason. Subjects with invalid or unevaluable PET data will 
be excluded fromefficacyanalyses. Criteria for declaring an image invalid or not evaluable will 
be specified in advance in the Image Review Charter. 
7.2.1.
Efficacy Analysis Population for Accuracy Evaluation (EFFA)
The EFFA will include reading results for all valid and interpretablescansfromall 83 autopsy 
cases from study A16. The analysis set will be used to conduct the primaryobjective #1 efficacy 
analyses #1 and #2 (refer to Section 10.3.1 and 10.3.2), and secondary objective #1 analysis #1 
and #2 (refer to section 10.4.1).
For scans that will be read twice for intra-reader reliabilityevaluation, the first read will be 
included in the EFFA.
Sixteen cases enrolled as supplementary academic center (SAC) autopsy cases only had 
neuropathologist diagnosis from one hemisphere. Therefore, the visual reads from the 
corresponding side will be used in the primary objective analyseswhere the accuracy of τAD 
visual reads is assessed, since the τAD visual read data is available from both sides of the brain.
For secondary objective analyses where the accuracy of τAD++ visual reads is assessed, the 
τAD++ read for thewhole brain will be used due to data availability. 
7.2.2.
Efficacy Analysis Population for Precision Evaluation (EFFP)
The EFFP are defined according to analyses, as below:


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7.2.2.1.
EFFP1
EFFP1 will include reading results for all valid and interpretable scans fromall 242cases from 
studiesA16 and A05. The analysis set will be used to conduct primary objective #2efficacy 
analysis (refer to Section 10.3.3), and secondary objective #2 efficacy analysis (refer to section 
10.4.2).
For scans that will be read twice for intra-reader reliabilityevaluation, the first read will be 
included in the EFFP1.For the 16 SAC cases, the overall visual interpretation based on whole 
brain will be used.
7.2.2.2.
EFFP2
EFFP2 will include reading results for all valid and interpretable scans from the 159cases from 
study A05. The analysis set will be used to conduct analysis for secondary objective #3(refer to 
Section 10.4.3).
For scans that will be read twice for intra-reader reliabilityevaluation, the first read will be 
included intheEFFP2.
7.2.2.3.
EFFP3
EFFP3 will include reading results for all valid and interpretable scans fromthe 20 cases 
randomly selected to evaluate intra-reader reliability. The analysis set will be used to conduct 
efficacy analysis for secondary objective #4(refer to Section 10.4.4).For the 16 SAC cases, the 
overall visual interpretation based on whole brain will be used.


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8.
DATA PRESENTATIONS AND DATA MANAGEMENT
8.1.
Data Presentations
The data will be presented with tables and listings in the following categories:
1. Demographic profile for the study participants
2. Analyses of the primary, secondaryand exploratory efficacy data
8.2.
Data Management
The data will be collected using an electronic case report form (eCRF) system that was
developed by data vendor American College of Radiology (ACR).  There willbe an edit check 
and quality control before the database lock to ensure the highest possible quality of the study 
data.
Derived working datasets will be created using the Statistical Analysis System (SAS) software. 
Data analyses and summary tables will begenerated using SAS version 9.0or higher.  
8.3.
General Post Text Summary 
8.3.1.
Table and Individual Patient Data Listing Format Considerations
The tables and listings will be numbered using a decimal system to reflect main levels of unique 
tables and listings and sub-levels of replicate tables and the listings with two digits per level 
(e.g., Table XX.YY.ZZ…). Tables will be presented in Appendix 14 and individual patient data 
listings are presented in Appendix 16. 


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9.
BASELINE PATIENT DATAAND EFFICACY ENDPOINT
9.1.
Demographic,PET Scan, and Autopsy Data
The baseline data will be carried forward from the previous studies 18F-AV-1451-A05 and 18F-
AV-1451-A16, which include the following:
Demographics: age, gender, race, and ethnicity
PET scan and autopsy information:
Date of flortaucipir PET scan, date of autopsy, and Interval between image and autopsy. 
9.2.
Neuropathological Evaluation
All neuropathological measurements on brain tissue will be obtained from study A16, which 
were evaluated in a standardized fashion in a qualified laboratory.  
Neuropathological assessment was derived from the NIA-AA guidelines (Hyman et al., 2012).  
The truth standard (TS)for primary objective #1 efficacy analysis#1was 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
AAdapted from Hyman et al., 2012.
The TS for primaryobjective #1 efficacy analysis#2was 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
AAdapted from Hyman et al., 2012.


