Conditions: Alzheimer Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 205
Healthy volunteers: no

Brief summary:
This study will evaluate whether visual interpretation of flortaucipir-PET (positron emission tomography) scans, examining patterns of tracer uptake at baseline, can predict the rate of clinically-meaningful cognitive decline due to AD after 18 months. All scans are acquired from cohorts of a previously completed study, I8D-MC-AZES (NCT02245737, lanabecestat, Eli Lilly and Company sponsor).

Detailed description:

Arms:
arm 1: No study drug will be administered. Scans previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) will be read by independent, blinded readers.

Interventions: intervention 1: flortaucipir F18 intervention 2: Brain PET Scan
Intervention descriptions: intervention 1: No study drug will be administered. Scans previously acquired from Study I8D-MC-AZES (NCT02245737, Eli Lilly and Company sponsor) at baseline will be read by independent, blinded readers. IV injection, 240 megabecquerel (MBq) (6.5 mCi), single dose in AZES intervention 2: positron emission tomography (PET) scan of the brain

Protocol document:
Prot_000.pdf: 
18F-AV-1451-PX01 Protocol v1.0 
 
Evaluation of the relationship between baseline flortaucipir PET signal and cognitive change in 
subjects with early Alzheimer's disease participating in the I8D-MC-AZES Protocol Addendum 
D5010C00009 (2.1) (Tau Imaging) 
 
NCT03901105 
Approval date: 12 Mar 2019




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TABLE OF CONTENTS
1.
RATIONALE/INTRODUCTION................................................................................................... 4
2.
STUDY OBJECTIVES................................................................................................................... 5
2.1.
Primary Objectives.................................................................................................................... 5
2.2.
Secondary Objectives ................................................................................................................ 5
2.3.
Exploratory Objectives .............................................................................................................. 5
3.
STUDY DESIGN........................................................................................................................... 6
4.
PROCEDURES AND METHODS ................................................................................................. 7
4.1.
Selection and Number of Investigators (Readers)....................................................................... 7
4.2.
Selection/number of Images: ..................................................................................................... 7
4.3.
Blinded Read Method:............................................................................................................... 7
4.4.
Data Collection ......................................................................................................................... 8
4.5.
Good Clinical Practice and Monitoring...................................................................................... 8
5.
STATISTICAL METHODS ........................................................................................................... 8
5.1.
General Statistical Considerations.............................................................................................. 8
5.2.
Population for Analysis ............................................................................................................. 8
5.3.
Power Analysis ......................................................................................................................... 8
5.4.
Efficacy Analysis ...................................................................................................................... 9
5.4.1.
Primary Objective Analysis .............................................................................................. 9
5.4.2.
Secondary Objective Analysis........................................................................................... 9
5.4.2.1.
Clinically Meaningful Deterioration at 18 Months by Tau 
Status ......................................................................................................................... 9
5.4.2.2.
Mean Change of Cognitive/Functional Assessments at 18 
Months by flortaucipir PET visual interpretation (τAD++ vs. 
non-τAD++) ............................................................................................................... 9
5.4.2.3.
Inter-reader Reliability.............................................................................................. 10
5.4.3.
Exploratory Analysis ...................................................................................................... 10
5.4.3.1.
Cognitive/Functional Assessments Deterioration at 24 months, 
by Tau Status............................................................................................................ 10
5.4.3.2
Clinically Meaningful Deterioration by τAD vs τAD- tau 
status........................................................................................................................ 10
5.4.3.3
Diagnostic Performance of Flortaucipir Scan in Predicting 
Clinical Deterioration ............................................................................................... 10
6.
Study Documentation ................................................................................................................... 11
6.1.
Investigators (Readers)............................................................................................................ 11


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6.2.
Use of Study Scan Data for Research Purposes........................................................................ 11
7.
REFERENCES............................................................................................................................. 12


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1.
RATIONALE/INTRODUCTION
Study PX01 is designed to further evaluate the relationship between flortaucipir uptake as 
measured by Positron emission tomography (PET) at baseline and the subsequent rate of 
cognitive decline due to Alzheimer’s disease (AD) observed over an 18-month longitudinal 
follow up by utilizing a therapeutic trial cohort that had flortaucipir PET scans and up to 2 years
of cognitive follow-up. The subjects whose scans will be read in study PX01 were recruited to a 
PET substudy of the I8D-MC-AZES (AZES) therapeutic clinical trial evaluating the BACE
(Beta-site amyloid precursor protein-cleaving enzyme 1) inhibitor AZD3293 (LY3314814), also 
known as lanabecestat, for the treatment of patients with early AD.  The AZES study was 
terminated early after an independent assessment concluded that the trial was not likely to meet 
the primary endpoint upon completion and therefore, the trial was stopped for futility. 
The subjects enrolled in the PET substudy of AZES had flortaucipir PET scans at baseline and at 
multiple follow-up timepoints.  At the time the study was terminated/completed, 205 subjects
with a baseline flortaucipir PET scan had completed 18 month cognitive follow-up evaluations.  
These subjects will be used as the primary efficacy population for study PX01. Although a subset 
of these subjects (approximately 90 subjects) completed the 24 month follow-up visit, the 24 
month change from baseline data were reserved for exploratory analyses, with 18 months 
primary endpoints used for direct comparison to the A05 Confirmatory Cohort (A05C) Phase 3
study results.
In the present study, readers will visually interpret each baseline flortaucipir PET scan to identify 
patterns of tracer uptake that predict risk of clinically meaningful deterioration as determined by 
Clinical Dementia Rating Scale Sum of Box (CDR-SB) value change (1 point or more increase) 
within 18 months. The approach used is similar to study A05C, which was a confirmatory study 
for longitudinal progression in 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.  


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2.
STUDY OBJECTIVES
2.1.
Primary Objectives

To assess whether a visual interpretation (τAD++ vs. non τAD++ pattern) of the 
baseline flortaucipir PET scan can predict the risk of subjects’ clinically 
meaningful cognitive and functional deterioration within 18 months of scan, as 
measured by the Clinical Dementia Rating Scale Sum of Box (CDR-SB) change 
from baseline. 
2.2.
Secondary Objectives

To assess whether a visual interpretation (τAD++ vs. non τAD++ pattern) of the 
baseline flortaucipir PET scan can predict the risk of subjects’ clinically 
meaningful cognitive and functional deterioration within 18 months of scan, as 
measured by Mini-Mental State Examination (MMSE), Alzheimer’s Disease 
Assessment Scale–Cognitive subscale (ADAS-Cog11), Pfeffer Functional 
Activities Questionnaire (FAQ), and CDR Global change from baseline. 

To assess the relationship between visual interpretation (τAD++ vs. non τAD++ 
pattern)  of the baseline flortaucipir PET scan and magnitude of cognitive and 
functional deterioration within 18 months of scan, as measured by the mean 
change from baseline of CDR-SB, MMSE, ADAS-Cog11, and FAQ.

To assess inter-reader reliability of the flortaucipir F 18 PET scan visual 
interpretation by 5 independent, blinded readers.  
2.3.
Exploratory Objectives

To assess whether a visual interpretation (τAD++ vs. non τAD++ pattern) of the 
baseline flortaucipir PET scan can predict the risk of subjects’ clinically 
meaningful cognitive and functional deterioration within 24 months of scan, as 
measured by the Clinical Dementia Rating Scale (CDR), MMSE, ADAS-Cog11 
and FAQ change from baseline. 

