Clinical trial NCT02016560
Conditions: Alzheimer's Disease
Sponsor: Avid Radiopharmaceuticals
Start date: 2013-12-01; Completion date: 2017-07-28
Enrollment: 383 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Phase 2/3 cross-sectional and longitudinal observational study evaluating imaging characteristics of flortaucipir in control subjects and patients with clinically defined MCI and AD dementia (AD).

Detailed description:
This study was conducted in 2 phases: a Phase 2 Exploratory Phase and a Phase 3 Confirmatory Phase. An overarching goal of the Exploratory Phase of this protocol was to further investigate the pattern of flortaucipir PET imaging across the disease course, in cognitively healthy subjects through patients with cognitive decline. To accomplish this goal, the protocol investigated flortaucipir results in younger and older cognitively healthy normal volunteers and patients with clinical diagnoses for cognitive complaints, ranging from MCI to mild and moderate AD dementia. Additionally, the Exploratory Phase of this protocol investigated relationships between flortaucipir PET signal and cognitive decline over the 18-month study period.

The second, Confirmatory Phase of the study was designed to provide independent validation of the relationships observed in the exploratory analyses of the first phase. In particular, the goal of the second phase was to confirm the relationship between flortaucipir uptake in the brain as measured by PET signals at baseline and the subsequent rate of cognitive decline observed over the 18-month longitudinal follow up.

Arms: arm 1: Subjects will receive an IV injection, 370 megabecquerel (MBq) (10 millicurie \[mCi\]), single dose of florbetapir F 18 at baseline. Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of flortaucipir at baseline. arm 2: Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 at baseline. Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of flortaucipir at baseline, 9 months and 18 months. arm 3: Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 at baseline. Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of flortaucipir at baseline, 9 months and 18 months. arm 4: Subjects will receive an IV injection, 370 MBq (10 mCi), single dose of florbetapir F 18 and flortaucipir at baseline.
Interventions: intervention 1: florbetapir F 18 intervention 2: Flortaucipir F18 intervention 3: Brain PET Scan
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: positron emission tomography (PET) scan of the brain

Protocol documents:
SAP_002.pdf: 
18F-AV-1451-A05 SAP Confirmatory Addendum v1.0 
 
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 
 
NCT02016560 
Approval date: 05 Jan 2018


Avid Radiopharmaceuticals                                                                                               
Protocol 18F-AV1451-A05 
        
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Final Version 1.0 
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CONFIDENTIAL 
 
Protocol No. 18F-Flortaucipir-A05  
 
An open label, multicenter study, evaluating the safety and imaging characteristics 
of flortaucipir in cognitively healthy volunteers, subjects with Mild Cognitive 
Impairment, and subjects with Alzheimer’s Disease 
 
Confirmatory (Second Phase)  
Addendum to Statistical Analysis Plan 
 
Prepared for: 
Avid Radiopharmaceuticals, Inc 
 
Final Version 1.0 
Date 05Jan2018 
 
 
Prepared by: 
 
Chiltern International Inc. 
Revision History 
Version 
Date 
Revision Author 
Comments 
1.0 
05Jan2018 
 
 
 
 
 
 
This document is the confidential information of Avid Radiopharmaceuticals. It may not 
be disclosed to parties not associated with the clinical investigation or used for any 
purpose without the prior written consent of Avid Radiopharmaceuticals. 
 


Avid Radiopharmaceuticals 
Protocol 18F-AVl451-A05 
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Addendum Statistical Analysis Plan 
:? af9 


Avid Radiopharmaceuticals                                                                                               
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Final Version 1.0 
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Table of Contents 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................... 4 
2 
INTRODUCTION ........................................................................................................................................ 6 
3 
STUDY OBJECTIVE .................................................................................................................................. 6 
4 
STUDY DESIGN .......................................................................................................................................... 6 
4.1 
BLINDING ................................................................................................................................................ 7 
5 
EFFICACY VARIABLES ........................................................................................................................... 7 
5.4.1 
Quantitative Imaging Assessment of Flortaucipir Scan ................................................................. 7 
5.4.2 
Quantitative Imaging Assessment of Florbetapir Scan .................................................................. 7 
5.4.3 
Cognitive and Functional Assessments .......................................................................................... 7 
5.4.4 
Volumetric MRI Assessments .......................................................................................................... 7 
6 
STATISTICAL METHODS ........................................................................................................................ 8 
6.1 
GENERAL METHODOLOGY ...................................................................................................................... 8 
6.2 
ADJUSTMENTS FOR COVARIATES ............................................................................................................ 8 
7 
STATISTICAL ANALYSIS ........................................................................................................................ 8 
7.1 
DISPOSITION OF SUBJECTS ...................................................................................................................... 8 
7.2 
ANALYSIS POPULATIONS ......................................................................................................................... 8 
7.2.5 
Efficacy Population ........................................................................................................................ 8 
7.3 
ANALYSIS OF EFFICACY PARAMETERS .................................................................................................... 8 
7.3.1 
Relationship between Quantitative Tau Load and Baseline Cognitive/Functional 
Measurement .................................................................................................................................................. 8 
7.3.2 
Relationship between Quantitative Tau Load and Cognitive/Functional Change at 18 
Months Visit.................................................................................................................................................... 9 
7.3.3 
Relationship between Quantitative Tau Load and Other Biomarkers ............................................ 9 
8 
COMPUTER SOFTWARE ......................................................................................................................... 9 
9 
REFERENCES ............................................................................................................................................. 9 
 


Avid Radiopharmaceuticals                                                                                               
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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 
AE 
adverse event 
ANART 
American National Adult Reading Test 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BNT 
Boston Naming Test 
C 
Celsius 
cm 
centimeters 
CNS  
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DBP 
diastolic blood pressure 
DSST 
digit symbol substitution test 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
eCRF 
electronic case report form 
FAQ 
Pfeffer Functional Activities Questionnaire 
FDG 
18F- flurodeoxyglucose 
H 
high 
hCG 
human chorionic gonadotropin 
IND 
investigational new drug 
IV 
intravenous 
JOLO 
Benton Judgment of Line Orientation Test 
Kd 
dissociation constant 
kg 
kilograms 
L 
low 
LOC 
loss of consciousness 
LS 
least squares 
max 
maximum 
MBq 
megabecquerel 
mCi 
millicuries 
MCI 
mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 


Avid Radiopharmaceuticals                                                                                               
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MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
mSv 
millisievert 
n 
number of subjects 
N 
normal 
nM 
nanomolar 
OSU TBI-ID 
Ohio State University Traumatic Brain Injury Identification Method 
PET 
positron emission tomography 
ROI 
region of interest 
RR 
respiration rate 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
SUVr 
standardized uptake value ratio 
TBI 
Traumatic Brain Injury 
TEAE 
treatment-emergent adverse event 
TEMP 
temperature 
WHO 
World Health Organization 
 


Avid Radiopharmaceuticals                                                                                               
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2 
INTRODUCTION 
 
The quantitative assessment of Flortaucipir scan (standard uptake value ratio, SUVr) is 
important in helping to better understanding how brain tau load (as measured by 
flortaucipir scans) correlates with cognitive function progress. However quantitative 
analysis of tau PET imaging is a rapidly evolving field and not yet routine in Core 
laboratories. Therefore, Avid’s imaging science team will assume the role for this part of 
imaging analysis, and the results (SUVr values) will be used in exploratory analyses in 
this study, and will be reported in CSR with other analysis results.  To keep Avid staff 
blinded to the key information, the quantitative scan analysis process will be happening 
post main study database lock, which including the lock of both clinical and tau/amyloid 
imaging scan qualitative assessments (visual reads) results. Therefore this addendum 
SAP is created to describe the relative steps, and the planned analyses that will include 
imaging quantitative assessments. 
 
3 
STUDY OBJECTIVE 
 
This SAP will detail the exploratory analyses that involve flortaucipir and florbetapir 
quantitative assessments. All the analyses included here are for exploratory purpose. 
 
4 
STUDY DESIGN 
 
The process of imaging quantitative analysis (including both flortaucipir and florbetapir 
imaging) will be following the steps as below: 
 
 
 
The details of this process is documented in A05 study blinding document.  


Avid Radiopharmaceuticals                                                                                               
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4.1 
Blinding 
 
Avid imaging science team will assume the role of quantitative imaging analyses, 
including both flortaucipir scans, and florbetapir scans. Therefore the team will be 
blinded to any other study data, including both clinical and imaging qualitative 
assessments until the analyses results are sent to TPO for addendum TFL production, and 
addendum lock memo signed.  
 
 
5 
EFFICACY VARIABLES 
 
5.1.1 Quantitative Imaging Assessment of Flortaucipir Scan 
 
For the flortaucipir image, standardized uptake value ratios (SUVr) will be calculated 
using a subject specific white matter based parametrically derived reference region 
(parametric estimate of reference signal intensity, PERSI1). The global cortical target 
ROI will consist of a weighted average of voxels found, through multi-block barycentric 
discriminant analysis (MUBADA) to best sepaparate the amyloid positive AD/MCI and 
amyloid negative CN subjects, from the A05 exploratory cohort. In addition, cortical 
region ROI SUVr based on modified AAL regions will also be calculated. The details are 
documented in imaging analysis plan.   
 
 
  
5.1.2 Quantitative Imaging Assessment of Florbetapir Scan 
 
For the Florebetapir 18 F image, standardized uptake values (SUV) for target areas such 
as the frontal cortex, temporal cortex, parietal cortex, posterior cingulate cortex, anterior 
cingulate cortex and the precuneus will be calculated from each image.  Standardized 
uptake value ratios (SUVr) will be calculated for target areas by calculating the ratio of 
the specific SUV to the entire cerebellum SUV.  The global cortical average SUVr will 
be calculated as the average across these six target brain regions. 
 
5.1.3 Cognitive and Functional Assessments 
 
Cognitive and functional assessments as detailed in section 6.4.2.2 of A05 confirmatory 
SAP, include MMSE, ADAS, FAQ, and CDR. 
 
5.1.4 Volumetric MRI Assessments 
 
Volumetric MRI assessments are detailed in section 6.4.2.6 of A05 confirmatory SAP.  
 


Avid Radiopharmaceuticals                                                                                               
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6 
STATISTICAL METHODS 
 
6.1 
General Methodology 
 
 Frequency distributions including counts and percentages will be included for all 
categorical outcomes. Summary statistics including mean, standard deviation, median, 
minimum and maximum values will be presented for all continuous outcomes. Unless 
otherwise specified, hypothesis testing will be two-sided with type I error rate of 0.05. 
 
All statistical analyses will be performed using SAS® version 9.3 or higher.  
 
6.2 
Adjustments for Covariates 
 
None. 
 
7 
STATISTICAL ANALYSIS 
 
7.1 
Disposition of Subjects 
 
Flortaucipir and florbetapir images that are not quantifiable due to reasons such as 
technical issues and etc. will be documented in details in a note to file (NTF). The 
number of subjects with imaging received by Avid imaging science team, number of 
subjects with imaging quantitative analysis completed, and number of subjects with 
imaging scans fail to complete quantitation will be presented in a table, along with 
reasons of why quantitation failed. A listing will also be provided.   
 
 
7.2 
Analysis Populations 
 
 
7.2.5 Efficacy Population 
 
The efficacy population for the analyses covered in this addendum SAP will include all 
subjects with a valid flortaucipir quantitative scan analysis result (SUVr value).      
 
 
 
7.3 
Analysis of Efficacy Parameters 
 
7.3.1 Relationship between Quantitative Tau Load and Baseline 
Cognitive/Functional Measurement   
 


Avid Radiopharmaceuticals                                                                                               
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To evaluate the relationships between brain tau load as measured by flortaucipir SUVr 
value and the cognitive and functional assessments, scatter plots between MUBADA 
SUVr and each of the baseline cognitive and functional assessments as detailed in section 
5.1.3 will be generated. Pearson correlation analyses will be conducted for each of these 
pairs, and the correlation coefficient will be provided along with the 95% confidence 
intervals (CI), and the associated p-values.  
 
7.3.2 Relationship between Quantitative Tau Load and Cognitive/Functional 
Change at 18 Months Visit 
 
Similar analyses will be conducted as detailed in section 7.3.1, by changing baseline 
cognitive/function measurements to cognitive/functional measurements change from 
baseline at 18 months. 
 
7.3.3 Relationship between Quantitative Tau Load and Other Biomarkers 
 
Similar analyses will be conducted as detailed in section 7.3.1, by changing baseline 
cognitive/function measurements to the biomarkers such as below: 
1. Amyloid level as assessed by florbetapir SUVr; 
2. MRI volumetric assessments as detailed in A05 confirmatory SAP section 6.4.2.6. 
 
 
 
 
8 COMPUTER SOFTWARE 
 
All analyses will be performed by Chiltern International Inc. using Version 9.3 or later of 
SAS software.  All summary tables and data listings will be prepared utilizing SAS 
software. 
 
For continuous variables, descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum, maximum, 25th pct, and 75
th pct) will be generated.  
The standard operating procedures (SOPs) of Chiltern International Inc. will be followed 
in the creation and quality control of all data displays and analyses. 
 
 
9 REFERENCES 
 
1. Southekal S, Devous MD, Kennedy I, Navitsky M, Lu M, Joshi AD, Pontecorvo MJ, Mintun 
MA. Flortaucipir F 18 Quantitation using a Parametric Estimate of Reference Signal Intensity 
(PERSI). Journal of Nuclear Medicine (submitted). 

SAP_003.pdf: 
18F-AV-1451-A05 SAP Exploratory v1.0 
 
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 
 
NCT02016560 
Approval date: 27 Nov 2017


Avid Radiopharmaceuticals                                                                                               
Protocol 18F-AV1451-A05 
        
Statistical Analysis Plan 
Final Version 1.0 
Chiltern International Inc. 
1 of 48 
 
CONFIDENTIAL 
 
Protocol No. 18F-AV1451-A05  
 
An open label, multicenter study, evaluating the safety and imaging characteristics of 
Flortaucipir in cognitively healthy volunteers, subjects with Mild Cognitive 
Impairment, and subjects with Alzheimer’s Disease 
 
Exploratory (First Phase) 
Statistical Analysis Plan 
 
Prepared for: 
Avid Radiopharmaceuticals, Inc 
 
Final Version 1.0  
Date 27Nov2017 
 
 
Prepared by: 
 
Chiltern International Inc. 
Revision History 
Version 
Date 
Revision Author 
Comments 
1.0 
27Nov2017 
 
 
 
This document is the confidential information of Avid Radiopharmaceuticals. It may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of Avid Radiopharmaceuticals. 
 


Avid Radiopharm11ceuticals 
Protocol 18F-AVl451-A05 
Statistical Analysis Plan 
SIGNATURE 
FinAI Wrslon 1.0 
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CONFIDENTIAL 


Avid Radiopharmaceuticals                                                                                               
Protocol 18F-AV1451-A05 
        
Statistical Analysis Plan 
Final Version 1.0 
Chiltern International Inc. 
3 of 48 
 
CONFIDENTIAL 
 
Table of Contents 
 
1 
1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................ 5 
2 
INTRODUCTION ........................................................................................................................................ 7 
3 
STUDY OBJECTIVES ................................................................................................................................ 8 
3.1 
EXPLORATORY PHASE, CROSS-SECTIONAL OBJECTIVES .......................................................................... 8 
3.2 
EXPLORATORY PHASE, LONGITUDINAL OBJECTIVES ............................................................................... 9 
4 
STUDY DESIGN .......................................................................................................................................... 9 
4.1 
GENERAL DESIGN .................................................................................................................................... 9 
4.2 
DISCUSSION OF STUDY DESIGN ............................................................................................................. 11 
4.3 
METHOD OF ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS ........................................................ 11 
4.4 
BLINDING .............................................................................................................................................. 11 
4.5 
DETERMINATION OF SAMPLE SIZE ......................................................................................................... 12 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ............................... 12 
5.1 
CHANGES IN THE CONDUCT OF THE STUDY ........................................................................................... 12 
5.2 
CHANGES FROM THE ANALYSES PLANNED IN THE PROTOCOL/CIP ....................................................... 12 
6 
BASELINE, EFFICACY AND SAFETY EVALUATIONS ................................................................... 13 
6.1 
SCHEDULE OF EVALUATIONS ................................................................................................................ 13 
6.2 
TIME POINT ALGORITHMS ..................................................................................................................... 16 
6.2.1 
Relative Day ................................................................................................................................. 16 
6.2.2 
Windows ....................................................................................................................................... 16 
6.3 
SCREENING AND BASELINE ASSESSMENTS ............................................................................................ 16 
6.4 
EFFICACY VARIABLES ........................................................................................................................... 18 
6.4.1 
Primary Efficacy Variable(s) ........................................................................................................ 18 
6.4.1.1 
Quantitative assessment of images for Flortaucipir (SUVr based) .............................................................. 18 
6.4.1.2 
Qualitative assessment for Flortaucipir and Diagnostic Performance ......................................................... 18 
6.4.2 
Secondary Efficacy Variables ....................................................................................................... 19 
6.4.2.1 
Amyloid Beta Status Based on Florbetapir .................................................................................................... 19 
6.4.2.2 
Quantitative Imaging for Florbetapir (SUVr based) ..................................................................................... 19 
6.4.2.3 
Cognitive and Functional Assessments .......................................................................................................... 19 
6.4.3 
Additional Efficacy Variables ....................................................................................................... 22 
6.4.3.1 
ApoE Genotyping ............................................................................................................................................ 22 
6.4.3.2 
Genetic Samples .............................................................................................................................................. 22 
6.4.3.3 
MRI Scan of the Brain ..................................................................................................................................... 23 
6.4.3.4 
Optional Cerebrospinal fluid (CSF) collection by Lumbar Puncture (LP) .................................................. 23 
6.5 
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETIC PARAMETERS ............................... 23 
6.5.1 
Handling of Pharmacokinetic Parameter Outliers ....................................................................... 23 
6.6 
SAFETY ASSESSMENTS .......................................................................................................................... 23 
6.6.1 
Extent of Exposure and Compliance to Study Treatment.............................................................. 23 
6.6.2 
Adverse Events .............................................................................................................................. 23 
6.6.3 
Clinical Laboratory Evaluations .................................................................................................. 25 
6.6.4 
Other Observations Related to Safety ........................................................................................... 26 
6.6.4.1 
Vital Signs ........................................................................................................................................................ 26 