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9.3.
Flortaucipir F 18PET Imaging Evaluation
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).
Flortaucipir F18 PET images will be interpreted by visual examination using the following 
criteria:
ReadOutcome
Objective Image Features
Not consistent with AD pattern 
(τAD-)
No increased neocortical activity, or increased neocortical 
activity isolated to the mesial temporal, anterolateral 
temporal, and/or frontal regions.
AD pattern 
(τAD)
τAD+
In either hemisphere, increased neocortical activity in the 
posterolateral temporal (PLT) or occipital region(s). 
τAD++
In either hemisphere, increased neocortical activity in the 
parietal/precuneus region(s), or frontal region(s) with 
increased uptake in the PLT, parietal, or occipital 
region(s). 
For the purpose of testing primary objective #1, a scan interpretation will be considered positive 
(hypothesized to correspond to a B3 NFT score for primaryobjective #1 efficacy analysis1and 
an NIA-AA score of high AD pathology for primaryobjective #1 efficacy analysis#2)if the 
scan was interpretedas at least consistent with an AD pattern (τAD+ or τAD++).
For the purpose of testing secondary objective #1, a scan interpretation will be considered 
positive (hypothesized to correspond to a B3 NFT score for secondary objective #1 efficacy 
analysis #1 and an NIA-AA score of high AD pathology for secondaryobjective #1 efficacy 
analysis #2) if the scan was interpretedas  τAD++.


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10.
EFFICACY ANALYSIS
10.1.
General Considerations
Categorical variables will be summarized as frequencies and percentages by enrolling diagnostic 
group(Dementia, MCI, or CN).  Continuous variables will be summarized usingdescriptive 
statistics (n, mean,median, standard deviation, minimum and maximum) byeach diagnostic 
group.  
All inferential statistics will be performed at the 2-sided, 0.05 level of significance.
SAS Version 9.0or above will be used to perform all analyses.
10.2.
Multiple comparisons/multiplicity of hypotheses testing
Three hypotheses will be tested for the two co-primary objectives, as detailed in section 10.3. 
This trial will beconsideredsuccessful if all threeprimary efficacy analyses achieve their 
success criteria.
10.3.
Analyses of the Primary Objectives
10.3.1.
Primary Objective #1 Efficacy Analysis 1: Accuracy of Flortaucipir F 18PET 
ScanInterpreted as AD Pattern in Detecting NFT Tau Stage
The first primary analysis will evaluate the accuracy of flortaucipir F 18PET scanin detecting 
neurofibrillary tangle as measured by NFT stage (truth standard), as detailed in Table 1 of 
section 9.2. 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 
flortaucipir PET reading interpretations will be ≥ 50%.
This analysis will be based on the EFFA, as defined in 7.2.1.
The following table contains terms used to define sensitivity, specificity, accuracy, positive 
predictivevalue (PPV), negative predictive value (NPV), likelihood ratio positive (LR+) and 
likelihood ratio negative (LR-):
Diagnostic Test: Flortaucipir F 18PET 
Scan Read Result
Truth Standard
NFT B3
NFT B0-B2
Positive: Flortaucipir F 18 neocortical 
uptake; AD pattern(τAD+, τAD++)
True Positive (TP)
False Positive (FP)
Negative: Flortaucipir F 18 neocortical 
uptake; not consistent with AD pattern  
(τAD-)
False Negative (FN)
True Negative (TN)
The sensitivity, which evaluates how gooda test is at detecting a positive disease, will be 
calculated as:


17 


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The calculation of sensitivity, specificity, NPV, PPV, LR+ and LR-analyses, as well as the 
confidence interval calculation will be identical to primary analysis #1, with ADNC as TS. 
10.3.3.
PrimaryObjective #2 EfficacyAnalysis: Inter-Reader Agreement of 
FlortaucipirF 18PET Scan Interpreted as AD Pattern  
The overall reader to reader reliability across 5 readers forinterpreting the flortaucipir PET scan 
will be assessed using Fleiss’Kappa.The primary hypothesis to be tested is that thelower 
bound of two-sided 95% confidence intervalof Fleiss’Kappa will be greater than or equal to 0.6.
This analysis will be basedon the EFFP1,as defined in7.2.2.1. 
The degree of agreement between two readers for the interpretation of flortaucipir PET scan will 
be assessedin a pair-wise mannerusing Cohen’s Kappa statistics. 
The percent of agreement between the two readers will be calculated for each reader pair. The 
over percent of agreement across 5 readers will be calculated too. All these results will be 
summarized in tables. 
10.4.
Analysis of Secondary Objectives
10.4.1.
Test theRelationship Between Ante-mortem Flortaucipir F 18 PET Imaging of 
an AD Pattern with Uptake Beyond the Temporal/Occipital Regions (τAD++) 
and Tau Neurofibrillary Pathology Associated with AD, as Measured at Autopsy
To further evaluation the diagnosticperformance of flortaucipir scans, the same scan 
interpretation from the readers will be reclassified as an AD pattern with uptake beyond the 
temporal/occipital regions (τAD++: positive) vs. otherwise (τAD+/τAD-: negative)and 
comparedto the TS as detailed in section 9.2. That is, calculating the diagnostic performance 
statistics following the tables as below:
Secondary Objective #1 Efficacy Analysis #1
Diagnostic Test: Flortaucipir F 18PET 
Scan Read Result
Truth Standard
NFT Score B3
[Truth Positive]
NFT Score B0–B2
[Truth Negative]
Positive: Flortaucipir F 18 neocortical 
uptake; τAD++ pattern
True Positive (TP)
False Positive (FP)
Negative: Flortaucipir F 18 neocortical 
uptake; non-τAD++ pattern  (τAD-/
τAD+)
False Negative (FN)
True Negative (TN)
And:


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Secondary Objective #1 Efficacy Analysis #2
Diagnostic Test: Flortaucipir F 18PET 
Scan Read Result
Truth Standard
High AD 
Neuropathologic 
Change
[Truth Positive]
Not,Low, or 
IntermediateAD 
Neuropathologic 
Change
[Truth Negative]
Positive: Flortaucipir F 18 neocortical 
uptake; τAD++ pattern
True Positive (TP)
False Positive (FP)
Negative: Flortaucipir F 18 neocortical 
uptake; non-τAD++ pattern  (τAD-/τAD+)
False Negative (FN)
True Negative (TN)
The calculation of sensitivity, specificity, NPV, PPV, LR+, LR-, as well as the associate 95% CI 
will be the same as described in section 10.3.1.
10.4.2.
Inter-Reader Reliability of Flortaucipir F 18PET Scan Interpreted as τAD++ 
Pattern 
This analysis will assess thereliability of flortaucipir F 18scan interpreted as τAD++ pattern 
across 5 readers. Same as analysis described in section 10.3.3, Fleiss’ Kappa and the associated 
two-sided 95% CI will be calculated. The hypothesis to be tested is that the lower bound of two-
sided 95% confidence interval of Fleiss’ Kappa will be greater than or equal to 0.6. This analysis 
will be based on the EFFP1, as defined in 7.2.2.1. 
10.4.3.
Inter-Reader Agreement of Flortaucipir F 18PET ScanInterpreted as AD 
Pattern  for Intended Clinical Use Population
The subjects enrolled in study A05 were representative cases ofthe intended clinical use 
population for flortaucipir F 18scan. This analysis will evaluate the inter-reader reliability of 
flortaucipir scan interpretedas AD pattern withthis intended clinical practice population.
Analyses similar to 10.3.3 will be conductedusing EFFP2, which will be based on 159A05 
cases as defined in 7.2.2.2.
10.4.4.
Intra-Reader Agreement of Flortaucipir F 18PET Scan Visual Interpretation
Interpreted as ADPattern  
Intra-reader reliability will be assessed using randomly selected 20 cases(EFFP3) as defined in 
section 7.2.2.3.These randomly selected cases will be read twice by every reader. ACohen’s
Kappa statisticswill be used to assess the agreement of the two reading results (scans that are 
interpreted as an AD pattern, i.e., τAD (τAD+/τAD++) vs τAD-) by every reader. 
The percent of agreement between the two readings from same reader will be calculated for each 
reader. All these results will be summarized in tables.