To assess the diagnostic performance of baseline flortaucipir F 18 PET scan in 
predicting clinically meaningful deterioration at 18 months


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3.
STUDY DESIGN
All training and reads will be conducted in accordance with the image review charter (IRC). Five 
imaging physicians will be trained in-person on the flortaucipir F 18 PET scan read methodology 
using the previously established visual read method (identical to that used for the 18F-AV-1451-
A05C Study).  
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, 
each reader will independently read 205 flortaucipir F18 PET baseline scans from the Study 
I8D-MC-AZES “A 24-Month, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Efficacy, Safety, Tolerability, Biomarker, and Pharmacokinetic Study of 
AZD3293 in Early Alzheimer’s Disease (the AMARANTH study)” in a random sequence. For 
the flortaucipir PET imaging, a 30 minute  PET acquisition was conducted approximately 75 min 
following an i.v. administration of approximately 240 MBq flortaucipir F 18 which is 
comparable to a 20 minute acquisition conducted approximately 80 minutes following an i.v. 
administration of approximately 370 MBq flortaucipir F 18 as obtained in studies A16 and 
A05C.  
The study population for study AZES consisted of subjects aged 55 to 85 years with MCI due to 
AD or probable AD by NIA-Alzheimer’s Association criteria (Albert 2011), with MMSE of 20 
to 30 inclusive, a CDR global score of 0.5 (MCI), or 0.5 or 1 (AD) with a memory box score ≥
0.5, and a score of ≤85 on the Delayed Memory Index of the Repeatable Battery for the 
Assessment of Neuropsychological Status.  All subjects were amyloid positive by florbetapir
PET or lumbar puncture. Qualified subjects were randomized to receive either 0 (placebo), 20, or 
50 mg lanabecestat daily for a planned duration of 2 years.  The primary objective of the study 
was to evaluate the efficacy of AZD3293 on cognitive and functional outcomes in patients with 
early AD as measured by the CDR-SB. Subjects returned for periodic follow-up visits up to 24 
months post baseline, where change from baseline performance was assessed on cognitive and 
functional scales including the core scales used in other flortaucipir studies (CDR, MMSE, FAQ 
and ADAS).  The study also included a longitudinal sub-study of flortaucipir F 18 PET. Patients 
who underwent florbetapir F 18 PET scanning at screening in the main AZES study to document 
the presence of amyloid for the study inclusion and participated in the amyloid PET sub-study 
were planned to also have a flortaucipir F 18 PET scan performed at baseline, Week 52, and 
Week 104 at participating sites. 205 subjects completed baseline flortaucipir F 18 PET scans and 
completed CDR-SB at 18 months, while approximately 90 subjects completed CDR-SB at 24 
months. Only the baseline flortaucipir F 18 PET scan is being read in the present study. 


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4.
PROCEDURES AND METHODS
4.1.
Selection and Number of Investigators (Readers)
Five qualified physicians will be used to perform the blinded reads. Readers will be selected 
using the following criteria:

Board Certified in Radiology or Nuclear Medicine

Experience interpreting PET scans
4.2.
Selection/number of Images:
A total of 205 unique scans will be read for this study in a random sequence.  Scans are from a 
subset of AZES patients who received a baseline flortaucipir F 18 PET scan in a substudy and 
completed the 18 month AZES CDR assessment.
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. 
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). 


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4.4.
Data Collection
Flortaucipir scan read data will be collected using electronic case report forms (eCRFs) designed 
for this study. All other data including the demographic/baseline characteristics and all 
cognitive/functional assessments, for subjects included in Study PX01, will be from the locked 
database of Study AZES.  The locked AZES database was accessed by permission of the study 
sponsor, Eli Lilly and Company.  
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 (ICH), 
Good Clinical Practice (GCP) and Avid/CRO Standard Operating Procedures.
Monitoring of study data will be performed by the Imaging CRO and be performed in 
accordance with their SOPs.
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 (SAP).
5.2.
Population for Analysis
Five readers will independently interpret the flortaucipir F 18 PET scans collected from the 
AZES PET substudy. No new subjects will be enrolled for purposes of this study. 
Valid images will be considered unevaluable in the present study 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 Image Review Charter. The majority reads on each 
flortaucipir F 18 scan (baseline) from these 5 readers will be used to determine the tau status of 
the corresponding study subject.
The AZES study was terminated early for futility, therefore not all subjects had the opportunity 
to complete the full term follow up. To avoid bias, it was decided to include only the subjects
that had 1) a valid baseline flortaucipir scan (no later than 91 days post randomization, 
considering that the flortaucipir scans were added to this study after the initiation of AZES); and 
2) a CDR assessment at 18 months visit. 205 subjects met these criteria, and approximately 90 of 
these subjects completed a CDR assessment at the 24 month visit.
5.3.
Power Analysis
This study will include up to 205 subjects who have a valid baseline flortaucipir scan, and a 
change from baseline value of CDR-SB at 18 months. In Study TZAX, which had a similar 
design and entry criteria, approximately 75% of subjects were rated as τAD++ and 25% were 


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rated as non-τAD++. Among non- τAD++ subjects (reference group), approximately 40% had an 
increase of 1 point or more on CDR-SB at 18 months follow up visit. Assuming a distribution of 
visual reads and CDR-SB change in this study is similar to that for TZAX, a sample of 205 
subjects will provide  90% power to detect a risk ratio of 1.65 or larger, under a two-sided type I 
error rate of 5%.
5.4.
Efficacy Analysis
5.4.1.
Primary Objective Analysis
The primary analysis for this study will evaluate whether or not the baseline tau status as 
determined by flortaucipir F 18 scans will predict the risk of subjects’ clinically meaningful 
cognitive and functional deterioration within 18 months of scan. The clinically meaningful 
deterioration (CMD) for the primary objective analysis is defined as Clinical Dementia Rating 
Scale Sum of Box (CDR-SB) change from baseline with an increase of 1 point or more.
A Poisson regression model will be used to calculate the ratio of risk for τAD++ subjects over 
non-τAD++ (τAD+/ τAD-) subjects. The risk ratio, along with a 95% confidence interval and the 
associated p-value will be provided.  CMD as defined in the section above will be used as the 
dependent variable, and the model will be adjusted for baseline age, CDR-SB score, and 
therapeutic treatment assignment from AZES study.
5.4.2.
Secondary Objective Analysis
5.4.2.1.
Clinically Meaningful Deterioration at 18 Months by Tau Status
To fully assess the prognostic value of tau scan, these CMDs will be assessed for the secondary 
objective analysis: 
1) MMSE decreased by 3 points or more;
2) ADAS Cog-11 increased by 4 points or more;
3) FAQ increased by 3 points or more;
4) CDR global with any increase.
The analyses will be identical to what is described in section 5.4.1, with dependent variables 1-4 
for CMDs as described above, and the adjustment of corresponding baseline scores.
5.4.2.2.
Mean Change of Cognitive/Functional Assessments at 18 Months by 
flortaucipir PET visual interpretation (τAD++ vs. non-τAD++)
To assess the mean change of CDR-SB, MMSE, ADAS, and FAQ at 18 month by tau status, a 
mixed model with repeated measures (MMRM) will be used. For each analysis, the change from 
baseline value from relative measurement will be the dependent variable, and the model will 
include the fixed effects of tau status (τAD++ or non-τAD++), visit (categorical covariate), tau 
status-by-visit interaction, and therapeutic treatment assignment from AZES study, as well as
corresponding baseline measurement score, and baseline age as continuous covariates. The null 
hypothesis is that the least squared mean contrast between τAD++ and non-τAD++ groups at
month 18 visit equals zero. An unstructured covariance matrix will be used to model the within-