Avid Radiopharmaceuticals                                                                                               
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6.6.4.2 
Electrocardiogram (ECG) ............................................................................................................................... 27 
6.7 
PHARMACODYNAMICS PARAMETERS .................................................................................................... 27 
7 
STATISTICAL METHODS ...................................................................................................................... 27 
7.1 
GENERAL METHODOLOGY .................................................................................................................... 27 
7.2 
ADJUSTMENTS FOR COVARIATES .......................................................................................................... 27 
7.3 
HANDLING OF DROPOUTS OR MISSING DATA ........................................................................................ 27 
7.4 
INTERIM ANALYSES AND DATA MONITORING ....................................................................................... 28 
7.5 
MULTI-CENTER STUDIES AND POOLING OF CENTERS ............................................................................ 28 
7.6 
MULTIPLE COMPARISONS/MULTIPLICITY .............................................................................................. 28 
7.7 
ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE .......................................................... 28 
7.8 
EXAMINATION OF SUBGROUPS .............................................................................................................. 28 
8 
STATISTICAL ANALYSIS ...................................................................................................................... 28 
8.1 
DISPOSITION OF SUBJECTS ..................................................................................................................... 28 
8.2 
PROTOCOL DEVIATIONS/VIOLATIONS ................................................................................................... 29 
8.3 
ANALYSIS POPULATIONS ....................................................................................................................... 29 
8.3.1 
Enrolled Population...................................................................................................................... 29 
8.3.2 
Safety Population .......................................................................................................................... 29 
8.3.3 
Efficacy Population ...................................................................................................................... 29 
8.4 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................................................... 30 
8.5 
PRIOR AND CONCOMITANT THERAPY .................................................................................................... 30 
8.6 
ANALYSIS OF EFFICACY PARAMETERS .................................................................................................. 30 
8.6.1 
Exploratory Phase, Cross-sectional Analysis ............................................................................... 30 
8.6.1.1 
Analysis of Primary Efficacy Variable .......................................................................................................... 30 
8.6.1.2 
Analysis of Second Efficacy Variable ............................................................................................................ 31 
8.6.1.3 
Exploratory Analyses ...................................................................................................................................... 32 
8.6.2 
Exploratory Phase, Longitudinal Analysis ................................................................................... 33 
8.6.2.1 
Analysis of Primary Efficacy Variable .......................................................................................................... 33 
8.6.2.2 
Analysis of Second Efficacy Variable ............................................................................................................ 34 
8.6.2.3 
Analysis of additional Efficacy Variable ....................................................................................................... 34 
8.6.2.4 
Exploratory Analyses ...................................................................................................................................... 34 
8.7 
ANALYSIS OF SAFETY ............................................................................................................................ 38 
8.7.1 
Extent of Exposure and Compliance to Study Treatment.............................................................. 38 
8.7.2 
Adverse Events .............................................................................................................................. 39 
8.7.3 
Clinical Laboratory Evaluations .................................................................................................. 40 
8.7.4 
Other Observations Related to Safety ........................................................................................... 40 
8.7.4.1 
Vital Signs ........................................................................................................................................................ 40 
8.7.4.2 
Electrocardiogram............................................................................................................................................ 40 
8.8 
PHARMACODYNAMICS ........................................................................................................................... 40 
9 
COMPUTER SOFTWARE ....................................................................................................................... 40 
10 REFERENCES ........................................................................................................................................... 41 
11 
APPENDICES............................................................................................................................................. 44 
11.1 
APPENDIX 1 – LABORATORY RESULTS – POTENTIALLY CLINICALLY SIGNIFICANT CRITERIA ............... 44 
11.2 
APPENDIX 2 – VITAL SIGNS AND ECGS – POTENTIALLY CLINICALLY SIGNIFICANT CRITERIA ............. 48 
 


Avid Radiopharmaceuticals                                                                                               
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Statistical Analysis Plan 
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CONFIDENTIAL 
 
 
1 
1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Table 1: Abbreviations and Definitions of Terms 
 
 
AAL VOI
automatic anatomical labeling volume of interest
AB
amyloid-ß
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale-Cognitive 
AE
adverse event
ANART
American National Adult Reading Test
ATC
Anatomical Therapeutic Chemical
BMI
body mass index
BNT
Boston Naming Test
C
Celsius
CDR
Clinical Dementia Rating
cm
centimeters
CN
cognitively normal
CNS 
central nervous system
CRF
case report form
CRO
contract research organization
CSF
cerebrospinal fluid
DBP
diastolic blood pressure
DSST
digit symbol substitution test
ECG
electrocardiogram
EDTA
ethylenediaminetetraacetic acid
eCRF
electronic case report form
FAQ
Pfeffer Functional Activities Questionnaire
FDG
flurodeoxyglucose
H
high
IND
investigational new drug
IV
intravenous
JOLO
Benton Judgment of Line Orientation Test
Kd 
dissociation constant
kg
kilograms
L
low
LOC
loss of consciousness
LP
lumbar puncture
LS
least squares
max
maximum
MBq
megabecquerel
mCi
millicuries


Avid Radiopharmaceuticals                                                                                               
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MCI
mild cognitive impairment
MedDRA
Medical Dictionary for Regulatory Activities
min
minimum
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
mSv
millisievert
n
number of subjects
N
normal
nM
nanomolar
OCN
old cognitively normal
OSU TBI-ID
Ohio State University Traumatic Brain Injury Identification Method
PET
positron emission tomography
ROI
region of interest
rsf
resting state functional
SBP
systolic blood pressure
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
SUVr
standardized uptake value ratio
TBI
Traumatic Brain Injury
TEAE
treatment-emergent adverse event
TEMP
temperature
WHO
World Health Organization
YCN
young cognitively normal
 


Avid Radiopharmaceuticals                                                                                               
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2 
INTRODUCTION 
 
Molecular imaging biomarkers have the potential to aid in the diagnosis of patients with 
cognitive impairment who are being evaluated for Alzheimer’s disease (AD) (Dubois, 2010; 
McKhann, 2011). Positron emission tomography (PET) ligands such as florbetapir F 18 
(Wong, 2010) may provide a minimally invasive estimate of cortical beta amyloid (AB) 
neuritic plaque deposition, a hallmark pathology, and a required element for the evaluation of 
AD neuropathologic diagnosis (Hyman, 2012). Multiple studies comparing amyloid PET 
scans to histopathologic assessment of amyloid burden, in subjects for whom biopsy samples 
were available or who came to autopsy after receiving a PET amyloid scan, support the 
relationship between PET amyloid imaging results and cortical neuritic plaque density 
(Clark, 2011, 2012; Leinonen, 2008; Sojkova, 2011; Kantarci, 2011; Burack, 2010). The 
largest of these studies (Clark, 2012) demonstrated a high sensitivity and specificity for 
florbetapir PET to discriminate subjects with subsequent autopsy findings of no or sparse 
neuritic plaques (amyloid negative) from those with moderate to frequent plaques (amyloid 
positive).  
 
The ability to image brain amyloid with compounds such as florbetapir is an important 
advance for diagnosis of neurological disease. An amyloid negative florbetapir PET scan 
indicates the absence of a hallmark pathology and is inconsistent with a diagnosis of AD. 
However, because amyloid is believed to accumulate very early in the disease process (Jack 
et al., 2010) and may be present in other diseases or in clinically normal elderly subjects 
(Sperling et al. 2011; Price and Morris, 1999), the density or distribution of amyloid in 
subjects with a positive scan is not associated with Alzheimer’s disease severity, has not been 
established to predict rate of future deterioration and has not been established as a tool to 
predict or monitor response to therapy.  
 
In contrast to AB neuritic plaques, the density and distribution of phosphorylated tau, 
aggregated in neurofibrillary tangles, increases with AD-related cognitive impairment and 
correlates with neurodegeneration (Dickson et al., 1997; Duyckaerts et a., 1987). Thus, a PET 
imaging agent that binds to phosphorylated tau has potential application as a biomarker for 
disease severity/neurodegeneration and may be useful both for selecting patients for therapy 
and for monitoring disease progression in therapeutic trials.  
 
Flortaucipir (originally named [F-18]T807 by Siemens Molecular Imaging Biomarker 
Research group) has been developed as a positron emitting radiopharmaceutical for in vivo 
imaging of tau protein aggregates (Xia et al., 2013). Autoradiography results using tissue 
sections from human brains showed a strong signal in the grey matter of cortical slices from 
tau positive brains but weak or no binding in tau negative, AB positive, or tau and AB 
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Avid Radiopharmaceuticals                                                                                               
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yielded an estimated dissociation constant (Kd) of 15nM. A saturation binding experiment 
using purified Paired Helical Fragment Tau isolated brains of AD patients yielded a Kd value 
of 0.7 nanomolars (nM).  
 
The overarching goal of this protocol is to further investigate the spectrum of PET imaging 
results with Flortaucipir in patients with cognitive decline and healthy controls. To 
accomplish this goal, the protocol will investigate Flortaucipir results in younger and older 
controls and patients with cognitive complaints ranging from mild cognitive impairment 
(MCI) to mild and moderate AD. Additionally, this protocol will investigate correlations 
between Flortaucipir PET imaging and other biomarkers associated with AD and will test the 
relationship between Flortaucipir PET imaging and cognitive decline over the 18 month 
study period.  
 
3 STUDY OBJECTIVES 
 
This study will be conducted in two phases, an exploratory phase and a confirmatory phase. 
This statistical analysis plan is for the exploratory phase of this study. The exploratory phase 
of this study will be comprised of a cross-sectional component and a longitudinal component.  
 
3.1 Exploratory Phase, Cross-sectional Objectives 
The primary objective of the cross-sectional component is: 
• To compare Flortaucipir imaging results in subjects with AD to subjects with MCI 
and cognitively healthy older individuals 
 
The secondary objective of the cross-sectional component is:  
• To establish a database of cognitively healthy individuals to show the spectrum of 
Flortaucipir imaging results in cognitively healthy individuals across a range of age 
strata  
 
Exploratory objectives of the cross-sectional component are:  
• To determine whether greater degrees of cognitive impairment correlate with higher 
Flortaucipir uptake in subjects with an amyloid positive status  
• To explore whether tests of specific cognitive domains correlate with regional 
Flortaucipir uptake  
• To explore the relationships between Flortaucipir uptake and biomarkers of 
neurodegeneration and neurological disease (cerebrospinal fluid (CSF) markers 
including tau, phospho-tau and beta-amyloid (AB), genetic markers, PET amyloid 
imaging, and brain atrophy assessed by volumetric magnetic resonance imaging (MRI))  
• To expand the Flortaucipir safety database  
 


Avid Radiopharmaceuticals                                                                                               
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3.2 Exploratory Phase, Longitudinal Objectives 
The primary objective of the longitudinal component is: 
• To assess the rate of change of tau deposition as measured by Flortaucipir uptake over 
time 
 
The exploratory objectives of the longitudinal component are:  
• To explore associations between changes in Flortaucipir uptake in the brain and 
clinical and functional measures, as well as, biomarkers of neurodegeneration and 
neurological disease (CSF markers including tau, phospho-tau and beta-amyloid 
(AB), genetic markers, PET amyloid imaging, and brain atrophy assessed by 
volumetric MRI) 
• To expand the Flortaucipir safety database 
 
4 STUDY DESIGN 
 
4.1 General Design 
 
This study is an open label, multicenter Phase 2 study. This study is conducted in two phases, 
an exploratory (first) phase and complimentary (second) phase. The study will enroll 
cognitively healthy volunteers, subjects with mild cognitive impairment (MCI) and subjects 
with Alzheimer’s disease. Approximately 230 subjects will be enrolled in the study: 80 
cognitively healthy volunteers (20 subjects who will be  ≥20 to ≤40 years of age, and 60 
subjects  who will be ≥ 50 years of age), 80 subjects with MCI, 70 subjects with AD (60 
subjects with a Mini-Mental State Examination (MMSE) ≥20, and 10 subjects with an 
MMSE > 10 and < 20). For the 60 cognitively healthy volunteers ≥ 50 years of age, these 
subjects will be distributed across age deciles (50-59, 60-69, 70-79 and >80).  
 
All subjects will provide informed consent before starting any study procedures.  
 
Screening assessments may take place over several days and will include demographic 
information, cognitive testing, safety assessment, and MRI, including both volumetric and 
standard clinical sequences. Subjects who qualify for the study will undergo both a 
florbetapir F 18 PET imaging session and a Flortaucipir PET imaging session. The imaging 
sessions must be performed at least 48 hours apart, but not more than 60 days apart. The 
order of the scans is interchangeable. Some subjects, who are ≥ 50 years of age, will have the 
option to also participate in cerebrospinal fluid (CSF) collection by lumbar puncture (LP).  
 
Subjects who are ≥ 50 years of age will return for have a follow-up visits at 9 (+/-2) months 
18 (+/-2) following the initial Flortaucipir scan. Cognitive assessments and updates to 
concomitant medications and medical history will be collected at each follow-up visit. 
Subjects will also have follow-up Flortaucipir scans and MRI, including both volumetric and 


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standard clinical sequences. A sub-set of subjects may have the option to have an additional 
resting state functional (rsf) MRI sequence scan in addition to the volumetric and standard 
clinical sequences at both the screening MRI and follow-up MRIs. Subjects or their 
designated decision maker will be contacted by phone at 5 and 14 months following the 
initial Flortaucipir scan to collect updated concomitant medications and medical history.   
 
Florbetapir F 18 PET Imaging Session:  
 
For the florbetapir F 18 PET imaging session, an intravenous (IV) catheter will be placed for 
administration of florbetapir F 18 injection. Subjects will receive a single IV bolus injection 
target dose of 370 MBq (10 mCi) of florbetapir F 18 injection followed by a saline flush. At 
approximately 50 minutes following injection, a continuous 10-minute brain scan (2 
acquisitions of 5 minute duration) will begin.  
 
Adverse events will be continuously monitored during the florbetapir F 18 PET imaging 
session. A physician or physician designee must evaluate the subject for adverse events prior 
to injection and prior to discharge from the imaging center. Subjects who experience an 
adverse event will not be discharged from the imaging center until the event has resolved or 
stabilized.  
 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days of the post-injection of florbetapir F 18, but not before 48 hours 
post-injection, to confirm subject well-being and to collect information about any new 
adverse events. If both of these days are not business days, the follow-up phone call can 
occur the following business day.  
 
Flortaucipir PET Imaging Session(s):  
 
For the Flortaucipir PET imaging session(s), an IV catheter will be placed for administration 
of Flortaucipir injection. Subjects will receive a single IV bolus injection target dose of 370 
MBq (10 mCi) of Flortaucipir injection followed by a saline flush. At approximately 80 
minutes post dose, a continuous 20-minute brain scan (4 acquisitions of 5-minute duration) 
will be obtained. If at any point during the imaging session it is determined that the subject is 
not able to continue, or that it is not in the best interest of the subject to continue, imaging 
will be discontinued. The image data that has been collected up to that point will be analyzed. 
Clinical laboratory tests will be obtained prior to injection and upon completion of each 
imaging session. Adverse events will be monitored continuously during the imaging session. 
Subjects who experience any adverse event during an imaging session will not be discharged 
until the event has resolved or stabilized.  
 


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A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days of the imaging day, but not before 48 hours post-injection, to 
confirm subject well-being and to collect information about any new adverse events. If both 
of these days are not business days, the follow-up phone call can occur the following 
business day. 
 
4.2 
Discussion of Study Design 
 
This trial is designed to evaluate the brain tau protein imaging properties and safety of 
Flortaucipir to be used in subjects with cognitive impairment (first and second phases) and 
healthy volunteers (first phase only). Subjects will be categorized into groups of AD,  MCI, 
and cognitively normal (CN). Comparing the mean standardized uptake value ratios (SUVr) 
from each category will support the primary objective of detecting a significant difference of 
Flortaucipir imaging results among diagnostic groups. CN subjects will also be further 
stratified by age. This stratification will establish a database of imaging results to collect data 
on the accumulation of brain tau protein across age ranges. Another goal of this protocol is to 
establish a relationship between Flortaucipir imaging results and cognitive assessments. 
Allowing all subjects to complete various cognitive assessments will provide evidence 
whether greater degrees of cognitive impairment will be correlated with higher levels of 
Flortaucipir uptake. This relationship is important in this protocol in order to determine the 
utility and predictive power of Flortaucipir on the severity of cognitive impairment. 
 
4.3 
Method of Assignment of Subjects to Treatment Groups 
 
Florbetapir F 18:  
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) of 
florbetapir F 18 injection.  
 
Flortaucipir:  
All subjects except for young cognitive normal (YCN) subjects will receive a single IV bolus 
administration target dose of 370 MBq (10 mCi) of Flortaucipir injection at each of the 
baseline, 9 months, and 18 months visits. YCN subjects will only receive a single IV bolus 
administration of Flortaucipir injection with a target dose of 370 MBQ (10 mCi) at baseline 
visit. 
 
4.4 
Blinding 
 
A blinded design was not used for this trial, because all subjects will receive the same 
medication.  
 


Avid Radiopharmaceuticals                                                                                               
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For the exploratory (first) phase, Avid personnel will not be blinded to longitudinal cognitive 
data nor to the PET scans (both florbetapir and Flortaucipir).  The blinding of imaging and/or 
clinical information at confirmatory phase will be discussed at confirmatory SAP. 
 
4.5 
Determination of Sample Size 
 
A total of 230 subjects (80 cognitively healthy volunteers, 80 MCI and 70 AD) will be 
enrolled in the Exploratory Phase of this study. To explore the Flortaucipir SUVr values 
across age strata among cognitively healthy subjects, these subjects will be divided into 5 age 
groups as 20-40 years old, 50-59 years old, 60-69 years old, 70-79 years old and 80 years old 
or above. There will be 15 subjects in each of the 50 or older age groups and about 20 
subjects from age group 20-40 years old. From a preliminary analysis of study T807000, the 
standard deviation (SD) of SUVr from combination region of interest (ROI) was 0.06 for 
subjects with low probability of AD. Therefore assuming a 0.06 SD, a sample of 15 subjects 
will give an approximately 90% probability to observe a 95% confidence interval as accurate 
as +/-0.04 around the point estimation.  
 
From previous studies, the amyloid positive rate is approximately 50% among MCI patients 
and approximately 80% from AD subjects. Therefore 80 MCIs and 70 ADs will likely result 
in 40 amyloid positive MCIs and 56 amyloid positive ADs. Also from study T807000, the 
combination ROI SUVr difference between CN and AD was 0.39, with a pooled SD of 0.27. 
Assume a pooled SD of 0.30, a sample of 60 CNs and 56 amyloid positive ADs will give a 
90% power to detect a 0.18 difference between the CN and AD groups. 
 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES 
 
5.1 
Changes in the Conduct of the Study 
 
There were no changes in the conduct of the study at the time of preparing this statistical 
analysis plan. 
 
5.2 
Changes from the Analyses Planned in the Protocol/CIP 
 
The protocol was amended (version 07 August 2015, Amendment 2). In this amendment the 
study was divided into two phases, exploratory (first) phase and confirmatory (second) phase. 
Currently, this SAP provides the planned analyses for the exploratory (first) phase of the 
study.


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6 
BASELINE, EFFICACY AND SAFETY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Exploratory (First) Phase and Confirmatory (Second) Phase: 
 
 


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Longitudinal Component  
Exploratory (First) Phase Only: 
 
 


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6.2 Time Point Algorithms 
 
6.2.1 Relative Day 
 
The date of first dose of study drug (Flortaucipir) will be considered relative day 1, and 
the day before the first dose of study drug will be relative day -1.  Relative days will be 
calculated as follows only when the full assessment date is known (i.e., partial dates will 
have missing relative days): 
 
For days on or after the first dose of study drug: 
Date of Assessment – Date of First Dose of Study Drug + 1. 
 
For days before the first dose of study drug: 
Date of Assessment – Date of First Dose of Study Drug. 
 
6.2.2 Windows 
 
No window algorithm is being used for this study. 
 
6.3 Screening and Baseline Assessments 
 
Screening may take place over several days. All screening assessments should be 
performed within 30 days of the initial Flortaucipir PET imaging session (with the 
exception of the MRI if previously performed). Screening assessments will include:  
• Informed consent;  
• Demographics (age, gender, race, ethnicity, education, alcohol, drug use, and 
smoking);  
• Medical history, physical and neurological exams, concomitant medications;  
• Disease history (date/months since symptom onset, date/months since diagnosis, 
family history of neurologic disease) for cognitively impaired subjects;  
• Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-
ID);  
• Mini-Mental State Exam (MMSE);  
• Safety assessments: Vital signs (pulse rate, respiratory rate, supine blood pressure, 
height and weight), electrocardiogram (ECG), safety labs (hematology, chemistry, 
and urinalysis);  
• Serum beta-hCG test (for females of childbearing potential defined as pre-
menopausal or less than 2 years post-menopausal and not surgically sterile);  
• MRI imaging including standard clinical sequences and volumetric MRI;  
• Optional CSF collection by LP 
• A physician will see the patient during the screening visit.  
 