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10.5.
Other Efficacy Analyses
10.5.1.
Accuracy of Flortaucipir F 18Scan in Detecting Tau Neurofibrillary Pathology 
Associated with Alzheimer’s Disease (AD), Based onMajority Scan 
Interpretations
For each image, the majority interpretation of 5 independent readers will be derived using 
individual readers’ interpretation results.  Diagnostic performance of this majority interpretation 
will be assessed relative to the autopsy NFT score TS as per primaryobjective #1efficacy 
analysis #1 (refer to Section Error! Reference source not found.0.3.1) and again relative to the 
NIA-AA autopsy diagnosis TS as per primary objective #1 efficacy analysis #2 (refer to Section 
Error! Reference source not found.0.3.2).
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 flortaucipir F 18PET 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.
10.5.2.
Inter-Reader Agreement of Flortaucipir F 18PET Scan Interpreted as AD 
Pattern  for Autopsy Population
The inter-reader agreement analysis across5 readers of flortaucipir F 18PET scaninterpretation
(interpreted as AD pattern)will be repeated based on the EFFA.Fleiss’ Kappa, and other 
statistics,will be calculated the same as described in section 10.3.3.
10.5.3.
Additional Visual Interpretation ReliabilityAssessmentof Flortaucipir F 18
Scan Interpreted as τAD++Pattern  
These additional visual interpretationreliabilityassessments will be conducted for flortaucipir F 
18scansbased ontheτAD++pattern:
1) Inter-reader reliabilityfor scans including clinical use population only (A05 cases):
Fleiss’ Kappa, and other statistics will be calculated the same as described in section 
10.3.3., based on EFFP2.
2) Inter-readerreliabilityfor scans including autopsy cases only (A16cases):
Fleiss’ Kappa, and other statistics will be calculated the same as described in section 
10.3.3., based on EFFA.


Statistical Analysis Plan for 18F-AV-1451-FR01
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3) Intra-reader reliability for scans included in EFFP3:
Cohen’s kappa and other statistics will be calculated the same as describedin section 
10.4.4, based on EFFP3.
10.5.4.
Diagnostic Performance Calculation for Flortaucipir F 18PET Scan Reader 
Interpretation vs. Modified Autopsy NFT Score TS (B0/1 vs. B2/3)
Flortaucipir F 18scan visual interpretation, both as described in primary objective #1 analyses 
and secondary objective #1 analyses will be compared to a modified autopsy NFT score TS, 
which classifiesNFT score B2 and B3 as truth standard positive, and NFT score B0 and B1 as 
truth standard negative. 
The diagnostic performance statistics calculation will be based on the tables as below:
Flortaucipir scan interpretation τAD pattern (τAD+/τAD++) as scan reads positive:
Diagnostic Test: Flortaucipir F 18PET 
Scan Read Result
Modified Truth Standard
NFT Score B2/B3
[Truth Positive]
NFT Score B0/B1
[Truth Negative]
Positive: Flortaucipir F 18 neocortical 
uptake; AD pattern(τAD+, τAD++)
True Positive (TP)
False Positive (FP)
Negative: Flortaucipir F 18 neocortical 
uptake; not consistent with AD pattern  
(τAD-)
False Negative (FN)
True Negative (TN)
And τAD++ pattern as scan reads positive:
Diagnostic Test: Flortaucipir F 18PET 
Scan Read Result
Modified Truth Standard
NFT Score B2/B3
[Truth Positive]
NFT Score B0/B1
[Truth Negative]
Positive: Flortaucipir F 18 neocortical 
uptake; τAD++ pattern
True Positive (TP)
False Positive (FP)
Negative: Flortaucipir F 18 neocortical 
uptake; non-τAD++ pattern  (τAD-/τAD+)
False Negative (FN)
True Negative (TN)
The calculation of sensitivity, specificity, NPV, PPV, LR+, LR-, as well as the associate 95% CI 
will be the same as described in section 10.3.1.


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11.
SENSITIVITY ANALYSIS
The primary objective analyses will be repeated by using the whole brain visual reads (for τAD 
pattern) for SAC cases. Identical analyses will beconducted as described in section 10.3. 


Statistical Analysis Plan for 18F-AV-1451-FR01
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12.
SAFETY ASSESSMENT
No flortaucipir F18 scan/dosing will be given to patient in this study, therefore the safety 
evaluation will not be conducted.


Statistical Analysis Plan for 18F-AV-1451-FR01
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13.
REFERENCES
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