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subject variance-covariance. If the unstructured covariance structure matrix results in a lack of 
convergence, the following tests will be used in sequence: heterogeneous Toeplitz covariance 
structure, heterogeneous autoregressive covariance structure, and compound symmetry 
covariance structure. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom.  
5.4.2.3.
Inter-reader Reliability
The inter-reader reliability of flortaucipir scan interpretation (τAD++ vs. non-τAD++) across the 
5 independent readers will be assessed using a Fleiss’ Kappa statistics. The overall percent of 
agreement, Fleiss’ Kappa, and 95% CI around Kappa value will be provided. 
5.4.3.
Exploratory Analysis
5.4.3.1.
Cognitive/Functional Assessments Deterioration at 24 months, by 
Tau Status
To further evaluate the prognostic value of a flortaucipir scan, analyses described from 5.4.1 –
5.4.2 (except 5.4.2.3) will be repeated using subjects who completed both baseline and 24 month 
clinical assessments. 
5.4.3.2
Clinically Meaningful Deterioration by τAD vs τAD- tau status
In addition, exploratory analyses will be planned to contrast scan visual interpretations of τAD 
(τAD+/ τAD ++) vs. τAD- , repeating analyses as described from 5.4.1-5.4.2 using both 18 
months and 24 months follow-up data. Details will be described in the SAP.
5.4.3.3
Diagnostic Performance of Flortaucipir Scan in Predicting Clinical 
Deterioration 
The diagnostic performance (sensitivity/specificity) will be assessed by using CMD as truth 
standard (TS) as defined in section 5.4.1 and 5.4.2.1. The 95% CI around the 
sensitivity/specificity will be calculated using Wilson Score method.


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6.
STUDY DOCUMENTATION
Avid will be responsible for the submission of the protocol to the Institutional 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.   CRFs 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

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 (TMF). 
6.2.
Use of Study Scan Data for Research Purposes 
Patients who participated in the AZES study 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
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of 
mild cognitive impairment due to Alzheimer’s disease: recommendations from the National 
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease. Alzheimer’s Dement. 2011;7:270-279.
TZAX (Tau Imaging in H8A-MC-LZAX):  A post-hoc evaluation of the relationship between 
flortaucipir PET signal and cognitive change in subjects with mild Alzheimer’s disease 
participating in the solanezumab Expedition 3 clinical trial tau imaging addendum (Protocol 
Addendum H8A-MC-LZAX (6.2) (Tau Imaging) Effect of Passive Immunization on the 
Progression of Mild Alzheimer’s disease:  Solanezumab (LY2062430) Versus Placebo
Protocol 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
Protocol 18F-AV-1451-A16: A Clinico-Pathological Study of the Correspondence Between 18F-
AV-1451 PET Imaging and Post-Mortem Assessment of Tau Pathology

SAP_001.pdf: 
18F-AV-1451-PX01 SAP v1.0 
 
Evaluation of the relationship between baseline flortaucipir PET signal and cognitive change in 
subjects with early Alzheimer's disease participating in the I8D-MC-AZES Protocol Addendum 
D5010C00009 (2.1) (Tau Imaging) 
 