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For efficacy analyses, baseline assessments may be performed at the screening visit or +/- 
30 days of the initial Flortaucipir Imaging Visit.  
 
Baseline assessments will include:  
• Alzheimer’s Disease Assessment Scale- Cognitive subscale (ADAS-Cog11);  
• Neuropsychological test battery (Digit Symbol Substitution Test (DSST), Digit 
span forward and backward ,Trail Making A and B, Logical Memory Test, 
Immediate and Delayed Recall Story A , Animal list generation, Boston Naming 
Test (BNT) (30 item), American National Adult Reading Test (ANART), Clock 
Drawing Test, Benton Judgment of Line Orientation test);  
• Pfeffer Functional Activities Questionnaire (FAQ). For the MCI and AD groups 
only.  
 
Tau pathology can be associated with Traumatic Brain Injury (TBI), therefore the OSU 
TBI-ID (Corrigan and Bogner 2007) short version will be used to screen for a history of 
traumatic brain injury. It is the briefest version that still provides several summary indices 
on which the original version was validated. To shorten the instrument, TBIs resulting in 
loss of consciousness (LOC) are emphasized over less severe injuries. Classifying worst 
injury based on the OSU TBI-ID will all be displayed. The following classifies worst 
injury: 
• 1= Improbable or possible TBI without LOC- if interview all questions numbered 
1-5 are all ‘no’ or if response to question 6, interview data reports never having 
LOC, with or without being dazed or having memory lapses. 
• 2= Mild TBI with LOC- if in response to question 6, interview data reports LOC 
does not exceed 30 minutes for any injury. 
• 3= Moderate TBI-  if in response to question 6 , interview data reports LOC for 
one injury is between 30 minutes and 24 hours. 
• 4= Severe TBI- if in response to question 6, interview data reports LOC for any 
one injury exceeds 24 hours. 
 
Weight will be displayed in kilograms (kg), height will be displayed in centimeters (cm), 
and temperature will be displayed in Celsius (C). Weights, heights, or temperatures 
recorded in alternate units will be converted to the units being displayed using standard 
conversion formulas. Body mass index (BMI) will be calculated as weight (kg) divided 
by height squared (cm2). 
 
Each subject’s age (years) will be calculated based on his/her date of informed consent 
and will be truncated to a whole number.  Because only year of birth is collected, January 
1 will be imputed for the month and day of birth.  To calculate age, count the number of 
months between the date of informed consent and the imputed birthdate.  Divide the 
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addition, age will be categorized into 5 groups: 20-40 years, 50-59 years, 60-59 years, 70-
79 years, and 80 years or older.  
 
The number of years of education for a subject will be calculated for individuals who 
have specified the level of schooling he/she has obtained. The years of education will be 
calculated as follows: elementary school = 6 years, middle school = 8 years, high school 
= 12 years, college/university = 16 years, graduate/master’s degree = 18 years, 
PhD/multiple graduate degrees/medical degree = 20 years. Otherwise, if a subject 
specified the number of years of education, then this number will be used.  
 
For safety analyses (vital signs, lab and ECG), baseline will be defined as the last 
assessment recorded on or prior to the start of Flortaucipir. 
 
Baseline for ECGs will be calculated as the average of the two ECGs administered on the 
imaging day prior to Flortaucipir administration. If only one ECG was administered prior 
to Flortaucipir administration, the baseline will be defined as the singular ECG 
administered prior to Flortaucipir administration.   
 
6.4 Efficacy Variables 
 
6.4.1 Primary Efficacy Variable(s) 
 
6.4.1.1 Quantitative assessment of images for Flortaucipir (SUVr based) 
 
For the Flortaucipir image, standard uptake value ratios (SUVr) will be calculated to 
estimate tau load globally and for each individual region. For global assessment, a target 
region derived statistically with a Multiblock Barycentric Discriminant Analysis 
(MUBADA) method will be used; at individual region level, VOIs determined in the 
AAL atlas masked to exclude white matter and CSF for parietal, temporal, occipital, 
anterior hippocampal parahippocampal and fusiform gyri will be applied. For all SUVr 
value calculations, a selected white matter region derived using a parametric estimated 
signal reference intensity (PERSI) method will be used as reference region.    
 
6.4.1.2 Qualitative assessment for Flortaucipir and Diagnostic Performance 
 
At the exploratory phase, the baseline flortaucipir scan images will be visually interpreted 
by Avid’s imaging experts. The scans will be classified as either  
• AD pattern (AD+) 
• AD pattern and likely to progress (AD++)  
• Not consistent with an AD pattern (AD-) 
 
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6.4.2 Secondary Efficacy Variables 
 
6.4.2.1 Amyloid Beta Status Based on Florbetapir 
 
Florbetapir F 18 images will be assessed by expert readers blinded to the diagnostic 
group for the subjects. The images will then be classified as either AB+ (amyloid 
positive) or AB- (amyloid negative). For images read by more than one reader, the 
majority or consensus read will be used for each subject.   
 
6.4.2.2 Quantitative Imaging for Florbetapir (SUVr based) 
 
For the Florebetapir 18 F image, the global cortical average SUVr will be calculated as 
the average across these six target brain regions: the medial frontal cortex, temporal 
cortex, parietal cortex, posterior cingulate cortex, anterior cingulate cortex and the 
precuneus with entire cerebellum as a reference region.  
 
6.4.2.3 Cognitive and Functional Assessments 
 
Except for Clinical Dementia Rating (CDR) scale, cognitive assessments will be 
performed at screening or baseline, at follow-up visits (9 (+/- 2) months, and 18 (+/- 2) 
months) during the study. CDR scales will be performed at 9 months and 18 months 
visits only. These cognitive assessments include the following:   
 
Mini-Mental State Examination (MMSE)  
 
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive function 
in elderly patients. The instrument is divided into 2 sections. The first section measures 
orientation, memory, and attention. The maximum score for the first section is 21. The 
second section tests the ability of the patient to name objects, follow verbal and written 
commands, write a sentence, and copy figures. The maximum score for the second 
section is 9. The range for the total MMSE score is 0 to 30, the sum of each correct 
answer, with higher scores indicating better cognition.  
 
Alzheimer’s Disease Assessment Scale—Cognitive subscale (ADAS-Cog11)  
 
The ADAS (ADAS-Cog; Rosen et al. 1984) was designed to assess the severity of the 
dysfunction in the cognitive and noncognitive behaviors characteristic of persons with 
AD. The cognitive subscale of the ADAS, the 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. 
 
Digit Symbol Substitution Test (DSST)  


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The DSST (Wechsler Adult Intelligence Scale F Revised, 1981) is a paper test of 
psychomotor performance in which the subject is given a key of numbers and matching 
symbols and a test section with numbers and empty boxes. Under each number the 
subject should write down the corresponding symbol as fast as possible. The score is the 
number of correct number-symbol matches made within the allowed time (90 seconds). 
The strategy to solve the DSST consists of sequential encoding and retrieval of numbers 
and corresponding symbols. Incidental memory, visuo-motor coordination, perceptual 
organization, and selective attention are key factors that determine the final score 
(Wechsler Adult Intelligence Scale Revised, 1981). The ability to sort out irrelevant 
information (e.g., symbols that may look alike) also impacts performance. This test has 
high test–retest reliability (Matarazzo and Herman, 1984). One point is given for each 
symbol correctly drawn during the ninety seconds, with the maximum score of 93. 
Greater totals denote lower disease severity. 
 
Digit span forward and backward (from Wechsler Memory Scale-Revised (WMS-R))  
 
Digit Span is composed of two tasks administered independently of each other: Digits 
Forward and Digits Backward. On both tasks, the examiner reads a series of number 
sequences to the subject. For each Digits Forward item, the subject is required to repeat 
the number sequence in the same order as presented. For Digits Backward, the subject is 
required to repeat the number sequence in the reverse order. The score ranges from 0-24, 
a maximum score of 12 for digit span forward and a maximum score of 12 for digit span 
backward, with lower scores indicating greater disease severity. 
 
Trail Making A and B  
 
The trail making test (Reitan and Wolfson, 1985) is a test of executive function. Part A 
consists of 25 circles numbered 1 through 25 distributed over a sheet of paper. The 
subject is instructed to connect the circles by drawing a line as quickly as possible in 
ascending numerical order. Part B consists of 25 circles containing either numbers (1 
through 13) or letters (A-L). The subject is instructed to connect the circles while 
alternating between numbers and letters in ascending order. The subject is timed. The 
total score is the time to complete Part A, with a maximum of  a 150 seconds and Part B 
with a maximum of is a 300 seconds. Timing is not stopped while correcting errors. 
Testing is stopped if the maximum time is reached. The total score is the number of 
seconds to complete both trails, where higher scores indicate greater disease severity. 
 
Logical Memory Test, Immediate and Delayed Recall, Story A (WMS-R)  
 
The logical memory test (Wechsler D. 1987) assesses the ability to recall a short story. 
Subjects are read a story and asked to recall the story immediately and after a delay. The 


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maximum score is 25, and each point obtained based on how much of the story is correct. 
Higher scores indicate better cognition. 
 
Animal List Generation  
 
The animal list generation (Morris et al. 1989) is used to measure verbal fluency. The 
subject is asked to name as many animals as possible in 60 seconds. The total score is the 
count of all admissible words, where lower scores denote greater cognitive impairment. 
 
Boston Naming Test (BNT) (30 item)  
 
The 30 item Boston Naming Test (Kaplan, et al. 1983) is a measure of the ability to 
orally label 30 line drawings of objects. The objects are presented to the subject in order 
of frequency, from most frequent to least frequent. The maximum score is 30, where 
higher scores indicate better cognition, obtained from the number of spontaneously given 
correct responses in addition to the number of correct responses following a stimulus cue. 
 
American National Adult Reading Test (ANART)  
 
ANART (Grober and Sliwinski 1991) is a measure for estimating premorbid verbal 
intelligence. The subject is presented with a word list and asked to pronounce the words. 
One point is given for each correctly pronounced word, with a maximum score of 45, 
where lower scores indicate greater disease severity. 
 
Clock Drawing Test  
 
The clock drawing test (Goodglass and Kaplan 1983) has two components: a command 
condition and a copy condition. In the command condition, the subject draws a clock 
according to verbal instructions. In the copy condition, the subjects copy a model clock 
drawn at the top of a form. The score ranges from 0-5 where a point is obtained from 
approximately circular face, symmetry of number placement, correctness of numbers, 
presence of two hands, and presence of two hands set to the correct time. Higher scores 
suggest better cognition. 
 
Benton Judgment of Line Orientation Test (JOLO)  
 
The JOLO (Benton 1978) is a non-motor measure of visual perceptual ability where there 
is no time demand. The task asks subjects to match two lines by their angel of orientation 
to a test set of lines presented below the stimulus lines. Each correct response is given 
one point and the maximum score is 30, where higher scores denote lesser disease 
severity. 
 
 


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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 informant to rate 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 cognitive impairment. 
 
6.4.2.3.1 Clinical Meaningful Changes 
 
Clinically meaningful changes will be defined by categorizing the change in 
psychometric scores, as follows: 
1. a 3 point or more drop in MMSE relative to baseline; 
2. a 4 point or more increase in ADAS Cog 11 relative to baseline; 
3. a 3 point or more increase in FAQ relative to baseline ; 
4. a 1 point or more increase in CDR SB relative to 9 month ; 
5. a 12 point or more increase in ADAS+FAQ composite relative to baseline 
6. CDR global score will be categorized as decreasing; stay the same; increasing 
from 9 month. 
 
 
6.4.3 Additional Efficacy Variables 
 
6.4.3.1 ApoE Genotyping 
 
ApoE genotyping will be performed at the initial Flortaucipir imaging session for those 
subjects whose ApoE is unknown.  For analysis purposes, subjects will be categorized as 
ApoE ε4 positive (ε4+) if at least one allele is an ε4 allele and ApoE ε4 negative (ε4-) if 
neither allele is an ε4 allele.   
 
6.4.3.2 Genetic Samples 
 
A one-time blood collection (10 mL, blood) will be performed on the day of the initial 
Flortaucipir imaging session for genetic analysis. Where local regulations allow, samples 
will be stored and analysis may be performed on genetic variants thought to play a role in 
dementia or related diseases. Samples will only be used for investigations related to 
disease and drug or class of drugs under study in the context of this clinical program. 
They will not be used for broad exploratory unspecified disease or population genetic 
analysis. No prospective analyses will be performed using this data. 
 


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6.4.3.3 MRI Scan of the Brain 
 
MRI, including both volumetric and standard clinical sequences, will be conducted at 
each tau scan visit. Volumetric measurements, including the whole brain, grey matter, 
ventricle, and hippocampus will be performed. The brain volumes will be normalized for 
analysis purpose.  
 
6.4.3.4 Optional Cerebrospinal fluid (CSF) collection by Lumbar Puncture (LP)  
 
Some subjects (depending on site participation) who are ≥ 50 years of age who qualify 
for the study will be offered to consent for optional CSF collection by LP. The LP should 
be performed at least 48 hours apart from the PET imaging sessions and should be 
performed within +/- 60 days of the initial Flortaucipir Imaging Visit. Each LP will be 
done by a qualified physician who is experienced in performing the procedure. Subjects, 
or their designated decision maker, will call the investigator to report any adverse events 
associated with the LP procedure.  The CSF will be assessed for biomarkers of 
neurodegeneration and neurological disease (tau, phosphor-tau and beta-amyloid (AB)). 
 
6.5 Drug Concentration Measurements and Pharmacokinetic Parameters 
 
6.5.1 Handling of Pharmacokinetic Parameter Outliers 
 
No pharmacokinetic parameters or drug concentration measurements will be collected 
during this study. 
 
6.6 Safety Assessments 
 
6.6.1 Extent of Exposure and Compliance to Study Treatment 
 
During the florbetapir F 18 imaging session, subjects will receive a single IV bolus 
administration target dose of 370 MBq (10 mCi) of florbetapir F 18 injection followed by 
a 10 minute PET brain scan (2 acquisitions of 5 minute duration) at 50 minutes post 
injection. During the Flortaucipir imaging session, all subjects will receive a single IV 
bolus administration target dose of 370 MBq (10 mCi) of Flortaucipir injection. At 
approximately 80 minutes post dose, scanning will begin. Four 5-minute acquisitions will 
be taken.  Exposure to study drug will be summarized using the total administered dose at 
each scan visit for Flortaucipir and Florbetapir F 18 injection respectively.  
 
6.6.2 Adverse Events 
 
The investigator’s verbatim term of both serious and non-AEs will be mapped to system 
organ class (SOC) and preferred terms using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). 
 


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Treatment-emergent AEs (TEAEs) are undesirable experiences, signs, or symptoms that 
begin or worsen in intensity or frequency at the time of or after the administration of 
study drug, and prior to the end of observation windows defined as following: the TEAE 
window for Flortaucipir will be from injection of Flortaucipir until 48 hours post 
Flortaucipir injection.  For florbetapir F 18, the TEAE window will be from injection of 
florbetapir F 18 until 48 hours post florbetapir injection. The injection of florbatapir and 
flortaucipir dosages will be at least 48 hours apart. Trial-emergent AEs are undesirable 
experiences, signs or symptoms happened after subjects’ enrollment to this trial but 
before the exploratory phase imaging sessions, or between the florbetapir and flortaucipir 
sessions but outside the 48 hour windows following the administrating of Flortaucipir or 
Florbetapir F 18 injection. These will be recorded on the AE page of the electronic case 
report form (eCRF). Any event happens during study visits will be captured in medical 
history form, unless the site physicians consider they are related to the study drugs. 
 
Serious AEs (SAEs) are events that result in one of the following outcomes or constitute 
one of the following events: 
• Death 
• Initial or prolonged hospitalization (other than that required by protocol; “social 
hospitalization” or any hospitalization for non-medical reasons does not constitute 
an SAE 
• A life-threatening experience (that is, immediate risk of dying) 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Considered significant by the investigator for any other reason 
 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
 
For the summarization of TEAEs by seriousness, events recorded with missing 
seriousness will be summarized as serious. 
 
Investigators will be instructed to report their assessment of the potential relatedness of 
each AE to protocol procedure, concomitant medication, and/or investigational product. 
The assessment of the relationship of an AE to the administration of the investigational 
product is a clinical decision based on all available information at the time of the 
completion of the eCRF. For the summarization of TEAEs by relationship to study drug 
or protocol procedure, events recorded with missing relationship will be summarized as 
Related. 
 


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In addition to assessing the relationship of the administration of the investigational 
product to AEs, an assessment is required of the severity of the event. The following 
classifications should be used: 
 
Mild: 
A mild AE is an AE, usually transient in nature and generally not interfering with normal 
activities. 
 
Moderate: 
A moderate AE is an AE that is sufficiently discomforting to interfere with normal 
activities. 
 
Severe: 
A severe AE is an AE that incapacitates the subject and prevents normal activities. Note 
that a severe event is not necessarily a serious event. Nor must a serious event necessarily 
be severe. 
 
For the summarization of TEAEs by intensity, events recorded with missing intensity will 
be summarized as Severe. 
 
6.6.3 Clinical Laboratory Evaluations 
 
Clinical laboratory evaluation will be performed at screening, prior to administration of 
Flortaucipir injection, and after completion of Flortaucipir imaging for each of the scan 
sessions, including the makeup scan session if the original planned scan session fail. 
Tests will include: 
• Hematology (5 mL EDTA): hemoglobin, hematocrit, RBC, WBC, MCH, MCHC, 
neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, platelets, 
morphology, MCV, and RBC morphology. 
• Chemistry (6 mL blood): total bilirubin, alkaline phosphatase, ALT (SGPT), AST 
(SGOT), urea nitrogen, creatinine, glucose, uric acid, calcium, phosphorus, total 
protein, albumin, total cholesterol, triglycerides, sodium, potassium, bicarbonate, 
chloride, magnesium, globulin, GGT. 
• Urinalysis (10 mL, urine): Samples will be used to assess glucose, RBC, WBC, 
specific gravity, pH, protein, ketones, urobilinogen, blood, nitrite, microscopic, 
color, bilirubin, casts, epithelial cells, leukocyte, esterase, and bacteria. 
• Serum beta hCG, qualitative: performed at screening for females of childbearing 
potential who are not surgically sterile. A serum pregnancy test may also be 
obtained prior to injection at the Imaging Visit if required by the local site. 
• Urine beta hCG:  performed at the imaging visit(s) prior to injection for females 
of childbearing potential (defined as pre-menopausal, less than 2 years post-
menopausal or not surgically sterile). 


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• ApoE Genotyping (10ml, blood): will be performed at the initial Flortaucipir 
imaging session for those subjects whose ApoE results are unknown. 
 
Baseline for clinical laboratory evaluations will be calculated as described in section 6.3.  
Change from baseline for continuous post-baseline assessments will be calculated as the 
result at the visit minus the baseline value.  For applicable laboratory tests, laboratory 
values will be defined as low, normal, or high relative to the normal reference ranges for 
each subject’s age and sex.  Criteria for potentially clinically significant laboratory results 
are defined in Appendix 1 of the SAP.  A result will be considered potentially clinically 
significant if the result occurs post-baseline and no test results at or prior to baseline for 
the parameter in question meet the same criteria for potential clinical significance. 
 