NCT03901105 
Approval date: 16 Apr 2019
 


Avid Radiopharmaceuticals
Study 18F-AV-1451-PX01
                 Statistical Analysis Plan
Protocol No. 18F-AV-1451-PX01
Protocol Addendum D5010C00009 (2.1) (Tau Imaging) A 24-Month, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, Safety, Tolerability, Biomarker, and 
Pharmacokinetic Study of AZD3293 in Early Alzheimer’s Disease (The AZES Study)
Statistical Analysis Plan
Prepared by:
Avid Radiopharmaceuticals, Inc
Final Version 1.0
16 April 2019
This document is the confidential information of Avid Radiopharmaceuticals. It may not 
be disclosed to parties not associated with the clinical investigation or used for any 
purpose without the prior written consent of Avid Radiopharmaceuticals.
Approval Date: 24-Apr-2019 GMT
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                 Statistical Analysis Plan
Table of Contents
1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS......................................................... 4
2
INTRODUCTION.................................................................................................................................. 5
3
STUDY OBJECTIVES.......................................................................................................................... 5
4
STUDY DESIGN.................................................................................................................................... 6
4.1
GENERAL DESIGN ............................................................................................................................. 6
4.2
DISCUSSION OF STUDY DESIGN.......................................................................................................... 6
4.3
METHOD OF ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS ....................................................... 7
4.4
BLINDING ......................................................................................................................................... 7
4.5
DETERMINATION OF SAMPLE SIZE ..................................................................................................... 7
5
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES............................... 8
5.1
CHANGES IN THE CONDUCT OF THE STUDY ........................................................................................ 8
6
BASELINE, EFFICACY AND SAFETY EVALUATIONS.................................................................. 9
6.1
SCHEDULE OF EVALUATIONS............................................................................................................. 9
6.2
TIME POINT ALGORITHMS ............................................................................................................... 10
6.2.1
Windows................................................................................................................................. 10
6.3
SCREENING AND BASELINE ASSESSMENTS ....................................................................................... 10
6.4
EFFICACY VARIABLES..................................................................................................................... 10
6.4.1
Primary Efficacy Variable(s)................................................................................................... 10
6.4.1.1
Tau Status Based on Flortaucipir ........................................................................................................10
6.4.1.2
Clinical Dementia Rating (CDR) Scale (Berg, 1988) ...........................................................................11
6.4.2
Additional Efficacy Variables.................................................................................................. 11
6.4.2.1
Cognitive Assessments.......................................................................................................................11
6.4.2.2
Clinically Meaningful Deterioration....................................................................................................12
7
STATISTICAL METHODS................................................................................................................ 14
7.1
DEFINITIONS AND CONVENTIONS..................................................................................................... 14
7.2
ADJUSTMENTS FOR COVARIATES ..................................................................................................... 14
7.3
HANDLING OF DROPOUTS OR MISSING DATA ................................................................................... 14
7.4
INTERIM ANALYSES AND DATA MONITORING .................................................................................. 15
7.5
MULTI-CENTER STUDIES AND POOLING OF CENTERS ........................................................................ 15
7.6
MULTIPLE COMPARISONS/MULTIPLICITY......................................................................................... 15
7.7
EXAMINATION OF SUBGROUPS......................................................................................................... 15
8
STATISTICAL ANALYSIS ................................................................................................................ 16
8.1
ANALYSIS POPULATION................................................................................................................... 16
8.2
SUMMARY OF THE ANALYSIS POPULATION ...................................................................................... 16
8.3
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS................................................................ 17
8.4
ANALYSIS OF EFFICACY PARAMETERS............................................................................................. 17
8.4.1
Analysis of Primary Efficacy Variable..................................................................................... 17
8.4.1.1
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by CDR-SB at 18 Months...............................................................................................17
8.4.2
Analysis of Secondary Efficacy Variable.................................................................................. 17
8.4.2.1
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by MMSE at 18 Months .................................................................................................17
8.4.2.2
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by ADAS-Cog11 at 18 Months.......................................................................................18
8.4.2.3
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by FAQ at 18 Months.....................................................................................................18
8.4.2.4
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by CDR Global at 18 Months .........................................................................................18
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Study 18F-AV-1451-PX01
                 Statistical Analysis Plan
8.4.2.5
Mixed Model Repeated Measures for Comparison of τAD++ vs. Non-τAD++ CDR-SB Change at 
18 Months18
8.4.2.6
MMRM for Comparison of τAD++ vs. Non-τAD++ MMSE Change at 18 Months...............................19
8.4.2.7
MMRM for Comparison of τAD++ vs. Non-τAD++ ADAS-Cog11 Change at 18 Months....................19
8.4.2.8
MMRM for Comparison of τAD++ vs. Non-τAD++ FAQ Change at 18 Months..................................19
8.4.2.9
Inter-reader Consistency.....................................................................................................................19
8.4.3
Exploratory Analysis............................................................................................................... 19
8.4.3.1
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by CDR-SB at 24 Months...............................................................................................19
8.4.3.2
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by MMSE at 24 Months .................................................................................................19
8.4.3.3
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by ADAS-Cog11 at 24 Months.......................................................................................20
8.4.3.4
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by FAQ at 24 Months.....................................................................................................20
8.4.3.5
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by CDR Global at 24 Months .........................................................................................20
8.4.3.6
Risk Ratio of τAD (τAD+/τAD++) vs. τAD- Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by CDR-SB at 18 Months and 24 Months .......................................................................20
8.4.3.7
Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful Deterioration 
Evaluated by MMSE at 18 Months and 24 Months...............................................................................................20
8.4.3.8
Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful Deterioration 
Evaluated by ADAS-Cog11 at 18 Months and 24 Months ....................................................................................20
8.4.3.9
Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful Deterioration 
Evaluated by FAQ at 18 Months and 24 Months ..................................................................................................20
8.4.3.10
Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful Deterioration 
Evaluated by CDR Global at 18 Months and 24 Months.......................................................................................20
8.4.3.11
MMRM for Additional Comparisons of CDR-SB Change across Tau Groups ......................................21
8.4.3.12
MMRM for Additional Comparisons of MMSE Change across Tau Groups.........................................21
8.4.3.13
MMRM for Additional Comparisons of ADAS-Cog11 Change across Tau Groups ..............................21
8.4.3.14
MMRM for Additional Comparisons of FAQ Change across Tau Groups ............................................21
8.4.3.15
Diagnostic Performance of Baseline Tau Status in Predicting Clinically Meaningful Deterioration 
Evaluated by CDR-SB ........................................................................................................................................21
8.4.3.16
Diagnostic Performance of Baseline Tau Status in Predicting Clinically Meaningful Deterioration 
Evaluated by MMSE...........................................................................................................................................23
8.4.3.17
Diagnostic Performance of Baseline Tau Status in Predicting Clinically Meaningful Deterioration 
Evaluated by ADAS-Cog11 ................................................................................................................................24
8.4.3.18
Diagnostic Performance of Baseline Tau Status in Predicting Clinically Meaningful Deterioration 
Evaluated by FAQ ..............................................................................................................................................24
8.4.3.19
Diagnostic Performance of Baseline Tau Status in Predicting Clinically Meaningful Deterioration 
Evaluated by CDR Global...................................................................................................................................24
8.4.4
Subgroup Analyses.................................................................................................................. 24
8.4.5
Sensitivity Analysis ................................................................................................................. 24
9
REFERENCES .................................................................................................................................... 25
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1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table 1: Abbreviations and Definitions of Terms
Aβ
amyloid-β
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale-Cognitive
CDR
Clinical Dementia Rating Scale
CDR-SB
Clinical Dementia Rating Scale-Sum of Boxes
CFB
Change from Baseline
CSR
clinical study report
FAQ
Pfeffer Functional Activities Questionnaire
LSM
least squares mean
MMRM
mixed model repeated measures
MMSE
Mini-Mental State Examination
PET
positron emission tomography
SAP
statistical analysis plan
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2
INTRODUCTION
Brain amyloid plaques, composed of amyloid-beta (Aβ) aggregates, and neurofibrillary 
tangles, composed of phosphorylated aggregated tau deposits, are defining pathological 
features of Alzheimer’s disease (AD). Thus, an amyloid negative florbetapir positron 
emission tomography (PET) scan of the brain, which indicates the absence of moderate or 
frequent Aβ neuritic plaques, is inconsistent with a diagnosis of AD. However, because 
amyloid is believed to accumulate very early in the AD process (Jack et al. 2010) and 
may be present in clinically normal elderly subjects (Price and Morris 1999; Sperling et 
al. 2011), the density or distribution of amyloid in subjects with a positive scan is not 
thought to reflect the severity of AD.
In contrast to Aβ neuritic plaques, the density and distribution in the brain of 
phosphorylated tau, aggregated in neurofibrillary tangles, increases with AD-related 
cognitive impairment and correlates with neurodegeneration (Duyckaerts et al. 1987). 
Thus, a PET imaging agent that binds to phosphorylated tau has the potential to indicate 
disease severity and with longitudinal measures could provide important information on 
disease progression. The PET tracer (18F-AV-1451) possesses a high affinity to human 
phosphorylated tau deposits. Up to three scans will be performed over
the two year study.
3
STUDY OBJECTIVES
The primary objective of this study is:

To assess whether a visual interpretation (τAD++ vs. non-τAD++ pattern) of the 
baseline flortaucipir PET scan can predict the risk of subjects’ clinically 
meaningful cognitive and functional deterioration within 18 months of scan, as 
measured by the Clinical Dementia Rating Scale (CDR) Sum of Boxes (CDR-SB) 
change from baseline (CFB). 
The secondary objectives of this study are:

To assess whether a visual interpretation (τAD++ vs. non-τAD++ pattern) of the 
baseline flortaucipir PET scan can predict the risk of subjects’ clinically 
meaningful cognitive and functional deterioration within 18 months of scan, as 
measured by Mini-Mental State Examination (MMSE), Alzheimer’s Disease 
Assessment Scale–Cognitive subscale (ADAS-Cog11), Pfeffer Functional 
Activities Questionnaire (FAQ), and CDR Global CFB. 

To assess the relationship between visual interpretation (τAD++ vs. non-τAD++ 
pattern)  of the baseline flortaucipir PET scan and magnitude of cognitive and 
functional deterioration within 18 months of scan, as measured by the mean 
change from baseline of CDR-SB, MMSE, ADAS-Cog11, and FAQ.
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
To assess inter-reader reliability of the flortaucipir visual interpretation by 5 
independent, blinded readers.  
The exploratory objectives of this study are:

To assess whether a visual interpretation (τAD++ vs. non-τAD++ pattern) of the 
baseline flortaucipir PET scan can predict the risk of subjects’ clinically 
meaningful cognitive and functional deterioration within 24 months of scan, as 
measured by the CDR, MMSE, ADAS-Cog11 and FAQ CFB. 

To assess the diagnostic performance of  baseline flortaucipir in predicting 
clinically meaningful deterioration at 18 months.
4
STUDY DESIGN
4.1
General Design
The D5010C00009 (AZES) study was a multicenter, randomized, double blind placebo-
controlled, parallel-group, longitudinal study evaluating the efficacy of LY3314814
(lanabecestat) in early AD subjects, whose primary efficacy measure was ADAS-Cog13. 
AZES was terminated for futility, however over 400 subjects received a bolus injection of 
flortaucipir F18 and quantitative imaging as part of a tau addendum.
Because the AZES study was terminated early for futility, not all subjects had the 
opportunity to complete the full term follow up. To avoid bias for these analyses, it was 
decided to include only the subjects that had: 1) a valid baseline flortaucipir scan (no later 
than 91 days post randomization, considering that the flortaucipir scans were added to 
this study after the initiation of AZES); and 2) a CDR assessment at 18 months visit. 205 
subjects met these criteria, and approximately 90 of these subjects completed a CDR 
assessment at the 24 month visit.
Five independent radiologists or nuclear medicine physicians visually interpreted the PET 
scans from the 205 qualified subjects as either τAD++ (a pattern indicating spread of 
aggregated tau beyond the posterolateral temporal [PLT] or occipital lobe), τAD + (a 
pattern indicating aggregated tau confined to posterolateral temporal/occipital lobe) or 
τAD- (inconsistent with an AD pattern).  The primary hypothesis tested by this study is 
that the risk of clinically meaningful cognitive deterioration would vary as a function of 
flortaucipir PET scan status at baseline. Specifically, that risk would be significantly 
greater for subjects in the τAD++ group as compared to those in the non-τAD++ group 
(including τAD- and τAD+).  
4.2
Discussion of Study Design
18F-AV-1451-PX01 (PX01) was designed to take advantage of the therapeutic trial 
cohort in AZES that had flortaucipir PET scans and up to 2 years cognitive follow-up to 
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further evaluate the relationship between flortaucipir PET signal and cognitive decline.  
Patients who had a florbetapir PET scan at screening in the main AZES study to 
document the presence of amyloid for study inclusion and participated in the longitudinal
amyloid PET sub-study also received a flortaucipir PET scan performed at baseline, 12 
months, and 24 months at participating sites. Patients who established eligibility by 
historical amyloid scan were not eligible to participate in the flortaucipir (tau) addendum 
unless they also had an optional subsequent florbetapir scan as part of the main AZES
study. Flortaucipir PET scans were conducted in over 400 study participants. Once the
randomization targets for Addendum 2 were reached, enrollment was considered
complete and, at the discretion of the sponsor, enrollment of additional patients was
stopped. Flortaucipir PET scanning was conducted under the management of a central 
PET vendor. The PET imaging data was acquired after injection of flortaucipir F 18. The 
baseline flortaucipir scan was performed only after amyloid positivity had been
demonstrated. There was at least 16 hours between the follow-up florbetapir scan and the 
flortaucipir scan at week 104 or early discontinuation due to the half-life of 18-fluorine.
Procedures relevant to this addendum are provided in section 6.1.
PX01 was designed to evaluate the performance of flortaucipir scans in subjects with 
early AD to establish a relationship between baseline flortaucipir imaging results and 
longitudinal cognitive assessments. Longitudinal cognitive assessments, with CDR-SB
being the primary assessment, will provide evidence whether greater degrees of change in 
cognitive/functional impairment correlate with higher levels of flortaucipir uptake at 
baseline. This relationship is important in order to determine the utility and predictive 
power of flortaucipir on the degree of change in cognitive impairment in 18 to 24 months.
Since the parent study AZES was terminated prior to reaching the endpoint, not all study 
participants could complete study measurements as planned. Therefore, only 205 subjects 
with a valid baseline tau scan and a CDR assessment at week 78 (month 18) will be 
included in this study for efficacy analyses.
4.3
Method of Assignment of Subjects to Treatment Groups
4.4
Blinding
A blinded design was not used in PX01 for flortaucipir exposure because all subjects 
received flortaucipir F 18. Subjects and investigators were blind to lanabecestat treatment 
throughout the trial. 
4.5
Determination of Sample Size
This study will include up to 205 subjects who have a valid baseline flortaucipir scan, and 
a change from baseline value of CDR-SB at 18 months. In Study TZAX, which had a 
similar design and entry criteria, approximately 75% of subjects were rated as τAD++ 
and 25% were rated as non-τAD++. Among non-τAD++ subjects (reference group), 
approximately 40% had an increase of 1 point or more on CDR-SB at 18 months follow 
up visit. Assuming a distribution of visual reads and CDR-SB change in this study is 
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similar to that for TZAX, a sample of 205 subjects will provide 90% power to detect a 
risk ratio of 1.65 or larger, under a two-sided type I error rate of 5%.
  