6.6.4 Other Observations Related to Safety 
 
6.6.4.1 Vital Signs 
 
Vital signs (pulse rate, respiratory rate, and supine blood pressure) will be taken at the 
following time points:  
• Screening visit  
• Florbetapir F18 Imaging Day  
• immediately prior to injection of florbetapir F 18  
• Flortaucipir Imaging Day  
• Immediately prior to the administration of Flortaucipir injection  
• Within 5 minutes after completion of injection of Flortaucipir injection  
• After the completion of imaging prior to discharge  
 
Temperature will be obtained at the following time points:  
• Flortaucipir Imaging Day  
• Immediately prior to the administration of Flortaucipir injection  
• After the completion of imaging prior to discharge  
 
Baseline for vital signs will be calculated as described in Section 6.3.  Change from 
baseline for post-baseline assessments will be calculated as the result at the visit minus 
the baseline value.  Criteria for potentially clinically significant vital sign results are 
defined in Appendix 2 of this SAP.  A measurement will be considered potentially 
clinically significant if the measurement occurs post-baseline and no measurements at or 
prior to baseline for the parameter in question meet the same criteria for potential clinical 
significance. 
 
 


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6.6.4.2 Electrocardiogram (ECG) 
 
A resting 12-lead ECG will be recorded at screening. At the Flortaucipir imaging visits 
the ECGs will be taken at the following time points:  
• Two ECGs will be taken at approximately 5 minutes apart immediately prior 
(within approximately 10 minutes) to Flortaucipir injection administration.  
• One ECG will be taken immediately (within approximately five minutes) after 
completion of Flortaucipir injection.  
• One ECG will be taken after completion of the PET scan prior to discharge.  
 
Baseline for ECGs will be calculated as described in section 6.3.  Change from baseline 
for post-baseline assessments will be calculated as the result at the visit minus the 
baseline value.  Criteria for potentially clinically significant ECG results are defined in 
Appendix 2 of this SAP.  A result will be considered potentially clinically significant if 
the result occurs post-baseline and the baseline result for the parameter in question does 
not meet the same criteria for potential clinical significance. 
 
6.7 Pharmacodynamics Parameters 
 
No pharmacodynamics parameters will be collected during this study. 
 
7 STATISTICAL METHODS 
 
7.1 General Methodology 
 
All values will be summarized by the four diagnostic groups: young cognitively normal 
(YCN) subjects (healthy volunteers >=20 years of age and <= 40 years of age), old 
cognitively normal (OCN) subjects (healthy volunteers >=50 years of age), patients with 
AD, patients with MCI, and overall. Frequency distributions including counts and 
percentages will be included for all categorical outcomes. Summary statistics including 
mean, standard deviation, median, minimum and maximum values will be presented for 
all continuous outcomes. Unless otherwise specified, hypothesis testing will be two-sided 
with type I error rate of 0.05. 
 
All statistical analyses will be performed using SAS® version 9.3 or higher.  
 
7.2 Adjustments for Covariates 
 
Not applicable for the primary analyses. 
 
7.3 Handling of Dropouts or Missing Data 
 
Dropout subjects will not be replaced in this study.  For situations with no rules for 
handling missing data, the default will be no imputation. 


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A likelihood-based mixed effects model for repeated measures will be used to handle 
missing longitudinal follow up cognitive measurements, or flortaucipir SUVr data.  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.  
 
 
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 
 
This study will be conducted in approximately 30 centers. The data from all centers will 
be pooled. The pooled data will be analyzed and presented. 
   
7.6 
Multiple Comparisons/Multiplicity 
 
For the exploratory (first) phase analysis, no adjustment for multiplicity will be 
performed when analyzing the differences among diagnostic groups.   
 
 
7.7 
Active-Control Studies Intended to Show Equivalence 
 
Not applicable to this study. 
 
7.8 
Examination of Subgroups 
 
Flortaucipir SUVr values will be further investigated stratified by age group (>=75 vs. 
<75). 
 
8 
STATISTICAL ANALYSIS 
 
8.1 
Disposition of Subjects 
 
The number and percentage of subjects who were treated, who completed the study, and 
who discontinued from the study, as well as the reasons for discontinuing, will be 


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summarized. Subjects will be considered to have completed the study if they have 
completed all three flortaucipir imaging sessions and clinical visits. 
 
Data on screening failures (subjects who signed informed consent but were not entered 
into the trial) were not collected on the CRF, are not included in the database and will not 
be presented. 
 
8.2 
Protocol Deviations/Violations 
 
Subjects who entered the study even though they did not satisfy one or more of the 
inclusion/exclusion criteria will be listed.  Deviations/violations from the protocol will be 
documented, the Avid/contract research organization (CRO) monitor will then be 
informed and a course of action will be agreed upon. 
 
8.3 
Analysis Populations 
 
8.3.1 Enrolled Population 
 
The enrolled population will consist of all subjects who signed inform consent and have 
data captured in the clinical database.  Disposition information will be summarized using 
the enrolled population. 
 
8.3.2 Safety Population 
 
The safety population will consist of all subjects that received either an injection of 
flortaucipir or florbetapir dosage. The summary of safety will be defined according to the 
study drugs subjects received: for the safety summary of flortaucipir scans, the safety 
population consist of all subjects that received an injection of Flortaucipir;for the safety 
summary of florbetapir scan, the safety population is defined as all subjects that received 
and injection of Florbetapir injection.  
 
All baseline and safety endpoints will be summarized and efficacy endpoints listed using 
the safety population. 
 
8.3.3 Efficacy Population 
 
The efficacy population will include all subjects from safety population that received an 
injection of Flortaucipir plus valid flortaucipir imaging data available (either visual reads 
or SUVr).  
 
All analyses involving amyloid imaging outcomes will be based on the efficacy 
population. For flortaucipir SUVr related analyses, any scans deemed to be 
unquantifiable due to technical reasons will be excluded from analyses. 


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8.4 
Demographic and Other Baseline Characteristics 
 
All baseline summaries will be based on the safety population. 
 
Frequency distributions and summary statistics for demographic and baseline variables 
will be presented by diagnostic groups, and for all subjects combined. Key demographic 
and baseline characteristics to be summarized include: age, gender, race, ethnicity, 
height, weight, BMI, education, alcohol history, recreational drug use history, smoking 
history, medical history, family disease history, cognitive assessments, worst brain injury 
history, physical examination, and neurological examination.  
 
All demographic and baseline characteristics data will be presented in listings. 
 
8.5 
Prior and Concomitant Therapy  
 
A current version of the World Health Organization (WHO) Drug Dictionary will be used 
to classify medications by preferred term and WHO Anatomical Therapeutic Chemical 
(ATC) classification of ingredients. ATC classification level 3 will be used. If level 3 is 
missing, then level 2 will be used. If level 2 is missing, then level 1 will be used. Any 
medication given before the day of administration of study drug is considered a prior 
medication. Any medication given on or after the day of administration of study drug is 
considered a concomitant medication. A medication can be considered both prior and 
concomitant. The most conservative algorithms will be implemented in case a medication 
has partial start/stop date information. 
 
Descriptive statistics, such as frequency counts and percentages will be provided to 
summarize the use of medications other than the study drug reported throughout the 
study.  The number and percentage of subjects who received other treatment will be 
shown by WHO classification of ingredients and by preferred term.  No statistical tests 
will be performed on prior and concomitant medications.  All prior and concomitant 
medications data will be presented in listings. 
 
8.6 
Analysis of Efficacy Parameters 
 
8.6.1 Exploratory Phase, Cross-sectional Analysis 
 
8.6.1.1 Analysis of Primary Efficacy Variable 
 
Quantitative Assessment of Images 
 
 
 
A one-way ANOVA will be used to compare the mean flortaucipir SUVr values between 
diagnostic groups (AD, MCI, and OCN). The F test in the corresponding ANOVA model 


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will used to test for the difference in SUVr values among all diagnostic groups while 
contrasts within the ANOVA model will be used to perform pairwise comparisons 
between diagnostic groups.  
 
This analysis will be performed on the global cortical average SUVr (ie, MUBADA 
SUVr) as well as the SUVr for each brain region.  
 
Due to the obvious age difference, YCN group will not be included in the analysis as 
described above. A two sample t-test between OCN and YCN will be performed instead, 
to evaluate the differences between OCN and YCN subjects. 
 
An analysis of covariance (ANCOVA) will be used to compare the mean SUVr values 
between diagnostic groups (AD, MCI, and OCN) by amyloid beta status (AB+,  AB-), 
and compare mean SUVr values between amyloid beta status by diagnosis groups while 
adjusting for age as a continuous covariate.  The least square mean estimates will be 
provided, and proper contrast will be set to compare the LS mean differences within the 
ANCOVA models. This analysis will be performed on the global cortical average SUVr 
(MUBADA SUVr) as well as the SUVr for each brain region.  
 
Descriptive statistics for overall SUVr values for each brain region will be displayed for 
each diagnostic group as well as by Amyloid beta status (AB+, AB-). 
 
 
Scatter plots will be generated for Flortaucipir SUVr versus diagnostic groups (AD, MCI, 
OCN, and YCN) and Amyloid Beta status (AB+/AB-) across all subjects.  
 
Qualitative Assessment of Images 
 
Flortaucipir scan visual interpretation results, as explained in section 6.4.1.2 will be 
summarized by clinical diagnosis and by amyloid status as decided by visual 
interpretation of florbetapir scans. Except for YCN, the overall association of frequency 
by diagnosis groups and by amyloid status will be tested with a Mantel-Haenszel test. 
Pearson’s Chi-squared test, or Fisher’s exact test when appropriate, will be used to test 
for the general association of tau scan interpretation results by amyloid status, and tau 
scan interpretation results by clinical diagnosis respectively.  
 
     
8.6.1.2 Analysis of Second Efficacy Variable 
 
Age correlation with SUVr 
   
Pearson’s correlation coefficient will be used to determine the correlation of age with 
mean SUVr from cognitively healthy individuals. 


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Descriptive statistics will be performed according to cognitively healthy subject category 
and by the age groups. Subjects are divided to the age group of: YCN 20-40, OCN 50-59, 
OCN 60-69, OCN 70-79, and OCN >=80. 
 
Box plot (including individual data points plotted) for overall SUVr will be generated for 
all cognitively healthy subject categories by age group: YCN 20-40, OCN 50-59, OCN 
60-69, OCN 70-79, and OCN >=80. 
 
 
 
8.6.1.3 Exploratory Analyses 
 
8.6.1.3.1 Correlations between Flortaucipir uptake and cognitive impairment 
 
This analysis will be limited to the subjects with an amyloid beta positive (AB+) status. 
Partial Pearson’s correlation analysis adjusted for age will be conducted.  
 
The correlation analyses will be conducted between these measurements: baseline 
MUBADA SUVr versus baseline ADAS total, MMSE, and FAQ scores. 
 
To visually explore the cognitive domain relationship with flortaucipir uptake, scatter 
plots will be generated between the variables as described above.  
 
8.6.1.3.2 Correlations between Flortaucipir SUVr uptake and Biomarkers of 
neurodegeneration and neurological disease. 
          
Correlations analysis will be used to evaluate the association between baseline 
flortaucipir MUBADA SUVr results and florbetapir SUVr, with  Pearson’s correlation. 
Correlations will be completed using all subjects except for YCN.  
 
Scatter plot between MUBADA SUVr and florbetapir SUVr will be created to visually 
display the relationship, with diagnosis shape coded. 
 
Correlations will be used to evaluate the association between flortaucipir SUVr results 
and the atrophy assessed by volumetric MRI (whole brain, volume, total ventricle size, 
total gray volume). Correlations will be completed for AD/MCI subjects. 
 
The relationship between genetic markers including ApoE and MAPT will be assessed 
using ANCOVA models. The analysis will include all subjects except for YCN. For the 
ANCOVA model, MUBADA SUVr values will be used as dependent variable, and 
independent variables include ApoE E4 status (carriers vs. non-carries), Amyloid status 
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AB+,  AB-, E4 carriers, non E4 carriers,  AB+ E4 carriers,  AB+ non E4 carriers,  AB- E4 
carriers,  AB- non E4 carriers will be calculated through proper contrast set up, along with 
the 95% CI.  
 
Scatter plot of MUBADA SUVr values, overlay with box plots by MAPT genotypes 
(H1/H1, H1/H2 and H2/H2) will be used to display the tau load level by MAPT 
genotypes. If there are notable differences across MAPT genotypes, further analyses will 
be carry out accordingly, which will not be detailed in this SAP.  
 
8.6.1.3.3 Muti-variate models to explore possible factors for cognitive impairments  
 
To further explore the possible factors for cognitive impairment, multivariate models will 
be conducted.  The following variables will be used as dependent variables for each of 
these models: ADAS Cog 11, MMSE, and FAQ. Each of these models will include these 
variables as independent variables: baseline age, ANART, MUBADA SUVr, florbetapir 
SUVr, whole brain volume, and ApoE E4 status.  Stepwise selection technique will be 
used to build the most parsimonious model, with entry and stay selection p-value set at 
0.2. The analyses will be run separately with all subjects except for YCN, and with AB+ 
subjects only.  
 
8.6.2 Exploratory Phase, Longitudinal Analysis 
 
8.6.2.1 Analysis of Primary Efficacy Variable 
 
Mixed Model Repeated Measures for Evaluation of Flortaucipir SUVr over time  
 
 
 
Descriptive summary statistics for Flortaucipir SUVr will be provided by amyloid beta 
status (AB+, AB-) at baseline, 9 month, and 18 month across all subjects.  
 
Change from baseline for Flortaucipir SUVr will be estimated using repeated measures 
models for all subjects except for YCN subjects (who do not have follow-up flortaucipir 
scans at 9 months and 18 month).  Due to the concern of unequal variance for flortaucipir 
SUVr changes by amyloid status, the model will be run for AB+ subjects only, and for 
AB- subjects only separately. For this analysis, time will be considered to be categorical 
variable.  A mixed model will be run with MUBADA SUVr change from baseline as 
dependent variable, baseline MUBADA SUVr and age, and visit as independent 
variables.  In order to appropriately model the within subject covariance, the covariance 
structure must be pre-specified. Each model should be fit using the unstructured 
covariance structure. If this structure does not converge, covariance structure in the order 
as auto-regressive, Toeplitz structures and the compound symmetry will be used.  
 
The LS means of MUBADA SUVr change at each visit from the model will be displayed 
along with the corresponding 95% confidence intervals. In addition, p-values will be 


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provided for testing that whether or not the LS means at each visit is significantly 
different than zero. 
 
Spaghetti plots will be generated to display the relationship of Flortaucipir SUVr change 
across the follow up visits, by each subject.  The plot will use MUBADA SUVr as y-axis, 
subjects’ age at each visit as x-axis, and color code according to amyloid status.  
 
Explore Factors Associated with Flortaucipir SUVr Change using Multivariate 
Analysis  
 
The analysis will be completed for AB+ subjects. A multivariate step wise selection 
regression model will be used to explore factors associated with the change in 
Flortaucipir SUVr (MUBADA). The dependent variable will be Flortaucipir SUVr 
(MUBADA) change at 18 months. The independent variables include baseline 
information such as age, cognitive assessments (MMSE), APOE4 status (carrier or non-
carrier), florbetapir SUVr, and flortaucipir MUBADA SUVr. The significance level of 
entry and stay in the model will be both set as 0.2. For each variable in the final model, 
the parameter estimate, SE, 95% CI and associated p-value will be reported.  
 
8.6.2.2  Analysis of Second Efficacy Variable 
 
Not applicable for this section to this study. 
 
8.6.2.3  Analysis of additional Efficacy Variable 
 
Not applicable to longitudinal part of this study. 
 
8.6.2.4 Exploratory Analyses 
 
8.6.2.4.1 Mixed Model Repeated Measures for Comparison of Psychometric Assessment 
over time between diagnostic groups   
 
Descriptive summary statistics for each cognitive scale (ADAS, MMSE, FAQ, and 
ADAS+FAQ composite) at baseline, 9 month, and 18 month will be summarized by 
subjects’ tau and/or amyloid status of interest (details below). The change from baseline 
to 9 month and 18 month will be summarized in the same corresponding table. 
 
Change from baseline for each psychometric assessment will be analyzed using mixed 
model with repeated measures (MMRM) for subjects who have follow-up information for 
18 months (baseline, 9 months, and/or 18 month).   
 
The MMRM model will be run to include MCI/AD subjects with these tau and/or 
amyloid status classified as below respectively: 


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 1: Tau visual reads as AD++ vs. non-AD++ ; 
 2: Three level categorical variable by combining tau and amyloid status:   
a. AB+ AD++  (AB+ and tau pattern likely to progress) 
b. AB+ non-AD++ (AB+ and tau AD pattern but not likely to progress, i.e., 
AB+ AD+ subjects but not AD++, or AB+ AD- ) 
c. AB-  
 
For this analysis, time will be considered to be Categorical variable.  A mixed model will 
be used with psychometric score change at each visit as dependent variable. Independent 
variables include categorical variable baseline tau (AD++ vs non-AD++) and/or amyloid 
status by visual interpretation (category a, b, c defined above in this section), visit and 
interaction of tau status and visit, and baseline age, ANART score and psychometric 
score as continuous covariates.  In order to appropriately model the within subject 
covariance, the covariance structure must be pre-specified. Each model should be fit 
using the unstructured covariance structure. If this structure does not converge, then 
covariance structure in the order of the auto-regressive, and toeplitz structures and the 
compound symmetry will be used.  
 
The least squares (LS) mean from the model will be displayed separately for each Tau 
status and/ amyloid status by visual interpretation with the corresponding 95% 
confidence intervals and p-values testing that the LS mean is significantly different 
between any of the two categories.  
 
In addition, LS means difference between any of the two categories will be presented 
with the 95% confidence interval and p-value testing that the difference is significantly 
different than zero. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom.  
 
The LS means at each visit from the models described above will be displayed by line 
graphs, by the tau and/or amyloid status.  
 
CDR-SB scales were only collected at 9 and 18 months. Thus an ANCOVA model will 
be applied to explore the relationship between CDR-SB change and baseline tau/amyloid 
status. The model will use CDR-SB change from 9 month  as dependent variable, and 
independent variable will include categorical variable baseline tau and/or amyloid status 
by visual interpretation (as described above), and continuous covariates including 
baseline age, ANART score and psychometric score. LS means and difference in LS 
means for the tau/amyloid status will be calculated through proper contrast.  
 
 
To visually display the change of cognition/function assessments by subjects’ tau status, 
the follow plots will be made: cumulative frequency of each score change at 18 months 
as y-axis, score change at 18 months as x-axis.  The data points should be connected, and 


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displayed according to tau status (AD++ vs. non-AD++, or AB+AD++, AB+ non-AD++, 
and AB-). The plots will be completed for ADAS-Cog 11, MMSE, FAQ, ADAS+FAQ 
and CDR.  
 
 
  
8.6.2.4.2 Rate Ratio of Clinically Meaningful Changes by Baseline Tau Scan Status  
 
The analyses for clinically meaningful changes will be restricted to AD/MCI subjects 
only. 
  
Clinically meaningful changes assessed by psychometric scores are defined in section 
6.4.2.3.1 
 
For each of the categorized clinically meaningful changes (event) except for CDR global 
score change, a Poisson regression model will be applied. The model will have these 
defined event as dependent variable respectively, and the independent variables will 
include tau status at baseline (AD++ vs. non-AD++), visit and the interaction of tau status 
and visit as a categorical variable, and continuous covariates that include baseline 
psychometric score, age, and ANART.  
 
At each visit, person-year will be calculated for each subjects, as time from baseline to 
first event, or time from baseline to visit date or end of study if no event for the subject.  
 
General estimating equation (GEE) technique will be used to adjust for the intra subject 
correlation. The variance-covariance matrix is pre-specified: each model should be fit 
using the unstructured covariance structure. If this structure does not converge, the 
exchangeable, auto-regressive, and m-dependent structures will be fit and the model with 
the lowest BIC value will be selected to use. The rate ratio estimated at 18 month visit 
will be reported along with 95% confidence interval.   
 