5
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
5.1
Changes in the Conduct of the Study
There were no changes in the conduct of the study at the time of preparing this SAP.
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6
BASELINE, EFFICACY AND SAFETY EVALUATIONS
6.1
Schedule of Evaluations
Study Procedure
Screening
Randomization/
Baseline
Visit Number
V1
V2-V4
V6
V8
V10
V12
V14
V16
V20
V30
ED
Study Month (m)
3m
6m
9m
12m
15m
18m
24m
156w
Tau Addendum
Interval for Visit (d)
±7
±10
±7
±10
±7
Flortaucipir PET Imaging
X
X
X
X
X
X
Efficacy Measures
X
  CDR-SB
X
X
X
X
X
X
  MMSE
X
X
X
X
X
X
X
  ADAS
X
X
X
X
X
X
X
  FAQ
X
X
X
X
X
X
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6.2
Time Point Algorithms
6.2.1
Windows
For all analyses, results will be summarized at the planned study visit they were obtained. 
Data was collected in weeks in the AZES study, therefore the following conversion will 
be used to analyze in months:
Weeks
Months
13
3
26
6
52
12
65
15
78
18
104
24
6.3
Screening and Baseline Assessments
Baseline cognitive and functional assessments will include ADAS-Cog11, MMSE, CDR-
SB, and FAQ.  Baseline will be defined in the same manner as in the AZES study.
6.4
Efficacy Variables
6.4.1
Primary Efficacy Variable(s)
6.4.1.1
Tau Status Based on Flortaucipir
Flortaucipir images were visually assessed by five independent readers blinded to all 
demographic and clinical data information of the subjects. The majority read (i.e., the tau 
status for which 3 or more readers have agreed upon) was used as the tau status.
For the visual reads, the images were classified as either τAD++ (a pattern indicating 
spread of aggregated tau beyond the PLT lobe or occipital lobe), τAD + (a pattern 
indicating aggregated tau confined to PLT and/or occipital lobe) or τAD- (inconsistent 
with an AD pattern).  See table below for details.
Read Outcome
Objective Imaging Features
Not Consistent with AD pattern (τAD-)
No increased neocortical activity, or increased neocortical 
activity isolated to mesial temporal, anterolateral temporal, 
and/or frontal regions.
AD pattern
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 
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uptake in the PLT, parietal, or occipital region(s).
For the purposes of these efficacy analyses, image reads will be contrasted in the 
following ways: τAD++ vs. non-τAD++ (τAD+ and τAD-); τAD (τAD++ and τAD+) vs. 
τAD-; τAD++ vs. τAD-.
6.4.1.2
Clinical Dementia Rating (CDR) Scale (Berg, 1988)
The CDR examines 6 categories of cognitive functioning domains. Each domain is 
scored on a scale ranging from 0 to 3 (including 0.5). A CDR-SB will be generated as the 
sum of the values in each of the six domains. The CDR-SB sum scores ranges from 0-18, 
where higher scores indicate greater cognitive impairment. CDR was scheduled to be 
performed at screening, 6 months, 12 months, 18 months, and 24 months post-baseline. 
CDR-SB will be used as a continuous scale in exploratory objective analysis, when 
assessing the average CFB by tau status. 
For the primary analysis, the CDR-SB score CFB will be dichotomized in two groups: 
CDR-SB score change 1 point or more at 18 months, or otherwise.
The CDR Global score (a global rating of dementia) was derived based on CDR
item/domain values. CDR global will be dichotomized in two groups for exploratory 
analysis: any change in CDR global or otherwise.
Any CDR measurement collected outside of this intended visit schedule (e.g. Early 
Discontinuation) will not be included in the efficacy analysis.
6.4.2
Additional Efficacy Variables
6.4.2.1
Cognitive Assessments
These additional cognitive assessments from AZES will be analyzed:  
Mini-Mental State Examination (MMSE)
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive function 
in elderly patients. The range for the total MMSE score is 0 to 30, the sum of each correct 
answer, with higher scores indicating better cognition. MMSE was scheduled to be 
collected at screening, 3 months, 6 months, 12 months, 18 months, and 24 months post-
baseline. The score on a continuous scale will be used for secondary and exploratory 
analyses when assessing the average CFB by tau status. Any measurement collected 
outside of this intended visit schedule (e.g. Early Discontinuation) will not be included in 
the efficacy analysis.
Alzheimer’s Disease Assessment Scale—Cognitive subscale
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The ADAS (ADAS-Cog; Rosen et al. 1984) was designed to assess the severity of the 
dysfunction in the cognitive and non-cognitive behaviors characteristic of persons with 
AD. Although AZES reported ADAS-Cog13 as its primary endpoint, ADAS-Cog11 (a 
subset version of ADAS-Cog13 comprising of 11 questions) will be chosen for the PX01 
analyses to remain consistent with other historical Avid studies. The cognitive subscale 
ADAS-Cog11, consists of 11 items assessing areas of function most typically impaired in 
AD: orientation, verbal memory, language, and praxis. The overall score for ADAS-
Cog11 ranges from 0 to 70, with higher scores indicating greater disease severity, and is 
calculated as the sum of all 11 individual component scores. ADAS total score will be 
used as a continuous variable for the secondary and exploratory analyses to assess the 
average CFB by tau status. ADAS was scheduled to be collected at randomization 
(baseline), 3 months, 6 months, 12 months, 15 months, 18 months, and 24 months post-
baseline. Any measurement collected outside of this intended visit schedule (e.g. Early 
Discontinuation) will not be included in the efficacy analysis.
Pfeffer Functional Activities Questionnaire (FAQ), (Pfeffer et al. 1982) 
Functional status is conceptualized as the “ability to perform self-care, self-maintenance 
and physical activities.” The FAQ was developed to assess instrumental activities of daily 
living involving higher level functional skills such as shopping alone, writing checks, 
remembering appointments, etc. The FAQ asks the informant to rate the patient’s ability 
using the following scoring system: Dependent = 3; Requires assistance = 2; Has 
difficulty but does by self = 1; Normal = 0; Never did [the activity] but could do now = 0; 
Never did and would have difficulty now = 1. The sum scores ranges from 0-30, where 
higher scores indicate greater functional impairment. FAQ sum score will be used as a 
continuous variable in secondary objective analysis, when assessing the average CFB by 
tau status. FAQ was scheduled to be collected at randomization (baseline), 6 months, 12 
months, 18 months, and 24 months post-baseline. Any measurement collected outside of 
this intended visit schedule (e.g. Early Discontinuation) will not be included in the 
efficacy analysis.
6.4.2.2
Clinically Meaningful Deterioration 
The cognitive/functional assessments from 6.4.2.1 will be dichotomized to allow for the 
assessment of risk of clinically significant deterioration. Subjects will be categorized to 
these groups by the criteria accordingly.
CDR-SB: clinically significant deterioration is defined as a 1 point or more increase from 
baseline.
MMSE: clinically significant deterioration is defined as 3 points or more decrease from 
baseline. 
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FAQ: clinically significant deterioration is defined as 3 points or more increase from 
baseline. 
  
ADAS-Cog11: clinically significant deterioration is defined as 4 points or more increase 
from baseline. 
CDR Global: CDR global CFB will also be categorized as any increase (change >0) 
versus no change or decrease (change <= 0).
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7
STATISTICAL METHODS
7.1
Definitions and Conventions
All analysis will be performed using SAS version 9.2 or higher.
Data will be summarized using descriptive statistics (number of subjects [n], mean, 
standard deviation [SD], median, minimum [min], and maximum [max]) for continuous 
variables and frequency counts and percentages for discrete variables. Percentages will be
rounded to one decimal place, except 100% will be displayed without any decimal places 
and percentages will not be displayed for zero counts.
The tables and listings will be numbered using a decimal system to reflect main levels of 
unique tables and listings and sub-levels of replicate tables and the listings with 
maximum two digits per level (e.g., Table XX.YY.ZZ…). Tables will be numbered as 
14.YY.ZZ.  Baseline analysis will be reported in table series 14.1, and efficacy analysis 
in series 14.2.  Listings will be numbered as 16.YY.ZZ. 
Unless otherwise specified, hypothesis testing will be two-sided with type I error rate of 
0.05.
7.2
Adjustments for Covariates
Multivariate models using cognitive or function assessments as the dependent variables
will be adjusted for treatment arm [lanabecestat (20mg, 50 mg) or placebo], baseline
cognitive score, years of education (categorical), and age.
7.3
Handling of Dropouts or Missing Data
Dropout subjects will not be replaced in this study.  For situations with no rules for 
handling missing data the default will be no imputation.
Likelihood-based mixed effects models for repeated measures will be used to handle 
missing data for the cognitive/functional assessment mean CFB analyses.  The model 
parameters are simultaneously estimated using restricted likelihood estimation 
incorporating all of the observed data.  Estimates have been shown to be unbiased when 
the missing data are missing at random and when there is ignorable non-random missing 
data.
Repeated measures analyses will only use data from visits where the data was scheduled 
to be collected.  When subjects discontinue from the study early, there may be efficacy 
data measurements at visits where the variables were not scheduled to be collected. These 
data will appear in listings only.
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7.4
Interim Analyses and Data Monitoring
No interim analysis or data monitoring is planned for this study.
7.5
Multi-center Studies and Pooling of Centers
The data from all centers will be pooled. The pooled data will be analyzed and presented. 
  