8.6.2.4.3 Association of CDR Global Change at 18 Months with Tau Status 
   
The association of change in CDR global score at 18 months by tau status (AD++ vs. 
non-AD++) will be assessed using a Cochran-Armitage trend test. The analysis will be 
performed with MCI/AD subjects. Frequency table, along with p-values for the trend test 
will be provided. 
  
8.6.2.4.4 Diagnostic Performance of Baseline Tau Status in Predicting Clinical 
Meaningful Changes at 18 Months 
 
This analyses will be restricted to AD/MCI subjects only. 
 


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For each cognitive assessment of cognitive impairment and TAU status, a 2x2 table will 
be generated and the appropriated diagnostic performance parameters determined.  
 
CMC+ is defined as the clinically meaningful changes assessed by psychometric scores 
are defined in section 6.4.2.3.1. CMC- are those patient with related data but not meet the 
CMC+ definition. 
 
 
Clinical meaningful 
changes 
 CMC+
CMC-
AD++
  A
   B
Non-
AD++ 
   C
  D
 
Sensitivity is defined as the number of Tau+ subjects who are cognitively impaired 
divided by the total number of subject with cognitive impairment.: A/(A+C) 
 
Specificity is defined as the number of Tau- subjects who are not cognitively impaired 
divided by the total number of subjects without cognitive impairment. : D/(B+D) 
 
Accuracy is defined as the number of subjects with cognitive impairment who are Tau+ 
and the number of subjects without cognitive impairment who are Tau- divided by the 
total number of patients. : (A+D)/(A+B+C+D) 
 
Positive predictive Value is defined as the number of Tau+ subjects who are cognitively 
impaired divided by the total number of subjects who tested Tau+: A/(A+B) 
 
Negative predictive value is defined as the number of Tau- subjects who are cognitively 
not impaired divided by the total number of subjects who test Tau-: D /(C+D) 
 
Positive Likelihood Ratio (LR+) for positive result shows the odds of the cognitive 
impairment increases when TAU+:  Sensitivity/ (1-Specificity) 
 
Negative Likelihood Ratio (LR-) for negative result shows the odds of the cognitive 
impairment decreases when TAU- : (1-Sensitivity) /Specificity 
 


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Relative risk: (A/(A+B))/(C/(C+D)) 
 
The analyses from 8.6.4.2.1 – 8.6.2.4.2, and 8.6.2.4.4 will be repeated with subjects with 
AD/MCI diagnosis and baseline MMSE 20 -27, which is similar to the target enrolled 
population in confirmatory cohort. 
 
8.6.2.4.5 Muti-variate models to explore possible factors for cognitive impairments 
changes  
 
The analysis will be completed for AB+ subjects. A multivariate step wise selection 
regression model will be used to explore factors associated with the change in 
psychometric score change at 18 months. The dependent variable will be each of these 
psychometric score change at 18 months respectively: ADAS Cog 11, MMSE, and FAQ. 
The independent variables include baseline information such as psychometric score 
(baseline ADAS Cog-11, MMSE, or FAQ), age, ANART score, APOE4 status (carrier or 
non-carrier), florbetapir SUVr, and flortaucipir MUBADA SUVr. The significance level 
of entry and stay in the model will be both set as 0.2. For each variable in the final model, 
the parameter estimate, SE, 95% CI and associated p-value will be reported.  
 
Scatter plots will be generated for the following scenarios:  
 
1. Change of ADAS score at 18 month versus Flortaucipir MUBADA SUVr 
score at baseline by each diagnostic groups. 
2. Change of MMSE score at 18 month versus Flortaucipir MUBADA SUVr 
score at baseline by each diagnostic groups. 
3. Change of FAQ score at 9 month or 18 month versus Flortaucipir SUVr score 
at baseline by each diagnostic groups. 
 
 
8.7 
Analysis of Safety 
 
 
8.7.1 Extent of Exposure and Compliance to Study Treatment 
 
The total dose administered (mCi) of Flortaucipir and florbetapir F 18 will be 
summarized using descriptive statistics (n, mean, SD, median, min, max, 25th, and 75th 
pct).  Flortaucipir exposures will be summarized by each of the scans and all exposure 
data will be presented in listings. 
 
Because this is a study with only one bolus of study medication per imaging visit, 
compliance will not be summarized.   
 


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8.7.2 Adverse Events 
 
All AE summaries will be based on the set of TEAEs only.  TEAEs will be summarized 
alphabetically by SOC and preferred term; a subject will only be counted once per SOC 
and once per preferred term.  Subject counts and percentages will be presented for the 
following summaries: 
 
1. All TEAEs by system organ class (SOC) and preferred term; 
2. All TEAEs by preferred term (in order of descending frequency); 
3. All TEAEs by relationship to study drug, SOC, and preferred term; 
4. All TEAEs by relationship to protocol procedure, SOC and preferred term; 
5. All TEAEs by severity, SOC and preferred term 
 
For the summary of TEAEs by severity, if a subject has multiple events occurring in the 
same SOC or same preferred term, the event with the highest severity will be counted.   
 
TEAEs by relationship to study drug and protocol procedure will be summarized as 
Related vs. Not Related.  If a subject has multiple events occurring in the same SOC or 
same preferred term, the related event will be summarized.   
 
Listings will be presented by subject for all TEAEs as well as for Serious TEAEs, TEAEs 
associated with death, and TEAEs associated with study discontinuation. Listings will 
also present adverse events relative to the first dose and relative to the Flortaucipir 
injection. 


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8.7.3 Clinical Laboratory Evaluations 
 
Laboratory test values from the Flortaucipir imaging session at each time point and for 
change from baseline to end of study will be displayed using summary statistics (n, mean, 
SD, median, min, max, 25th pct, and 75th pct).  This will be calculated within each 
diagnostic group and on all subjects.  Potentially clinically significant laboratory results 
will be displayed using frequency and percentage of subjects with the result. 
 
All clinical laboratory data will be presented in listings.  Within each listing, laboratory 
values outside the normal ranges will be flagged as either high (H) or low (L).  In 
addition, shift tables will be presented to display the shift in the normal range categories 
(L, normal (N), H) from baseline to the final evaluation.  Baseline is defined in section 
6.3.   
 
8.7.4 Other Observations Related to Safety 
 
8.7.4.1 Vital Signs 
 
Observed vital sign measurements as well as changes from baseline will be summarized 
using descriptive statistics (n, mean, SD, median, min, max, 25th pct, and 75th pct) for 
each time point across all subjects and by diagnostic group. Clinically significant vital 
signs will be highlighted. 
 
All vital signs data will be presented in listings.  Baseline is defined in section 6.3.   
 
8.7.4.2 Electrocardiogram 
 
The ECG measures (QTc-B, QTc-F, QT, RR, PR, and QRS) from the Flortaucipir imaging 
session will be listed and summarized with descriptive statistics (n, mean, SD, median, 
min, max, 25th pct, 75th pct) at each time point by diagnostic group. At each post-baseline 
assessment, a paired t-test will be used to test the hypothesis that the change from 
baseline is not statistically different than zero.  This will be calculated within each 
diagnostic group and on all subjects.  Potentially clinically significant ECG results will be 
displayed using frequency and percentage of subjects with the result. 
 
 
8.8 
Pharmacodynamics 
 
No pharmacodynamics analyses are planned for this study. 
 
9 
COMPUTER SOFTWARE 
 


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All analyses will be performed by Chiltern using Version 9.3 or later of SAS software.  
All summary tables and data listings will be prepared utilizing SAS software. 
 
For continuous variables, descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum, maximum, 25th pct, and 75
th pct) will be generated.  
The standard operating procedures (SOPs) of Chiltern will be followed in the creation 
and quality control of all data displays and analyses. 
 
 
10 REFERENCES 
 
Albert, M. S., DeKosky, S. T., Dickson, D., et al. “The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging and Alzheimer’s Association workgroup.” The Alzheimer’s Association. Alzheimer’s 
and Dementia, 1-10, 2011.  
 
Burack, M.A., Hartlein, J., Flores, H.P., Taylor-Reinwald, L., Perlmutter, J.S., Cairns, N.J. 
“In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia”. 
Neurology. 2010;74(1):77-84.  
 
Chien, D.T., Bahri, S., Szardenings, A.K., Walsh, J.C., Mu, F., Su, M.Y., Shankle, W.R., 
Elizarov, A., Kolb, H.C., “Early clinical PET imaging results with the novel PHF-tau 
radioligand [18F]-T807.” J Alzheimers Dis, 2013 Jan 1l34(2):467-68  
 
Clark, C.M., Pontecorvo, M.J., Beach, T.G., Bedell, B.J., Coleman, R.E., Doraiswamty, 
P.M., Fleisher, A.S., Reiman, P.E.M., Sabbagh, M.N., Sadowsky, C.H., Schneider, J.A., 
Arora, A., Carpenter, A.P., Flitter. M.L., Joshi, A.D., Krautkramer, M.J., Lu, M., Mintun, 
M.A., Skovronsky, D.M. “Florbetapir PET for Detection of Amyloid Neuritic Plaques, 
Comparison to Neuropathology at Autopsy: A Prospective Cohort Study.” The Lancet 
Neurology, 2012; 11: 669–78.  
 
Clark, C.M., Schneider, J.A., Bedell, B.J., et al. “Use of florbetapir-PET for imaging beta-
amyloid pathology”. JAMA. 2011;305(3):275-283.  
 
Dickson, T.C., Saunder, H.L., Vickers, J.C. “Relationship between apolipoprotein E and the 
amyloid deposits and dystrophic neuritis of Alzheimer’s disease.” Neuropathol Appl 
Neurobiol. 1997; (23):483-491.  
 
Dubois, B., Feldman, H.H., Jacova, C., et al. “Research criteria for the diagnosis of 
Alzheimer’s disease: revising the NINCDS-ADRDA criteria.” Lancet Neurol. 6:734-46 
Review, 2007.  
 
Dubois B., Feldman H.H., Jacova C., et al. “Revising the definition of Alzheimer
's disease: a 
new lexicon”. Lancet Neurol. 2010;9(11):1118-1127.  


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CONFIDENTIAL 
 
 
Duyckaerts, C., Brion, J.P., Hauw, J.J., Flament-Durand, J. “Quantitative assessment of the 
density of neurofibrillary tangles and senile plaques in senile dementia of the Alzheimer type. 
Comparison of immunocytochemistry with a specific antibody and Bodian’s protargol 
method.” Acta Neuropathol. 1987;(7):129-135.  
 
Folstein, M.R., Folstein, S.E., and McHugh, P.R. “Mini Mental State: A practical method for 
grading the cognitive status of patients for the clinician.” Journal of Psychiatric Research, 12: 
189-198, 1975.  
 
Hyman, B.T., Phelps, C.H., Beach, T.G., et al. “National Institute on Aging-Alzheimer's 
Association guidelines for the neuropathologic assessment of Alzheimer's disease”. 
Alzheimers Dement. 2012;8(1):1-13. 
 
Jack, C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., Petersen, 
R.C., Trojanowski, J.Q. “Hypothetical model of dynamic biomarkers of the Alzheimer’s 
pathological cascade.” Lancet Neurol 9:119-128, 2010.  
 
Kantarci, K., Lowe, V.J., Boeve, B.F., Weigand, S.D., Senjem, M.L., Przybelski, S.A., et al. 
“Multimodality imaging characteristics of dementia with Lewy bodies”. Neurobiol Aging 
2011: Oct 20. [Epub ahead of print].  
 
Leinonen, V., Alafuzoff, I., Aalto S., Suotunen, T., Savolainen, S., Nagren, K., et al. 
“Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron 
emission tomography with carbon 11-labeled Pittsburgh Compound B”. Arch Neurol 2008; 
65(10):1304–1309.  
 
McKhann, G.M., Knopman, D.S., Chertkow, H., et al. “The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease”. Alzheimers 
Dement. May 2011;7(3):263-269.  
 
Price, J.L., Morris, J.C. ”Tangles and plaques in nondemented aging and “preclinical” 
Alzheimer’s disease.” Ann Neurol 45:358–368, 1999.  
 
Sojkova J., Driscoll I., Iacono D., Zhou Y., Codispoti K., Kraut M., et al. “In vivo fibrillar 
beta-amyloid detected using [11C] PiB positron emission tomography and neuropathologic 
assessment in older adults”. Arch Neurol 2011;68(2):232–240.  
 
Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., Iwatsubo, 
T., Jack, C.R., Jr., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, C.C., Siemers, 
E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, M., Wagster, M.V.,  


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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.  
 
Wechsler Adult Intelligence ScaleFRevised. San Antonio, TX: Psychological Corporation, 
1981.  
 
Wong, D.F., Rosenberg, P.B., Zhou, Y., et al. “In vivo imaging of amyloid deposition in 
Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)”. J Nucl 
Med. 2010;51(6):913-920.  
 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent for 
Alzheimer’s disease,” Alzheimers Dement. 2013, 1-11 


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11 APPENDICES 
11.1 Appendix 1 – Laboratory Results – Potentially Clinically Significant Criteria 
Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
Unit 
Low  
High 
SI 
Unit 
Conversion  
Factor 
SI 
Low 
SI 
High 
Hematology 
 
 
 
 
 
 
 
 
Hematocrit 
HCT  
% 
Male ≤ 
37% 
Female 
≤ 32% 
NA 
L/L 
0.01 
Male ≤ 
0.37 
Female 
≤ 0.32 
NA 
Hemoglobin 
Hgb  
g/dL 
Male ≤ 
11.5 
Female 
≤ 9.5 
NA 
g/L 
10 
Male ≤ 
115 
Female 
≤ 95 
NA 
White blood cell 
WBC  
10^3/mm3 
≤2.8 
≥16.0 
GI/L 
1 
≤2.8 
≥16.0 
Platelets 
PLT  
10^3/mm3 
≤ 75 
≥ 700 
GI/L 
1 
≤ 75 
≥ 700 
Mean corpuscular 
hemoglobin 
MCH  
pg/cell  
NA 
NA 
pg/cell  
1 
NA 
NA 
Mean corpuscular 
hemoglobin 
concentration 
MCHC  
g/dL 
NA 
NA 
g/L 
10 
NA 
NA 
Mean corpuscular 
volume 
MCV  
fl 
NA 
NA 
fl 
1 
NA 
NA 
Red blood cell 
RBC  
10^6/mm3 
≤ 3.5 
NA 
TI/L 
1 
≤ 3.5 
NA 
 
 
 
 
 
 
 
 
 
Differential 
 
 
 
 
 
 
 
 
Bands or (Band 
neutrophil (stab)) 
BAND  
% 
NA 
≥ 10% 
% 
1 
NA 
≥ 10% 
Basophil (absolute)  
Baso.  
10^3/mm3  
NA 
≥ 0.4 
GI/L 
1 
NA 
≥ 0.4 
Basophil (%) 
Baso.  
% 
NA 
≥ 5% 
% 
1 
NA 
≥ 5% 
Lymphocytes 
(absolute) 
lymphs  
10^3/mm3 
≤ 0.5 
≥ 4.5 
GI/L 
1 
≤ 0.5 
≥ 4.5 
Lymphocytes (%)  
lymphs  
% 
≤ 10% 
≥ 80% 
% 
1 
≤ 10% 
≥ 80% 


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Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
Unit 
Low  
High 
SI 
Unit 
Conversion  
Factor 
SI 
Low 
SI 
High 
Monocytes (absolute)  
MONO  
10^3/mm3  
NA 
≥ 1.5 
GI/L 
1 
NA 
≥ 1.5 
Monocytes (%) 
MONO  
% 
NA 
≥ 20% 
% 
1 
NA 
≥ 20% 
Neutrophils 
(absolute) 
NEUT  
10^3/mm3 
≤ 1.0 
NA 
GI/L 
1 
≤ 1.0 
NA 
Neutrophils (%) 
NEUT  
% 
≤ 15% 
≥ 90% 
% 
1 
≤ 15% 
≥ 90% 
Eosinophils 
(absolute) 
EOS  
10^3/mm3  
NA 
≥0.7 
GI/L 
1 
NA 
≥0.7 
Eosinophils (%) 
EOS  
% 
NA 
≥ 10% 
% 
1 
NA 
≥ 10% 
 
 
 
 
 
 
 
 
 
Chemistry 
 
 
 
 
 
 
 
 
Heart Function 
 
 
 
 
 
 
 
 
Aspartate 
transaminase 
AST  
IU/L 
NA 
≥3 x ULN 
U/L 
1 
NA 
≥3 x ULN 
Lactic 
dehydrogenase 
LDH  
U/L 
NA 
≥3 x ULN 
U/L 
1 
NA 
≥3 x ULN 
 
 
 
 
 
 
 
 
 
Liver Function 
 
 
 
 
 
 
 
 
Alkaline 
Phosphatase 
ALP  
IU/L 
NA 
≥ 3 x ULN 
U/L 
1 
NA 
≥ 3 x ULN 
Alanine 
transaminase 
ALT  
IU/L 
NA 
≥3 x ULN 
U/L 
1 
NA 
≥3 x ULN 
Total Bilirubin 
TBili  
mg/dL  
NA 
≥ 2.0 
umol/L  
17.1  
NA 
≥34.2 
Gamma-
glutamyltransferase 
GGT  
IU/L 
NA 
≥ 3 x ULN 
U/L 
1 
NA 
≥ 3 x ULN 
Total Protein 
TPRO  
g/dL 
≤ 4.5 
≥ 9.0 
g/L 
10 
≤ 45 
≥ 90 
Albumin 
ALB  
g/dL 
≤ 2.5 
≥ 6.5 
g/L 
10 
≤ 25 
≥ 65 
 
 
 
 
 
 
 
 
 
Renal Function 
 
 
 
 
 
 
 
 
Blood urea nitrogen  
BUN  
mg/dL  
NA 
≥ 30 
mmol/L  
0.357  
NA 
≥10.7 
Creatinine 
CREAT  
mg/dL  
NA 
≥ 2.0 
µmol/L  
88.4  
NA 
≥176.8 
 
 
 
 
 
 
 
 
 
Lipid Chemistry 
 
 
 
 
 
 
 
 
Total cholesterol 
chol  
mg/dL  
NA 
≥ 300 
mmol/L  
0.0259  
NA 
≥ 7.77 
Triglycerides 
TG 
mg/dL  
NA 
≥ 300 
mmol/L  
0.0113  
NA 
≥3.39 


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Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
Unit 
Low  
High 
SI 
Unit 
Conversion  
Factor 
SI 
Low 
SI 
High 
 
 
 
 
 
 
 
 
 
Electrolytes 
 
 
 
 
 
 
 
 
Chloride 
Cl 
MEq/L 
≤ 90 
≥ 112 
mmol/L  
1 
≤ 90 
≥ 112 
Potassium 
K 
MEq/L 
≤ 3.0 
≥ 5.8 
mmol/L  
1 
≤ 3.0 
≥ 5.8 
Sodium 
Na 
MEq/L 
≤ 130 
≥ 150 
mmol/L  
1 
≤ 130 
≥ 150 
Bicarbonate 
Bicarb  
MEq/L  
NA 
NA 
mmol/L  
1 
NA 
NA 
Magnesium 
MG 
mg/dL 
<1.0 
>4.4 
mmol/L 
0.411 
<0.41 
>1.81 
 
 
 
 
 
 
 
 
 
Metabolic 
 
 
 
 
 
 
 
 
Calcium 
Ca 
mg/dL 
≤ 7.0 
≥ 15.5 
mmol/L  
0.25 
≤1.75 
≥3.88 
Phosphorous 
P 
mg/dL 
<1.0 
>10.0 
mmol/L 
0.323 
<0.32 
>3.23 
Blood Glucose 
BGL  
mg/dL 
≤ 50 
(fasting)* 
≥ 180 
(fasting)* 
mmol/L  
0.0555 
≤2.8 
(fasting)* 
≥10.0 
(fasting)* 
Uric Acid 
URICA  
mg/dL  
NA 
Male ≥ 
10.5 
Female ≥ 
8.5 
µmol/L  
59.48  
NA 
Male ≥ 
624 
Female ≥ 
505 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
(Urine) protein 
UPROT  
0 to 3+  
NA 
Change≥2 
0 to 3+  
1 
NA 
Change≥2 
(Urine) glucose 
UGL  
0 to 3+  
NA 
Change≥2 
0 to 3+  
1 
NA 
Change≥2 
(Urine) hemoglobin  
UHgb  
0 to 3+  
NA 
Change≥2 
0 to 3+  
1 
NA 
Change≥2 
(Urine) white blood 
cells 
UWBC  
0 to 3+  
NA 
Change≥2 
0 to 3+  
1 
NA 
Change≥2 
(Urine) white blood 
cells (Microscopic 
test) 
UWBC  
WBC/hpf  
NA 
≥20 
WBC/hpf  
1 
NA 
≥20 
(Urine) red blood 
cells 
URBC  
0 to 3+  
NA 
Change≥2 
0 to 3+  
1 
NA 
Change≥2 
(Urine) red blood 
cells (Microscopic 
test) 
URBC  
RBC/hpf  
NA 
≥10 
RBC/hpf  
1 
NA 
≥10 
Specific gravity 
USpG  
0 to 3+  
NA 
NA 
0 to 3+  
1 
NA 
NA 
Specific gravity 
USpG  
 
≤ 1.005 
NA 
 
 
≤ 1.005 
NA 


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Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
Unit 
Low 
High 
SI 
Unit 
Conversion  
Factor 
SI 
Low 
SI 
High 
(Microscopic test) 


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11.2 Appendix 2 – Vital Signs and ECGs – Potentially Clinically Significant Criteria 
 
 
Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
Unit 
 
Reporting 
Format 
Potentially Clinically Significant 
Criteria 
Low 
High 
Vital Sign 
 
 
 
 
 
Systolic blood 
pressure 
SBP  
mmHg  
3.0 
≤ 90 and 
≥ 20 decrease 
≥ 180 and 
≥ 20 increase 
Diastolic blood 
pressure 
DBP  
mmHg  
3.0 
≤ 50 and 
≥ 15 decrease 
≥105 and 
≥ 15 increase 
Pulse rate 
PULSE  
bpm  
3.0 
≤ 50 and 
≥ 15 decrease 
≥ 120 and 
≥ 15 increase 
Body Temperature  
TEMP 
C° 
3.1 
NA 
≥ 1.11 C° 
increase 
≥ 2 F ° increase 
Respiration rate 
RESP  
#/min  
3.1 
≤ 10 
-- 
Weight 
WEIGHT  
kg  
4.1 
≥ 7% decrease 
≥ 7% increase 
 
 
 
 
 
 
QTcB 
 
 
 
 
> 500 msec or 
CfB > 60 msec 
QTcF 
 
 
 
 
> 500 msec or 
CfB > 60 msec 
 
Cfb=Change from Baseline 

Prot_000.pdf: 
18F-AV-1451-A05 Protocol Amendment 2 
 
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 
 
NCT02016560 
Approval date: 07 Aug 2015


/ 
Protocol 18F-AV-1451-A05 
Confidential 
Protocol Number: 18F-AV-1451-AOS 
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 
Date and Version: 
07 August 2015, Amendment 2 
Name of Compound: 
18F-AV-1451 ([F-18]T807) 
Sponsor: 
Avid Radiopha'tmaceuticals, Inc. 
Philadelphia, Pennsylvania USA 
Approvals/Signatures and Date: 
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 A vi d. 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
18F-AV-1451([F-
18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Title of Study: 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 
Planned number of subjects (Enrolled): 380 
The first Phase of the study will be divided into three groups: 
1. Cognitively healthy volunteer subjects  
a. Approximately 20 subjects ≥ 20 to ≤40 years of age 
b. Approximately 60 subjects ≥ 50 years of age 
2. Mild cognitive impairment (MCI) (n=80) 
3. Alzheimer’s disease (AD) subjects 
a. Approximately 60 subjects with an MMSE ≥ 20 
b. Approximately 10 subjects with an MMSE >10 and <20 
The second Phase of the study will enroll: 
4.   Approximately 150 subjects with cognitive impairment (MCI or demented subjects with 
a suspected neurodegenerative cause) and an MMSE ≥ 20 and ≤ 27.  For the purposes of 
ensuring a distribution of disease severity, a target of at least 1/3 of the enrolled subjects will 
have dementia.  
Name of compound: 18F-AV-1451(also known as [F-18]T807) 
Dose: 370 MBq (10 mCi) 
Route of Administration:  Intravenous (IV) bolus 
Study Phase:  II 
Study Centers:  Approximately 30 centers in the United States 
Trial Objectives: This study will be conducted in two phases, an exploratory phase and a 
confirmatory/validation phase, which will have separate subjects and analyses.  The first phase 
of this study will be comprised of a cross-sectional component and a longitudinal component. 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
18F-AV-1451([F-
18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
The second (confirmatory/validation) phase will focus on the relationship of baseline PET tau 
images to changes in longitudinal clinical measures. 
 
Exploratory Phase, Cross-sectional objectives: 
The primary objective of the cross-sectional component is: 
 To compare 18F-AV-1451 imaging results in subjects with AD to subjects with MCI and 
cognitively healthy older individuals 
The secondary objective of the cross-sectional component is: 
 To establish a database of cognitively healthy individuals to show the spectrum of 18F-
AV-1451 imaging results in cognitively healthy individuals across a range of age strata 
Exploratory objectives of the cross-sectional component are: 
 To determine whether greater degrees of cognitive impairment correlate with higher 18F-
AV-1451 uptake in subjects with an amyloid positive status 
 To explore whether tests of specific cognitive domains correlate with regional 18F-AV-
1451 uptake  
 To explore the relationships between  18F-AV-1451 uptake and biomarkers of 
neurodegeneration and neurological disease (CSF markers including tau, phospho-tau 
and beta-amyloid (Aβ), genetic markers, PET amyloid imaging, and brain atrophy 
assessed by volumetric MRI) 
 To expand the 18F-AV-1451 safety database 
Exploratory Phase, Longitudinal objectives: 
The primary objective of the first phase longitudinal component is: 
 To assess the rate of change of tau deposition as measured by 18F-AV-1451 uptake over 
time. 
Exploratory objectives of the first phase longitudinal component are: 
 To explore associations between changes in 18F-AV-1451 uptake in the brain and clinical 
and functional measures, as well as, biomarkers of neurodegeneration and neurological 
disease (CSF markers including tau, phospho-tau and beta-amyloid (Aβ), genetic 
markers, PET amyloid imaging, and brain atrophy assessed by volumetric MRI).   
 To expand the 18F-AV-1451 safety database 
Confirmatory Phase, Longitudinal objectives: 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
18F-AV-1451([F-
18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
The second phase of the study is designed to provide independent validation of the relationships 
observed in the exploratory analyses of the first phase.  In particular, the goal of the second 
phase is to confirm the relationship between 18F-AV-1451 uptake in the brain as measured by 
PET and the subsequent rate of cognitive decline observed over longitudinal follow up. 
 
Eligibility: 
Each of the groups is comprised of specific inclusion and exclusion criteria to determine patient 
eligibility.  See Section 5.3, Selection of Subjects. 
Study Design: 
This is a phase 2 cross-sectional and longitudinal observational study that will evaluate imaging 
characteristics of 18F-AV-1451 in control subjects and patients with MCI and AD. This study 
will be conducted in two phases, an exploratory/hypothesis generating phase and a 
confirmatory/validation phase, which will have separate subjects and analyses.   
All subjects will provide informed consent before starting any study procedures.  
For both the Exploratory and Confirmatory Phases, screening assessments may take place over 
several days and will include demographic information, cognitive testing, safety assessment, 
and MRI, including both volumetric and standard clinical sequences.  Raters administering the 
cognitive testing will be blinded to the 18F-AV-1451 scans for subjects in the Confirmatory 
Cohort. Subjects who qualify for the study will return to the clinic at a later date for a florbetapir 
F 18 PET imaging session and an 18F-AV-1451 PET imaging session.  Some subjects, who are ≥ 
50 years of age, in the exploratory phase may have the option to also participate in cerebrospinal 
fluid (CSF) collection by lumbar puncture (LP).  
Subjects who are ≥ 50 years of age will return for follow-up visits at 9 (+/-2) and 18 (+/-2) 
months following the initial 18F-AV-1451 scan. Cognitive assessments and updates to 
concomitant medications and medical history will be collected at each follow-up visit. Subjects 
in the Exploratory phase will also have follow-up 18F-AV-1451 scans and MRI, including both 
volumetric and standard clinical sequences. A sub-set of subjects in the Exploratory phase may 
have the option to have an additional resting state functional (rsf)MRI sequence scan in addition 
to the volumetric and standard clinical sequences at both the screening MRI and follow-up 
MRIs.  Subjects or their designated decision maker will be contacted by phone at 5 and 14 
months following the initial 18F-AV-1451 scan to collect updated concomitant medications and 
medical history. 
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Sponsor: 
Avid Radiopharmaceuticals, 
Inc. 
Name of Compound: 
18F-AV-1451([F-
18]T807)  
Active Ingredient(s): 
7-(6-[F-18]fluoropyridin-3-yl)-5H-
pyrido[4,3-b]indole 
Assessments and Endpoints: 
Each group will have a screening visit(s), a florbetapir F 18 PET imaging visit, a 18F-AV-1451 
PET imaging visit, and follow-up phone calls after each imaging visit.  
Florbetapir F 18 PET Imaging Session: 
For the florbetapir F 18 PET imaging session, subjects will receive a single IV bolus injection 
target dose of 370 MBq (10 mCi) of florbetapir F 18.  At 50 minutes following injection, a 
continuous 10-minute brain scan (2 acquisitions of 5 minute duration) will begin.   
18F-AV-1451 PET Imaging Session:  
For the 18F-AV-1451 PET imaging session, subjects will receive a single IV bolus injection 
target dose of 370 MBq (10 mCi) of 18F-AV-1451 At approximately 80 minutes post dose, 
scanning will begin. Four 5-minute acquisitions will be taken.  
For both imaging sessions adverse events will be monitored continuously during the imaging 
session. Subjects who experience any adverse event during an imaging session will not be 
discharged until the event has resolved or stabilized. 
A follow-up phone call to the subject, or designated decision maker, will be conducted within 2 
or 3 business days of the imaging day, but not before 48 hours post-injection, to confirm subject 
well-being and to collect information about any new adverse events.  If both of these days are 
not business days, the follow-up phone call can occur the following business day. 
In the Exploratory longitudinal component, subjects who are ≥ 50 years of age will have two 
longitudinal follow-up visits with 18F-AV-1451 PET imaging, MRI, cognitive assessments and 
updated medical history and concomitant medications. In the Confirmatory Cohort, longitudinal 
follow-up visits will consist of cognitive assessments and updated medical history and 
concomitant medications. No PET imaging or MRI is planned at the follow-up visits in the 
Confirmatory Cohort. Additional assessments that will be performed at each visit are detailed in 
Section 7.1.   
 
 
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Statistical Methods:   
In the exploratory study phase, descriptive statistics will be applied to describe the 18F-AV-1451 
SUVR distribution across age groups among cognitive healthy subjects. ANOVA analysis will 
be applied to detect the difference between clinical diagnosis groups. Analyses will be 
conducted to assess the relationship among 18F-AV-1451 uptake, cognitive function 
measurements, and other collected biomarkers. Longitudinal data from the exploratory study 
phase will be assessed periodically to determine the relationships between various 18F-AV-1451 
imaging parameters (e.g., composite and regional SUVr, voxel based statistics and visual 
interpretation) and the change from baseline in the various cognitive and functional assessments.  
These data will be used to generate hypotheses regarding the relationship between 18F-AV-1451 
PET tau imaging and cognitive/functional change that will be formally incorporated into an 
analysis plan and tested in the confirmatory phase of the study. 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................ 12 
2. 
TRIAL OBJECTIVES ...................................................................... 14 
2.1. 
Exploratory Phase, Cross-sectional objectives: ................................ 15 
2.2. 
Exploratory Phase, Longitudinal objectives: .................................... 15 
2.3. 
Confirmatory Phase, Longitudinal objectives: ................................. 15 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 16 
4. 
TEST DRUG AND CONTROL AGENTS ...................................... 16 
4.1. 
Descriptive Name:  18F AV-1451 ..................................................... 16 
4.2. 
Descriptive Name:  Florbetapir F 18 ................................................ 16 
4.3. 
Radioactive Labeling ........................................................................ 17 
4.4. 
Decay Characteristics ....................................................................... 17 
4.5. 
Formulation and Dose Florbetapir F 18 Injection ............................. 17 
4.6. 
Formulation and Dose 18F-AV-1451 Injection ................................. 18 
4.7. 
Packaging Florbetapir F 18 Injection ............................................... 18 
4.8. 
Packaging 18F-AV-1451 Injection .................................................... 18 
4.9. 
Storage and Handling Florbetapir F 18 Injection ............................. 18 
4.10. 
Storage and Handling 18F-AV-1451 Injection .................................. 18 
5. 
INVESTIGATIONAL PLAN ........................................................... 19 
5.1. 
Overall Design and Plan of Trial ...................................................... 19 
5.2. 
Planned Dosage and Duration of Treatment ..................................... 20 
5.2.1. 
Dosage and Administration .............................................................. 20 
5.2.2. 
Rationale for Dosages ....................................................................... 21 
5.3. 
Selection of Subjects ......................................................................... 21 
5.3.1. 
Inclusion Criteria .............................................................................. 21 
5.3.2. 
Exclusion Criteria ............................................................................. 23 
5.4. 
Prior and Concomitant Therapy ........................................................ 24 
5.5. 
Removal of Subjects from Trial ....................................................... 24 
5.6. 
Premature Termination of Trial/Closure of Center .......................... 24 
6. 
WARNINGS/PRECAUTIONS ........................................................ 25 
7. 
PROCEDURES AND METHODS .................................................. 25 
7.1. 
Assessment Periods .......................................................................... 25 
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7.1.1. 
Screening and Baseline Visit: ........................................................... 25 
7.1.2. 
Optional Cerebrospinal fluid (CSF) collection by Lumbar Puncture 
(LP) (Aβ, p-tau, t-tau); Exploratory Phase only ............................... 26 
7.1.3. 
Initial PET Imaging Visits: ............................................................... 27 
7.1.4. 
First and Second Longitudinal Follow-up Visits .............................. 28 
7.1.5. 
Longitudinal Follow-Up Phone Calls ............................................... 30 
7.2. 
Observations and Measurements ...................................................... 30 
7.3. 
Protocol for Image Collection .......................................................... 36 
7.4. 
Good Clinical Practice and Monitoring ............................................ 36 
7.5. 
Informed Consent and Subject Information ..................................... 36 
7.6. 
Documentation .................................................................................. 37 
7.7. 
Adverse Events (AE) ........................................................................ 37 
7.7.1. 
Adverse Event Monitoring ............................................................... 38 
7.7.2. 
Adverse Event Definitions ................................................................ 38 
7.7.3. 
Adverse Event Documentation ......................................................... 40 
7.7.4. 
Reporting of Serious Adverse Events ............................................... 40 
8. 
STATISTICAL ANALYSIS ............................................................ 40 
8.1. 
General Statistical Considerations .................................................... 40 
8.1.1. 
Sample Size Estimation .................................................................... 41 
8.1.1.1. 
Exploratory Phase ............................................................................. 41 
8.1.1.2. 
Confirmatory Phase .......................................................................... 41 
8.1.2. 
Exploratory Phase, Cross-sectional Component ............................... 42 
8.1.2.1. 
Primary Objective Analysis .............................................................. 42 
8.1.2.2. 
Secondary Objective Analysis .......................................................... 42 
8.1.2.3. 
Exploratory Objective Analyses ....................................................... 42 
8.1.3. 
Exploratory Phase, Longitudinal Component ................................... 42 
8.1.3.1. 
Primary Objective Analysis .............................................................. 42 
8.1.3.2. 
Exploratory objective analyses ......................................................... 43 
8.1.4. 
Confirmatory Phase .......................................................................... 43 
8.2. 
Safety Analysis ................................................................................. 43 
8.3. 
18F-AV-1451 Image Analysis ........................................................... 44 
9. 
USE OF DATA AND PUBLICATION ........................................... 44 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ................. 45 
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10.1. 
Institutional Review Board (IRB) ..................................................... 45 
10.2. 
Informed Consent ............................................................................. 45 
10.3. 
Protocol Adherence .......................................................................... 45 
10.4. 
Documents Necessary for Initiation of the Trial .............................. 46 
10.5. 
Investigational Product Control ........................................................ 46 
10.6. 
Data Collection ................................................................................. 46 
10.7. 
Adverse Events ................................................................................. 47 
10.8. 
Records Retention ............................................................................. 47 
11. 
APPENDICES .................................................................................. 48 
11.1. 
References ......................................................................................... 48 
11.2. 
Trial Flow Chart ............................................................................... 50 
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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AD 
Alzheimer’s disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale- Cognitive Subscale 
Adverse Event 
(AE) 
Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. 
Audit 
A systematic and independent examination of the trial-related activities 
and documents to determine whether the evaluated trial-related activities 
were conducted, and the data were recorded, analyzed, and accurately 
reported according to the protocol, applicable standard operating 
procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s). 
CHO 
Chinese Hamster Ovary 
Case Report Form 
(CRF) and 
electronic Case 
Report Form 
(eCRF) 
A printed or electronic form for recording study participants’ data during 
a clinical study, as required by the protocol. 
CNS 
Central Nervous System 
CRO 
Contract Research Organization: A person or organization (commercial, 
academic, or other) contracted by the sponsor to perform one or more of 
the sponsor’s trial-related duties and functions.  
CT 
 