7.6
Multiple Comparisons/Multiplicity
No multiple comparisons/multiplicity adjustment is planned.   
7.7
Examination of Subgroups
Subgroups of interest will be age, sex, and CDR Global group (see section 8.4.4).
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8
STATISTICAL ANALYSIS
8.1
Analysis Population
Five readers independently interpreted the 205 flortaucipir PET scans collected from the
AZES PET sub-study. No new subjects were enrolled for the purpose of this study.
Valid images were considered unevaluable in the present study only if 3 out of 5 readers 
independently declare the image unevaluable for the same reason. Subjects with invalid 
or unevaluable PET data were excluded from analyses. Criteria for declaring an image 
invalid or not evaluable is specified in the Image Review Charter. The majority read on 
each flortaucipir scan (baseline) from these 5 readers was used to determine the tau status 
of the corresponding study subject.
Subject disposition and baseline characteristics will be summarized using the entire 
analysis population (regardless if the baseline scan was evaluable or not). Analyses 
outlined in section 8.4 will be summarized using subjects in the analysis population who 
have a valid visual tau interpretation as described in section 6.4.1.1.
8.2
Summary of the Analysis Population
The analysis population will be summarized in the disposition table by total available 
scans, scans read, and breakdown of majority read (detailed in section 6.4.1.1).
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8.3
Demographic and Other Baseline Characteristics
Demographics and baseline summaries will be reported on the analysis population. Age 
(years), sex, education (categorical: 1-5, 6-9, 10-12, 13+ years), race, ethnicity, treatment 
(lanabecestat – -, 2-0 mg or 50 mg –or placebo), florbetapir SUVr (referenced to the 
cerebellum), ApoE4 (E4+/E4-), ADAS-Cog11, CDR-SB, CDR Global (categorical: 0, 
0.5, 1, 2, 3), FAQ, and MMSE will be reported in a table by enrolling diagnosis in the 
AZES study (AD or MCI).
8.4
Analysis of Efficacy Parameters
8.4.1
Analysis of Primary Efficacy Variable
8.4.1.1
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by CDR-SB at 18 Months
This analysis will test the hypothesis that the risk of progressing to a clinically 
meaningful event (>1 change) as determined by CDR-SB value change at 18 months will 
be significantly greater for subjects in the τAD++ group as compared to those in the non-
τAD++ group (τAD- and τAD+).  
Since the study goal is to evaluate the risk ratio of τAD++ group vs non-τAD++ group at 
month 18 instead of marginal risk ratio by tau status, only month 18 measurements will 
be included for this analysis.
As described in section 6.4.1.2, the primary efficacy variable will be the dichotomized 
CDR-SB score CFB (1 point or more increase vs. otherwise). Incidence of this clinically
meaningful event by tau visual read groups will be compared using a log-linear model 
adjusted for treatment arm (lanabecestat – 20 mg or 50 mg, or placebo), baseline age, 
years of education (categorical), and baseline CDR-SB score. The Poisson distribution 
will be chosen to describe the distribution of the dependent variable and a log link 
function will be used to model the risk ratio. To improve the model’s stability and 
reliability, a modified Poisson regression [Zou, 2004] model will be used using a robust 
error variance estimation, although there is only one observation per subject.
The risk ratio of τAD++ rated subjects progressing to the event over non-τAD++ rated
subjects along with the 95% confidence interval will be provided.
8.4.2
Analysis of Secondary Efficacy Variable
8.4.2.1
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by MMSE at 18 Months  
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The same analysis as described in section 8.4.1.1 will be performed for MMSE, however 
a CFB in MMSE <=-3 will be considered clinically meaningful.
8.4.2.2
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by ADAS-Cog11 at 18 Months  
The same analysis as described in section 8.4.1.1 will be performed for ADAS-Cog11, 
however a CFB in ADAS >=4 will be considered clinically meaningful. 
8.4.2.3
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by FAQ at 18 Months  
The same analysis as described in section 8.4.1.1 will be performed for FAQ, however a 
CFB in FAQ >=3 will be considered clinically meaningful. 
8.4.2.4
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by CDR Global at 18 Months
The same analysis as described in section 8.4.1.1 will be performed for CDR Global, 
however a CFB in CDR Global >0 will be considered clinically meaningful
8.4.2.5
Mixed Model Repeated Measures for Comparison of τAD++ vs. Non-τAD++ 
CDR-SB Change at 18 Months  
The objective of this analysis is to test the hypothesis that baseline tau status as 
determined by the flortaucipir scan will predict subjects’ cognitive deterioration.  
This analysis will test the hypothesis that the CDR-SB CFB at 18 months will be 
significantly larger (worse) for the τAD++ group compared to the non-τAD++ group
(τAD- and τAD+). The null hypothesis is that the least squares mean (LSM) difference 
between τAD++ and non-τAD++ groups at the month 18 visit equals zero.
This hypothesis will be tested using a mixed model repeated measures (MMRM). MMSE 
CFB will be the dependent variable. The model will include tau status, visit, and the tau 
status-visit interaction as fixed effects, and be adjusted for treatment arm (lanabecestat –
20 mg or 50 mg, or placebo), baseline CDR-SB score, age, and years of education
(categorical) as covariates.
An unstructured covariance matrix will be used to model the within-subject variance-
covariance. If the unstructured covariance structure matrix results in a lack of model 
convergence, the following tests will be used in sequence: heterogeneous Toeplitz 
covariance structure, heterogeneous autoregressive covariance structure, and compound 
symmetry covariance structure. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom.
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Descriptive statistics for the CDR-SB at baseline and all scheduled follow-up visits will 
be summarized by tau read status. The CFB to all follow-ups will be summarized in the 
same corresponding table.
CDR-SB LSM change will be graphed across time by τAD++ and non-τAD++ groups.
8.4.2.6
MMRM for Comparison of τAD++ vs. Non-τAD++ MMSE Change at 18 
Months  
The same analyses will be performed as described in Section 8.4.2.5 with the substitution 
of MMSE for CDR-SB. 
8.4.2.7
MMRM for Comparison of τAD++ vs. Non-τAD++ ADAS-Cog11 Change at 18 
Months  
The same analyses will be performed as described in Section 8.4.2.5 with the substitution 
of ADAS-Cog11 for CDR-SB. 
8.4.2.8
MMRM for Comparison of τAD++ vs. Non-τAD++ FAQ Change at 18 Months  
The same analyses will be performed as described in Section 8.4.2.5 with the substitution 
of FAQ for CDR-SB. 
8.4.2.9
Inter-reader Consistency
The inter-reader consistency of flortaucipir scan interpretation (τAD++ vs. non-τAD++) 
across the 5 independent readers will be assessed using a Fleiss’ Kappa statistics. The 
overall percent of agreement, Fleiss’ Kappa, and 95% CI around the Kappa will be 
summarized in a table. Pairwise comparisons between readers will also be presented with 
simple kappa statistics evaluating agreement.
8.4.3
Exploratory Analysis
8.4.3.1
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by CDR-SB at 24 Months
The same analysis as described in section 8.4.1.1 will be performed for CDR-SB at 24 
months. 
8.4.3.2
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by MMSE at 24 Months
The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in MMSE (≤ -3 point change) at 24 months.
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8.4.3.3
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by ADAS-Cog11 at 24 Months
The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in ADAS-Cog11 (≥4 point change) at 24 months.
8.4.3.4
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by FAQ at 24 Months
The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in FAQ (≥3 point change) at 24 months.
8.4.3.5
Risk Ratio of τAD++ vs. Non-τAD++ Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by CDR Global at 24 Months
The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in CDR Global (>0 point change) at 24.
8.4.3.6
Risk Ratio of τAD (τAD+/τAD++) vs. τAD- Subjects in Progression to Clinically 
Meaningful Deterioration Evaluated by CDR-SB at 18 Months and 24 Months
The same analysis as described in section 8.4.1.1 will be performed for CDR-SB, 
comparing τAD (τAD+/τAD++) and τAD- groups at 18 months and 24 months.
8.4.3.7
Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by MMSE at 18 Months and 24 Months
The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in MMSE (≤-3 point change), comparing τAD (τAD+/τAD++) 
and τAD- groups at 18 months and 24 months.
8.4.3.8
Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by ADAS-Cog11 at 18 Months and 24 Months
The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in ADAS-Cog11 (≥4 point change), comparing τAD 
(τAD+/τAD++) and τAD- groups at 18 months and 24 months.
8.4.3.9
Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by FAQ at 18 Months and 24 Months
The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in FAQ (≥3 point change) comparing τAD (τAD+/τAD++) and 
τAD- groups at 18 months and 24 months. 
8.4.3.10 Risk Ratio of τAD vs. τAD- Subjects in Progression to Clinically Meaningful 
Deterioration Evaluated by CDR Global at 18 Months and 24 Months  
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The same analysis as described in section 8.4.1.1 will be performed for clinically 
meaningful deterioration in CDR Global (>0) comparing τAD (τAD+/τAD++) and τAD-
groups at 18 months and 24 months.
8.4.3.11 MMRM for Additional Comparisons of CDR-SB Change across Tau Groups 
Differences between τAD++ vs non-τAD++LSM changes in CDR-SB at 24 months will 
also be tested and presented with the secondary analysis outlined in section 8.4.2.5.
Separate models similar to that outlined in 8.4.2.5 will be used to evaluate CDR-SB 
changes over time between τAD (τAD+ and τAD++) vs τAD-, and τAD++ vs τAD-.
8.4.3.12 MMRM for Additional Comparisons of MMSE Change across Tau Groups
Differences between τAD++ vs non-τAD++ LSM changes in MMSE at 24 months will 
also be tested and presented with the secondary analysis outlined in section 8.4.2.6.
Separate models similar to that outlined in 8.4.2.6 will be used to evaluate MMSE 
changes over time between τAD (τAD+ and τAD++) vs τAD-, and τAD++ vs τAD- . 
8.4.3.13 MMRM for Additional Comparisons of ADAS-Cog11 Change across Tau 
Groups 
Differences between τAD++ and non-τAD++ LSM changes in ADAS-Cog11 at 24 
months will also be tested and presented with the secondary analysis outlined in section 
8.4.2.7.
Separate models similar to that outlined in 8.4.2.7 will be used to evaluate ADAS Cog11 
changes over time between τAD (τAD+ and τAD++) and τAD-, and τAD++ and τAD-. 
8.4.3.14 MMRM for Additional Comparisons of FAQ Change across Tau Groups  
Differences between τAD++ and non-τAD++ LSM changes in FAQ at 24 months will 
also be tested and presented with the secondary analysis outlined in section 8.4.2.8.
Separate models similar to that outlined in 8.4.2.8 will be used to evaluate FAQ changes 
over time between τAD (τAD+ and τAD++) and τAD-, and τAD++ and τAD-.
8.4.3.15 Diagnostic Performance of Baseline Tau Status in Predicting Clinically 
Meaningful Deterioration Evaluated by CDR-SB  
This analysis will use dichotomized CDR-SB Change (1 point or more increase vs. 
otherwise at 18 months) as a truth standard to assess the diagnostic performance of 
baseline tau status as determined by flortaucipir scan. Sensitivity, specificity, accuracy, 
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PPV, and NPV will be presented in a table, along with their respective 95% Wilson score 
confidence intervals, with details as below:
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Clinically Meaningful Deterioration
  Change +
Change-
τAD++
A
B
Non-τAD++
C
D