Computed Tomography 
 
DSST 
 
Digit Symbol Substitution Test 
 
Efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
FDA 
US Food and Drug Administration  
FDG 
18F - Fluorodeoxyglucose 
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GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
Institutional 
Review Board 
/Independent 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
the safety, welfare and human rights of the subjects participating in a 
clinical study are protected. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
IV 
Intravenous 
Kd 
Dissociation Constant 
MAO 
Monoamine Oxidase 
MBq 
Megabecquerel 
mCi 
Millicurie 
MCI 
Mild Cognitive Impairment 
MHD 
Maximum Human Dose 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No Observable Adverse Effect Level 
NOEL 
No Observable Effect Level 
PET 
Positron Emission Tomography 
SUVR 
Standard Uptake Value Ratio 
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1. 
INTRODUCTION  
Molecular imaging biomarkers have the potential to aid in the diagnosis of patients with 
cognitive impairment who are being evaluated for Alzheimer’s disease (AD) (Dubois, 
2010; McKhann, 2011).  Positron emission tomography (PET) ligands such as florbetapir 
F 18 (Wong, 2010) may provide a minimally invasive estimate of cortical beta amyloid 
(Aβ) neuritic plaque deposition, a hallmark pathology, and a required element for the 
evaluation of AD neuropathologic diagnosis (Hyman 2012).  Multiple studies comparing 
amyloid PET scans to histopathologic assessment of amyloid burden, in subjects for 
whom biopsy samples were available or who came to autopsy after receiving a PET 
amyloid scan, support the relationship between PET amyloid imaging results and cortical 
neuritic plaque density (Clark 2011, 2012; Leinonen, 2008; Sojkova, 2011; Kantarci, 
2011; Burack, 2010).  The largest of these studies (Clark 2012) demonstrated a high 
sensitivity and specificity for florbetapir PET to discriminate subjects with subsequent 
autopsy findings of no or sparse neuritic plaques (amyloid negative) from those with 
moderate to frequent plaques (amyloid positive). 
The ability to image brain amyloid with compounds such as florbetapir is an important 
advance for diagnosis of neurological disease.  An amyloid negative florbetapir PET scan 
indicates the absence of a hallmark pathology and is inconsistent with a diagnosis of AD.  
However, because amyloid is believed to accumulate very early in the disease process 
(Jack et al., 2010) and may be present in other diseases or in clinically normal elderly 
subjects (Sperling et al. 2011; Price and Morris, 1999), the density or distribution of 
amyloid in subjects with a positive scan is not associated with Alzheimer’s disease 
severity, has not been established to predict rate of future deterioration and has not been 
established as a tool to predict or monitor response to therapy. 
In contrast to Aβ neuritic plaques, the density and distribution of phosphorylated tau, 
aggregated in neurofibrillary tangles, increases with AD-related cognitive impairment 
and correlates with neurodegeneration (Dickson et al., 1997; Duyckaerts et a., 1987).  
Thus, a PET imaging agent that binds to phosphorylated tau has potential application as a 
biomarker for disease severity/neurodegeneration and may be useful both for selecting 
patients for therapy and for monitoring disease progression in therapeutic trials. 
18F-AV-1451 (originally named [F-18]T807 by Siemens Molecular Imaging Biomarker 
Research group) has been developed as a positron emitting radiopharmaceutical for in 
vivo imaging of tau protein aggregates (Xia et al., 2013).  Autoradiography results using 
tissue sections from human brains showed a strong signal in the grey matter of cortical 
slices from tau positive brains but weak or no binding in tau negative, Aβ positive, or tau 
and A negative tissue.  Scatchard analysis based on this heterogeneous autoradiography 
assay yielded an estimated Kd of 15nM. A saturation binding experiment using purified 
Paired Helical Fragment Tau isolated brains of AD patients yielded a Kd value of 0.7 nM. 
AV-1451 was assessed in competitive binding assays against a panel of 72 of the most 
common central nervous system (CNS) targets and no clinically relevant inhibition was 
seen.   AV-1451 was positive in the in vitro hERG assay; however, in vivo cardiovascular 
safety pharmacology assessments in dogs showed no evidence of QT prolongation at 
doses up to 50x the intended maximum human dose (MHD).  Nonetheless, until 
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sufficient human cardiovascular safety data are available, initial clinical studies will 
exclude subjects with a history of risk factors for Torsades de Pointes and subjects taking 
drugs known to prolong the QT interval. 
In vivo safety pharmacology studies were also conducted in rats to determine potential 
effects on the CNS and respiratory systems. In these studies no clinically relevant effects 
were reported at doses exceeding 100x the intended MHD. Additionally, non-radioactive 
AV-1451 has been tested in single and repeat-dose toxicology studies in rat and dog.  In 
each of these studies the no observable adverse effect levels (NOAELs) were the highest 
doses tested (150x MHD for single, 50x MHD for repeat).   
Potential genotoxicity of non-radioactive AV-1451 was tested in both in vitro and in vivo 
assays.  In the in vitro assays, AV-1451 tested positive for potential genotoxicity.   
However, in the in vivo rat micronucleus assay at doses up to 750x MHD (scaled 
allometrically), AV-1451 showed no evidence of genotoxicity. The different results in the 
in vitro genotoxicity assays and the in vivo micronucleus study are likely related to 
differences in the exposure conditions encountered by the target cells in the different test 
systems. In vivo, AV-1451 is cleared rapidly; however, the in vitro experiments employ 
static, prolonged exposure of cells to high concentrations of the test article. While the in 
vitro data show the potential for genotoxicity, the in vivo data provide assurance that 
genotoxicity is unlikely to occur at clinically-relevant doses for human diagnostic studies. 
18F-AV-1451 has been evaluated in two human studies under the exploratory IND 
(Chien, et. al).  Adverse events reported have been mild and transient; none have been 
considered related to 18F-AV-1451 administration.   Preliminary evaluation of the PET 
images suggest that 18F-AV-1451 is eliminated from normal brain yielding only a diffuse 
pattern of background activity (Figure 1), whereas a regionally-specific gray matter 
distribution is observed in subjects with high probability AD (Figure 2).   
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Figure 1: 
 control subject (MMSE = 29) 
 
Figure 2: 
 AD subject (MMSE = 18) 
Human dosimetry has been obtained in nine subjects.  Generally, the radiotracer 
distribution was consistent among the subjects and showed rapid hepatobiliary clearance.  
There were three organs that received estimated doses higher than 0.05 mSv/MBq. The 
organ that received the largest estimated dose was the upper large intestinal wall 
(0.0962 ± 0. 0134 mSv/MBq), followed by the small intestine and the liver.  The 
Effective Dose was 0.0241 ± 0.0016 mSv/MBq. This results in an estimated Effective 
Dose of 8.92 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable to 
the effective dose of approved 18F-labeled compounds such as fluorodeoxyglucose (FDG) 
and florbetapir F 18 injection. 
The overarching goal of this protocol is to further investigate the spectrum of PET 
imaging results with 18F -AV-1451 in patients with cognitive decline and healthy 
controls.  To accomplish this goal, the protocol will investigate 18F-AV-1451 results in 
younger and older controls and patients with cognitive complaints ranging from mild 
cognitive impairment (MCI) to mild and moderate Alzheimer’s disease (AD). 
Additionally, this protocol will investigate correlations between 18F-AV-1451 PET 
imaging and other biomarkers associated with AD and will test the relationship between 
18F-AV-1451 PET imaging and cognitive decline over the 18 month study period. 
2. 
TRIAL OBJECTIVES 
This study will be conducted in two phases, an exploratory phase and a 
confirmatory/validation phase, which will have separate subjects and analyses.  The first 
phase of this study will be comprised of a cross-sectional component and a longitudinal 
component. The second (confirmatory/validation) phase will focus on the relationship of 
baseline PET tau images to change in longitudinal clinical measure. 
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2.1. 
Exploratory Phase, Cross-sectional objectives: 
The primary objective of the cross-sectional component is: 
 To compare 18F-AV-1451 imaging results in subjects with AD to subjects 
with MCI and cognitively healthy older individuals 
The secondary objective of the cross-sectional component is: 
 To establish a database of cognitively healthy individuals to show the 
spectrum of 18F-AV-1451 imaging results in cognitively healthy individuals 
across a range of age strata 
Exploratory objectives of the cross-sectional component are: 
 To determine whether greater degrees of cognitive impairment correlate with 
higher 18F-AV-1451 uptake in subjects with an amyloid positive status 
 To explore whether tests of specific cognitive domains correlate with regional 
18F-AV-1451 uptake  
 To explore the relationships between  18F-AV-1451 uptake and biomarkers of 
neurodegeneration and neurological disease (CSF markers including tau, 
phospho-tau and beta-amyloid (Aβ), genetic markers, PET amyloid imaging, 
and brain atrophy assessed by volumetric MRI) 
 To expand the 18F-AV-1451 safety database 
2.2. 
Exploratory Phase, Longitudinal objectives: 
The primary objective of the first phase of the longitudinal component is: 
 To assess the rate of change of tau deposition as measured by 18F-AV-1451 
uptake over time. 
The exploratory objectives of the first phase of the longitudinal component are: 
 To explore associations between changes in 18F-AV-1451 uptake in  the brain 
and clinical and functional measures, as well as, biomarkers of 
neurodegeneration and neurological disease (CSF markers including tau, 
phospho-tau and beta-amyloid (Aβ), genetic markers, PET amyloid imaging, 
and brain atrophy assessed by volumetric MRI) 
 To expand the 18F-AV-1451 safety database 
2.3. 
Confirmatory Phase, Longitudinal objectives: 
The second phase of the study is designed to provide independent validation of the 
relationships observed in the exploratory analyses of the first phase. In particular, the 
goal of the second phase is to confirm the relationship between 18F-AV-1451 uptake in 
the brain as measured by PET and the subsequent rate of cognitive decline observed over 
longitudinal follow up.  
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3. 
SPONSOR, INVESTIGATOR(S) AND OTHER 
PARTICIPANTS 
The trial is sponsored by: 
 
Avid Radiopharmaceuticals, Inc. 
 
The medical contact is: 
 
 
Approximately 30 centers in the United States will participate. 
4. 
TEST DRUG AND CONTROL AGENTS  
4.1. 
Descriptive Name:  18F AV-1451 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole 
 
MW = 262.27 amu 
4.2. 
Descriptive Name:  Florbetapir F 18     
4-[(1E)-2-[6-[2-[2-[2-(fluoro-18F)ethoxy]ethoxy]ethoxy]-3-pyridinyl]ethenyl]-N-methyl- 
benzenamine 
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MW= 359.4 amu 
4.3. 
Radioactive Labeling 
The compounds are labeled with [18F] fluorine that decays by positron (β+) emission and 
has a half-life of 109.77 min.  The principal photons useful for diagnostic imaging are the 
511 keV gamma photons, resulting from the interaction of the emitted positron with an 
electron. 
4.4. 
Decay Characteristics 
The time course of radioactive decay for Fluorine [18F] is shown below 
Min. 
Fraction Remaining
0 
1.000 
30 
0.827 
60 
0.685 
90 
0.567 
120 
0.469 
150 
0.388 
180 
0.321 
210 
0.266 
240 
0.220 
Physical decay chart for Fluorine [18F].  Half-life = 109.77 min. 
4.5. 
Formulation and Dose Florbetapir F 18 Injection 
Drug Product is formulated in 10% v/v ethanol, USP, 0.45% sodium ascorbate, USP, in 
0.9% sodium chloride injection, USP.  Subjects will receive a single IV administration of 
approximately 370 MBq (10 mCi) of Florbetapir F 18 Injection immediately prior to 
imaging.  The mass dose of florbetapir in each human dose will be ≤ 50 µg (0.14 μmol) 
per 10 mCi dose in total volume not exceeding 10 mL.  Florbetapir F 18 Injection expires 
at 10 hours post End-of-Synthesis (EOS) or when either the strength or specific activity 
shelf-life specifications (Not less than (NLT) 37 MBq/mL (1 mCi/ml) or NLT 7.4 
MBq/µg (0.2mCi/ μg), respectively) are met, whichever is soonest.   
Florbetapir F 18 Injection will be supplied from manufacturing facilities approved for 
commercial distribution under NDA 202-008. 
N
N 
H 
O
O
O
18F
18F-AV-45
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4.6. 
Formulation and Dose 18F-AV-1451 Injection 
18F-AV-1451 Injection is a clear solution containing 18F-AV-1451 (drug substance) 
formulated for intravenous bolus administration. Depending on the manufacturer, 18F-
AV-1451 Injection will be formulated in: 
 aqueous 21 mM sodium phosphate solution containing up to 10% (v/v) 
ethanol, or  
 a solution containing  10% (v/v) ethanol, USP in 0.9% sodium chloride 
injection, USP. 
Drug product of either formulation is manufactured to meet one common set of 
specifications. 
The expiration time and date of 18F-AV-1451 Injection are provided on the outer label of 
each dose based on specific activity or strength. 18F-AV-1451 Injection should be stored 
at room temperature. 
4.7. 
Packaging Florbetapir F 18 Injection 
Unit doses of Drug Product may be contained in a sterile, apyrogenic 10, 30 or 50 mL 
clear Type I Borosilicate glass serum vial closed with a 20 mm Fluro Tec®-coated 
4432/50-B2-40 gray elastomeric closure sealed with a 20 mm aluminum crimp seal, 
manufactured by Allergy Laboratories or may be contained in 2 mL, 5 mL, or 10 mL 
sterile apyrogenic NORM-JECT® polypropylene/high-density polyethylene syringes.  
4.8. 
Packaging 18F-AV-1451 Injection 
Each package of 18F-AV-1451 Injection includes a sterile apyrogenic sealed glass vial or 
sterile apyrogenic syringe containing 18F-AV-1451 Injection, a surrounding protective 
lead shield canister, and an outside delivery case. 
4.9. 
Storage and Handling Florbetapir F 18 Injection 
Florbetapir F 18 Injection is stored at 25ºC; excursions permitted to 15-30ºC. The product 
does not contain a preservative.  Florbetapir F 18 Injection should be stored within the 
original container or equivalent radiation shielding.  Florbetapir F 18 Injection must not 
be diluted. 
4.10. 
Storage and Handling 18F-AV-1451 Injection 
18F-AV-1451 Injection is stored at room temperature. 18F-AV-1451 Injection should be 
stored within the original container or equivalent radiation shielding.  18F-AV-1451 
Injection must not be diluted. 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Design and Plan of Trial 
This is a phase 2 cross-sectional and longitudinal observational study that will evaluate 
imaging characteristics of 18F-AV-1451 in control subjects and patients with MCI and 
AD. This study will be conducted in two phases, an exploratory/hypothesis generating 
phase and a confirmatory/validation phase, which will have separate subjects and 
analyses. Approximately 230 subjects will be enrolled in the Exploratory Phase of the 
study: 80 cognitively healthy volunteers, 80 subjects with MCI, 70 subjects with AD. 
Approximately 20 cognitively healthy volunteers will be ≥20 to ≤40 years of age. 
Approximately 60 cognitively healthy volunteers will be ≥ 50 years of age and will be 
distributed across age deciles (50-59, 60-69, 70-79 and >80). Approximately 150 subjects 
with cognitive impairment will be enrolled in the Confirmatory Phase.  
All subjects will provide informed consent before starting any study procedures.  
For both the Exploratory and Confirmatory Phases, screening assessments may take place 
over several days and will include demographic information, cognitive testing, safety 
assessment, and MRI, including both volumetric and standard clinical sequences.  Raters 
administering the cognitive testing will be blinded to the 18F-AV-1451 scans for subjects 
in the Confirmatory Cohort. Subjects who qualify for the study will undergo both a 
florbetapir F 18 PET imaging session and an 18F-AV-1451 PET imaging session.  Some 
subjects, who are ≥ 50 years of age, in the Exploratory Phase will have the option to 
participate in cerebrospinal fluid (CSF) collection by lumbar puncture (LP).  
Subjects who are ≥ 50 years of age will return for follow-up visits at 9 (+/-2) months and 
18 (+/-2) months following the initial 18F-AV-1451 scan. Cognitive assessments and 
updates to concomitant medications and medical history will be collected at each follow-
up visit. Subjects in the Exploratory Phase will also have follow up 18F-AV-1451 scans 
and MRI, including both volumetric and standard clinical sequences. A sub-set of 
subjects in the Exploratory Phase may have the option to have an additional resting state 
functional (rsf)MRI sequence scan in addition to the volumetric and standard clinical 
sequences at both the screening MRI and follow-up MRIs. All follow-up procedures 
should be collected within the specified visit window (See Section 7.1.4). Subjects or 
their designated decision maker will be contacted by phone at 5 and 14 months following 
the initial 18F-AV-1451 scan to collect updated concomitant medications and medical 
history. 
Avid personnel will be blinded to the Confirmatory Phase longitudinal cognitive data. 
Avid personnel will also remain blinded to the PET scans (both florbetapir and 18F-AV-
1451) performed on subjects in the Confirmatory Phase with the exception of periodic 
quality assurance (QA) assessments of a random subset of image data (not to exceed 20% 
unless issues identified that warrant additional review). These QA reviews will serve to 
ensure image quality and data integrity for the scans collected and managed by the 
imaging core laboratory.  Avid staff performing the PET scan QA assessment will not be 
aware of diagnostic group or cognitive test scores for the subjects/images being reviewed. 
 
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Florbetapir F 18 PET Imaging Session: 
For the florbetapir F 18 PET imaging session, an intravenous catheter will be placed for 
IV administration of Florbetapir F 18 Injection.  Subjects will receive a single IV bolus 
injection target dose of 370 MBq (10 mCi) of Florbetapir F 18 Injection followed by a 
saline flush.  At approximately 50 minutes following injection, a continuous 10-minute 
brain scan (2 acquisitions of 5 minute duration) will begin.   
Adverse events will be continuously monitored during the florbetapir F 18 PET imaging 
session.  A physician or physician designee must evaluate the subject for adverse events 
prior to injection and prior to discharge from the imaging center.  Subjects who 
experience an adverse event will not be discharged from the imaging center until the 
event has resolved or stabilized. 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days of the post-injection of florbetapir F 18, but not before 48 
hours post-injection, to confirm subject well-being and to collect information about any 
new adverse events.  If both of these days are not business days, the follow-up phone call 
can occur the following business day. 
 