Sensitivity = A/(A+C)

Specificity = D/(B+D)

Accuracy = (A+D)/(A+B+C+D)

PPV

NPV
8.4.3.16 Diagnostic Performance of Baseline Tau Status in Predicting Clinically 
Meaningful Deterioration Evaluated by MMSE  
The same analysis as described in section 8.4.3.15 will be performed for clinically 
meaningful deterioration in MMSE (≤-3 point change).
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8.4.3.17 Diagnostic Performance of Baseline Tau Status in Predicting Clinically 
Meaningful Deterioration Evaluated by ADAS-Cog11
The same analysis as described in section 8.4.3.15 will be performed for clinically 
meaningful deterioration in ADAS-Cog11 (≥4 point change).
8.4.3.18 Diagnostic Performance of Baseline Tau Status in Predicting Clinically 
Meaningful Deterioration Evaluated by FAQ
The same analysis as described in section 8.4.3.15 will be performed for clinically 
meaningful deterioration in FAQ (≥3 point change).
8.4.3.19 Diagnostic Performance of Baseline Tau Status in Predicting Clinically 
Meaningful Deterioration Evaluated by CDR Global 
The same analysis as described in section 8.4.3.15 will be performed for clinically 
meaningful deterioration in CDR Global (>0 point change).
8.4.4
Subgroup Analyses
The primary and secondary analyses described in sections 8.4.1 and 8.4.2, with the 
exception of inter-reader consistency, will be repeated by age group (≤75 years; > 75 
years), sex (female; male), and baseline CDR Global score (≥1; < 1). The analysis in 
8.4.2.4 will not be run by the CDR Global subgroups as this model is already adjusted for 
baseline CDR Global score.
8.4.5
Sensitivity Analysis
To avoid misinterpretation of potentially biased estimates caused by missing data, the 
MMRM analyses described in sections 8.4.2.5 through 8.4.2.8 will be run on the set of 90 
subjects who completed the 24 month visit.
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9
REFERENCES

Jack, C R, Knopman, D S, Jagust, W J, Shaw, LM, Aisen, P S, Weiner, M W, 
Petersen, R C, Trojanowski, J Q. Hypothetical model of dynamic biomarkers of 
the Alzheimer;s pathological cascade. Lancet Neruol 9(1): 119-128, 2010

Price, J.L., Morris, J.C. ”Tangles and plaques in nondemented aging and 
“preclinical”  Alzheimer’s disease.” Ann Neurol 45:358–368, 1999.

Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., 
Iwatsubo, T., Jack, C.R., Jr., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., 
Rowe, C.C., Siemers, E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-
Bogorad, M., Wagster, M.V., Phelps, C.H. 2011. “Toward defining the preclinical 
stages of Alzheimer's disease: Recommendations from the National Institute on 
Aging-Alzheimer's Association workgroups on diagnostic guidelines for 
Alzheimer's disease”. Alzheimers Dement 7(3), 280-92. 

Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988; 24:637-
639.

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. 

Rosen, W.G., Mohs, R.C., and David, K.L. A new rating scale for Alzheimer’s 
disease. American Journal of Psychiatry, 141: 1356-1364, 1984.

Pfeffer, R.I., Kurosaki, T.T., Harrah, C.H., Chance, J.M., Filos, S. Measurement 
of functional activities in older adults in the community. J Gerontol, 37(3): 323-
329, 1982.

Zou G. A Modified Poisson Regression Approach to Prospective Studies with 
Binary Data. American Journal of Epidemiology. 2004; 159 (7):702-706.
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