18F-AV-1451 PET Imaging Session(s):  
For the 18F-AV-1451 PET imaging session(s), an intravenous catheter will be placed for 
IV administration of 18F-AV-1451 Injection.  Subjects will receive a single IV bolus 
injection target dose of 370 MBq (10 mCi) of 18F-AV-1451 Injection followed by a saline 
flush. At approximately 80 minutes post dose, a continuous 20-minute brain scan (4 
acquisitions of 5-minute duration) will be obtained. If at any point during the imaging 
session it is determined that the subject is not able to continue, or that it is not in the best 
interest of the subject to continue, imaging will be discontinued.  The image data that has 
been collected up to that point will be analyzed. Clinical laboratory tests will be obtained 
prior to injection and upon completion of each imaging session. Adverse events will be 
monitored continuously during the imaging session. Subjects who experience any adverse 
event during an imaging session will not be discharged until the event has resolved or 
stabilized. 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days of the imaging day, but not before 48 hours post-injection, 
to confirm subject well-being and to collect information about any new adverse events.  
If both of these days are not business days, the follow-up phone call can occur the 
following business day. 
5.2. 
Planned Dosage and Duration of Treatment 
5.2.1. 
Dosage and Administration 
Florbetapir F 18: 
Subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) 
of Florbetapir F 18 Injection. 
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18F-AV-1451: 
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 
mCi) of 18F-AV-1451 Injection. 
5.2.2. 
Rationale for Dosages  
This trial is designed to evaluate the brain tau protein imaging properties and safety of 
18F-AV-1451 to be used in subjects with cognitive impairment and healthy volunteers. 
18F-AV-1451 will be administered IV in a radioactive target dose of 370 MBq with a 
maximum human mass dose (MHD) limited to 20 µg of compound by weight.  This dose 
is 150 fold lower than the NOAEL observed in the rat single dose toxicity study and is 50 
fold lower than the NOAEL observed in the rat and dog repeat dose toxicity studies. 
Human dosimetry has been obtained in nine subjects. The results estimated an Effective 
Dose of 8.92 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable to 
the effective dose of approved 18F-labeled compounds such as FDG and Florbetapir F 18 
Injection. 
The proposed dose has been shown to have acceptable image quality in preliminary 
human studies. No treatment related adverse events have been reported using this 
regimen.   
5.3. 
Selection of Subjects 
5.3.1. 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible to enroll in this trial as 
cognitively healthy volunteers:  
1. Male or female subjects ≥ 20 to ≤ 40 years of age  
(n = approximately 20)  
-OR-  
Male or female subjects ≥ 50 years of age  
(n = approximately 60) 
2. MMSE ≥ 29  
3. No significant history of cognitive impairment 
4. Can tolerate PET imaging procedures 
5. Can tolerate MRI scan procedures, and 
6. Subjects who signed an IRB approved informed consent prior to any study 
procedures. 
Subjects who meet all of the following criteria are eligible to enroll in the arm of this trial 
reserved for patients with MCI: 
1. Male or female subjects > 50 years of age 
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2. MMSE > 24 
3. Have MCI  consistent with NIA-Alzheimer’s Association working group’s 
diagnostic guidelines for AD: Alzheimer’s Dementia 7:270-9, 2011 (Albert 
2011), including the following: 
a. Have cognitive decline verified by the study physician.  
b. Evidence of objective impairment in one or more cognitive domains, with 
supporting evidence from objective testing if available,  
c. Preservation of independence in functional abilities,  
d. Not demented  
4. Have a study partner who has significant interaction with the subject and can 
report on the subject’s activities of daily living 
5. Can tolerate PET imaging procedures 
6. Can tolerate MRI scan procedures, and 
7. Ability to provide informed consent for study procedures (If the patient is 
ineligible to give informed consent, based on local standards, the patient’s legal 
representative may consent on behalf of the patient but the patient must still 
confirm assent. This person may serve as the study partner as well). 
Subjects who meet all of the following criteria are eligible to enroll in the arm of this trial 
reserved for patients with AD: 
1. Male or female subjects  > 50 years of age 
2. MMSE > 10 
a. Approximately 60 subjects with an MMSE >20 
b. Approximately 10 subjects with an MMSE >10 and < 20 
3. Subjects with possible or probable AD based on the NIA-Alzheimer’s Association 
working group’s diagnostic guidelines for AD: Alzheimer’s Dementia 7:263-9, 
2011 
4. Have a study partner who has significant interaction with the subject and can 
report on the subject’s activities of daily living 
5. Can tolerate PET imaging procedures 
6. Can tolerate MRI scan procedures, and 
7. Ability to provide informed consent for study procedures (If the patient is 
ineligible to give informed consent, based on local standards, the patient’s legal 
representative may consent on behalf of the patient but the patient must still 
confirm assent. This person may serve as the study partner as well). 
Subjects who meet all of the following criteria are eligible to enroll in the second phase 
of this trial: Confirmatory Cohort: 
1. Male or female subjects > 50 years of age (n = approximately 150) 
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2. Cognitively impaired subjects (MCI or dementia with a suspected 
neurodegenerative cause) with an MMSE ≥ 20 and ≤ 27. (For the purpose of 
ensuring a distribution of disease severity, a target of at least 1/3 of the enrolled 
subjects will have dementia). 
3. Have a study partner who has significant interaction with the subject and can 
report on the subject’s activities of daily living 
4. Can tolerate PET imaging procedures 
5. Can tolerate MRI scan procedures, and 
6. Ability to provide informed consent for study procedures (If the patient is 
ineligible to give informed consent, based on local standards, the patient’s legal 
representative may consent on behalf of the patient but the patient must still 
confirm assent. This person may serve as the study partner as well). 
5.3.2. 
Exclusion Criteria 
Subjects will be excluded from enrollment if they: 
1. Have current clinically significant psychiatric disease.  Subjects with behavior 
dysfunction in AD may be entered only after discussion and with approval of the 
sponsor.  The investigator should carefully consider whether subjects with 
behavior dysfunction in AD will be able to complete the imaging session 
2. Have evidence of structural abnormalities such as major stroke or mass on MRI 
that is likely to interfere with interpretation of a PET scan on MRI 
3. Have a history of moderate or severe traumatic brain injury (TBI) by OSU TBI-
ID method or evidence of brain injury by MRI or CT imaging 
4. Are claustrophobic or otherwise unable to tolerate the imaging procedure 
5. Have current clinically significant cardiovascular disease or clinically significant 
abnormalities on screening ECG (including but not limited to Fridericia’s 
corrected QT (QTcF) >450 msec) 
6. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart 
failure,  hypokalemia, family history of Long QT syndrome) or are taking drugs 
that are known to cause QT-prolongation (a list of prohibited and discouraged 
medications is provided by the Sponsor) 
7. Have a current clinically significant infectious disease, endocrine or metabolic 
disease, pulmonary, renal or hepatic impairment, or cancer that the investigator 
believes would affect study participation or scan results 
8. Have a history of significant or ongoing alcohol abuse or substance abuse or 
dependence 
9. Are females of childbearing potential who are not surgically sterile, not refraining 
from sexual activity or not using reliable methods of contraception. Females of 
childbearing potential must not be pregnant (negative serum β-HCG at the time of 
screening and negative urine β-HCG within 24 hours prior to injection) or 
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breastfeeding at screening. Females must agree to avoid becoming pregnant, and 
both females and males must agree to refrain from sexual activity or to use 
reliable contraceptive methods for 90 days following administration of 18F-AV-
1451 Injection 
10. Have had a non-study related radiopharmaceutical imaging or treatment 
procedure within 7 days prior to the 18F-AV-1451 or florbetapir F18 imaging 
session 
11. Are receiving any investigational medications, or have participated in a trial with 
investigational medications within the last 30 days 
12. In the opinion of the investigator, are otherwise unsuitable for a study of this type. 
5.4. 
Prior and Concomitant Therapy 
Except as noted below, all medications (prescription or over-the-counter) that have been 
started prior to screening may be continued during the course of the trial.  All 
medications that are continued from the start of the trial or that are started during the trial 
(other than the study medication) must be documented in the case record form on the 
Concomitant Medication Page of the Case Record Form (CRF).   
 Investigators must discuss with the sponsor and carefully consider whether subjects 
requiring psychotropic medications will be able to complete the imaging session. 
 Subjects who are taking drugs that are known to cause QT-prolongation may not be 
enrolled in the study (a list of prohibited and discouraged medications is provided by the 
Sponsor). 
Subjects may be permitted to enroll in a clinical trial with a potential disease modifying 
(anti-tau or anti-amyloid) investigational medication after discussion with the sponsor.  
5.5. 
Removal of Subjects from Trial 
Subjects must be removed from the trial if: 
1. Informed consent is withdrawn; or  
2. The investigator or the sponsor believes it is in the best interest of the subject to 
be removed from the trial. 
Subjects may be withdrawn from the trial if a serious adverse event occurs.   The date and 
reason for discontinuation should be noted on the CRF.  Subjects who discontinue 
prematurely should be seen for a final evaluation.  
5.6. 
Premature Termination of Trial/Closure of Center 
The sponsor may discontinue the trial at any time.  Reasons for discontinuation of the 
trial may include, but are not limited to, new information on safety or efficacy, requests 
from regulatory authorities, or changes in business priorities.  Additional reasons for 
center closure may include, but are not limited to, excessive protocol violations, 
inadequate regard for subject safety, failure to follow recommended procedures (e.g., 
documentation), failure or inability to accommodate Avid/CRO monitors or to provide 
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required access to data and source documents, staff turnover or inadequate staffing, and 
inadequate enrollment.  Except in cases affecting subject safety, the investigators will be 
given a minimum of 30 days to complete final study evaluations for ongoing subjects.  In 
all cases of center or study termination, appropriate steps will be taken to ensure the 
safety of study subjects. 
6. 
WARNINGS/PRECAUTIONS 
The most up-to-date and complete information regarding the use of 18F-AV-1451 
Injection can be found in the investigator's brochure.  
In brief, 18F-AV-1451 Injection is an experimental imaging agent that will be used at 
relatively low (tracer) doses.  However, because relatively little toxicological evaluation 
has been completed, and because  18F-AV-1451 Injection is in the early stages of clinical 
investigation, it is recommended that subjects receiving  18F-AV-1451 Injection be 
followed closely by means of adverse event reporting, vital signs, ECGs, and laboratory 
tests. 
There are no data on the effects of 18F-AV-1451 Injection in human perinatal 
development.  For this reason, females must avoid becoming pregnant.  Both females and 
males must use adequate contraceptive methods for 90 days after administration of 18F-
AV-1451 Injection.  18F-AV-1451 Injection must not be administered to females who are 
pregnant or lactating. 
7. 
PROCEDURES AND METHODS 
7.1. 
Assessment Periods  
See Section 11.2, Trial Flow Charts. 
This study will be comprised of a cross-sectional component and a longitudinal 
component. Subjects in both the Exploratory Phase and Confirmatory Phase will have 
screening visit(s), a florbetapir F 18 PET imaging visit, a 18F-AV-1451 PET imaging 
visit, and follow-up phone calls after each imaging visit. Subjects who are ≥50 years old 
will return for follow-up visits at 9 (+/-2) and 18 (+/-2) months following the initial 18F-
AV-1451 scan. Cognitive assessments and updates to concomitant medications and 
medical history will be collected at each follow-up visit. Subjects in the Exploratory 
Phase will also have follow-up 18F-AV-1451 scans and MRI. 
7.1.1. 
Screening and Baseline Visit: 
Screening may take place over several days.  All screening assessments should be 
performed within 30 days of the initial 18F-AV-1451 PET imaging session.  
Screening assessments will include: 
 Informed consent; 
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 Demographics (age, gender, race, ethnicity, education, alcohol, drug use, and 
smoking); 
 Medical history, physical and neurological exam, concomitant medications; 
 Disease history (date/months since symptom onset, date/months since 
diagnosis, family history of  neurologic disease) for cognitively impaired 
subjects; 
 Ohio State University Traumatic Brain Injury Identification Method (OSU 
TBI-ID); 
 Mini Mental State Exam (MMSE); 
 Safety assessments: Vital signs (pulse rate, respiratory rate, supine blood 
pressure, height and weight), ECG, safety labs(hematology, chemistry, and 
urinalysis); 
 Serum beta-hCG test  (for females of childbearing potential defined as pre-
menopausal or less than 2 years post-menopausal and not surgically sterile);  
 MRI imaging including standard clinical sequences and volumetric MRI;  
 A physician will see the patient during the screening visit. 
Baseline assessments may be performed at the screening visit or +/- 30 days of the initial 
18F-AV-1451 Imaging Visit. Raters administering the MMSE and baseline assessments 
described below will be blinded to the 18F-AV-1451 scans for subjects in the 
Confirmatory Cohort. 
Baseline assessments will include: 
 Alzheimer’s Disease Assessment Scale- Cognitive subscale (ADAS-Cog11); 
 Neuropsychological test battery (Digit Symbol Substitution Test (DSST), 
Digit span forward and backward ,Trail Making A and B, Logical Memory 
Test, Immediate and Delayed Recall Story A , Animal list generation, Boston 
Naming Test (BNT) (30 item), American National Adult Reading Test 
(ANART), Clock Drawing Test, Benton Judgment of Line Orientation test); 
 Subjects in the Confirmatory Cohort will also be administered the Clinical 
Dementia Rating (CDR) Scale;  
 Pfeffer Functional Activities Questionnaire (FAQ). For the MCI and AD 
groups only.  
7.1.2. 
Optional Cerebrospinal fluid (CSF) collection by Lumbar Puncture (LP) 
(Aβ, p-tau, t-tau); Exploratory Phase only  
Some subjects (depending on site participation) who are ≥ 50 years of age who qualify 
for the study will be offered to consent for optional CSF collection by LP.  The LP should 
be performed at least 48 hours apart from the PET imaging sessions and should be 
performed within +/- 60 days of the initial 18F-AV-1451 Imaging Visit. Each LP will be 
done by a qualified physician who is experienced in performing the procedure. Subjects, 
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or their designated decision maker, will call the investigator to report any adverse events 
associated with the LP procedure. 
7.1.3. 
Initial PET Imaging Visits: 
Subjects who qualify will have a florbetapir F 18 PET imaging session and their initial 
18F-AV-1451 PET imaging session. The imaging sessions must be performed at least 48 
hours apart, but not more than 60 days apart. The order of the scans is interchangeable. 
Florbetapir F 18 PET Imaging Session   
 For women of childbearing potential, a negative urine pregnancy test must be 
obtained within 24 hours prior to injection; 
 A physician or physician designee must see the subject prior to administration 
of Florbetapir F 18 Injection to determine if they are still suitable to undergo 
the scan; 
 Vital signs will be taken (pulse rate, respiratory rate, supine blood pressure, 
and weight) immediately prior to injection of florbetapir F 18; 
 Subjects will receive a single IV bolus injection of approximately 370 MBq 
(10 mCi) +10% of florbetapir F 18 followed by a saline flush. A 10-minute(2 
acquisitions of 5 minute duration) continuous, dynamic PET brain scan will 
begin approximately 50 minutes following the dose administration; 
 A physician or physician designee will see the subject prior to discharge from 
the imaging center to evaluate the subject’s readiness for discharge; 
 A follow-up phone call to the subject, or designated decision maker, will be 
conducted between 2 or 3 business days of the imaging day, but not before 48 
hours post-injection, to confirm subject well-being and to collect information 
about any new adverse events.  If both of these days are not business days, the 
follow-up phone call can occur the following business day. 
18F-AV-1451 PET Imaging Session: Raters administering the MMSE and baseline 
assessments will be blinded to the 18F-AV-1451 PET scan for subjects in the 
Confirmatory Cohort. 
 A physician must see the subject prior to administration of 18F-AV-1451 
Injection to determine if they are still suitable to undergo the scan; 
 For women of childbearing potential, a negative urine pregnancy test must be 
obtained; 
 Vital signs will be taken  at the following time points: 
o immediately prior to administration of 18F-AV-1451 Injection 
o within 5 minutes after completion of injection of 18F- AV-1451 Injection 
o after completion of the PET scan, prior to discharge; 
 ECGs will be taken at the following time points:  
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o Two will be taken approximately 5 minutes apart immediately prior to 
(within approximately 10 minutes) 18F-AV-1451 Injection administration 
o One will be taken within five minutes after completion of injection  
o One will be taken after completion of the PET scan, prior to discharge; 
 Blood and urine samples will be collected for safety labs prior to 
administration of 18F-AV-1451 Injection and after completion of the PET scan 
prior to discharge; 
 Blood will be collected for evaluation of ApoE genotype; 
 Blood will be collected for storage and genetic analysis (participant may opt 
out) ; 
 Subjects will receive a single IV bolus injection of approximately 370 MBq 
(10 mCi) +10% of 18F-AV-1451 Injection followed by a saline flush. At 
approximately 80 minutes post dose, a continuous 20-minute brain scan (4 
acquisitions of 5 minute duration) will be obtained.); 
 The injection site will be observed for excessive inflammation or damage to 
the surrounding tissue where the dose was injected; 
 The subject will be requested to void after completion of the PET scan; 
 Adverse events will be continuously monitored during the 18F-AV-1451 study 
imaging session; Subjects who experience an adverse event will not be 
discharged from the imaging center until the event has resolved or stabilized;  
 A physician will see the subject prior to discharge from the imaging center to 
evaluate the subject’s readiness for discharge; and 
 A follow-up phone call to the subject, or designated decision maker, will be 
conducted between 2 or 3 business days of the imaging day, but not before 48 
hours post-injection, to confirm subject well-being and to collect information 
about any new adverse events.  If both of these days are not business days, the 
follow-up phone call can occur the following business day. 
 
Longitudinal Visit Procedures 
The longitudinal component will consist of the following sequence of activities: 
7.1.4. 
First and Second Longitudinal Follow-up Visits  
Exploratory Phase: The first and second follow-up visits will consist of PET scan 
procedures, an MRI, cognitive assessments and updated medical history and concomitant 
medications. The first follow-up scan will occur 9 (+/-2) months following the subject’s 
initial 18F-AV-1451 scan. The second follow up scan will occur 18 (+/-2) months 
following the initial 18F-AV-1451 scan. The cognitive assessments and MRIs should be 
performed +/- 30 days of each corresponding 18F-AV-1451 PET imaging visit and within 
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the 9 (+/-2) months window. The cognitive assessments and MRI should take place in the 
same 30 day window. 
Confirmatory Phase Cohort: The first and second follow-up visits will consist of 
cognitive assessments and updated medical history and concomitant medications. The 
first follow-up visit will occur 9 (+/-2) months following the subject’s initial 18F-AV-
1451 scan. The second follow-up visit will occur 18 (+/-2) months following the initial 
18F-AV-1451 scan. 
Cognitive Assessments: Raters administering the below assessments will be blinded to 
the 18F-AV-1451 scans for subjects in the Confirmatory Cohort 
 Mini Mental State Exam (MMSE); 
 Alzheimer’s Disease Assessment Scale- Cognitive subscale (ADAS-Cog11); 
 Neuropsychological test battery (Digit Symbol Substitution Test (DSST), 
Digit span forward and backward ,Trail Making A and B, Logical Memory 
Test, Immediate and Delayed Recall Story A , Animal list generation, Boston 
Naming Test (BNT) (30 item), American National Adult Reading Test 
(ANART), Clock Drawing Test, Benton Judgment of Line Orientation test); 
 Clinical Dementia Rating (CDR) Scale; For the MCI and AD groups only. 
 Pfeffer Functional Activities Questionnaire (FAQ). For the MCI and AD 
groups only.  
Magnetic Resonance Imaging (MRI) (for Exploratory Phase cohort only)  
MRI, including both volumetric and standard clinical sequences, will be obtained at the 
first and second follow-up visits. 
18F-AV-1451 PET Imaging Session (for Exploratory Phase cohort only) 
The first follow-up scan will occur 9 (+/-2) months following the subject’s initial 18F-
AV-1451 scan. The second follow up scan will occur 18 (+/-2) months following the 
initial 18F-AV-1451 scan.  Procedures for the longitudinal follow-up scans will be 
identical to the initial scan: 
 A physician must see the subject prior to administration of 18F-AV-1451 
Injection to determine if they are still suitable to undergo the scan; 
 Updated medical history and concomitant medications; 
 For women of childbearing potential, a negative urine pregnancy test must be 
obtained; 
 Vital signs will be taken at the following time points: 
o immediately prior to administration of 18F-AV-1451 Injection 
o within 5 minutes after completion of injection of 18F- AV-1451 Injection 
o after completion of the PET scan prior to discharge; 
 ECGs will be taken at the following time points:  
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o Two will be taken approximately 5 minutes apart immediately prior to 
(within approximately 10 minutes) 18F-AV-1451 Injection administration   
o One will be taken within five minutes after completion of injection 
o One will be taken after completion of the PET scan prior to discharge; 
 Blood and urine samples will be collected for safety labs prior to 
administration of 18F-AV-1451 Injection and after completion of the PET scan 
prior to discharge; 
 Subjects will receive a single IV bolus injection of approximately (370 MBq) 
10 mCi (+10%) of 18F-AV-1451 Injection followed by a saline flush. At 
approximately 80 minutes post dose, a continuous 20-minute brain scan (4 
acquisition of 5-minute duration).  
 The injection site will be observed for excessive inflammation or damage to 
the surrounding tissue where the dose was injected; 
 The subject will be requested to void after completion of the PET scan; 
 Adverse events will be continuously monitored during the 18F-AV-1451 study 
imaging session; Subjects who experience an adverse event will not be 
discharged from the imaging center until the event has resolved or stabilized;  
 A physician will see the subject prior to discharge from the imaging center to 
evaluate the subject’s readiness for discharge; and 
  A follow-up phone call to the subject, or designated decision maker, will be 
conducted between 2 or 3 business days of the imaging day, but not before 48 
hours post-injection, to confirm subject well-being and to collect information 
about any new adverse events.  If both of these days are not business days, the 
follow-up phone call can occur the following business day. 
 
7.1.5. 
Longitudinal Follow-Up Phone Calls 
Subjects or their designated decision makers will be contacted by phone at 5 and 14 
months following the initial 18F-AV-1451 scan to collect updated concomitant 
medications and medical history. 
7.2. 
Observations and Measurements 
Informed Consent 
Potential subjects and legally authorized representatives, if applicable, will be allowed to 
read a written informed consent form.  The principal investigator or designee will explain 
all study procedures, risks, and alternative therapies to subject.  The subject will have an 
opportunity to have all questions answered.  The appropriate parties will then sign and 
date the informed consent form, indicating willingness to participate in the study (see 
Section 7.5). A copy of the signed informed consent will be given to the subject or 
legally authorized representative.  
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All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB) prior to use. 
Medical History, Neurologic Disease History  
The investigator or designee will obtain a case history at the screening visit. 
 Relevant demographic information  
 Review of body systems 
 Social history 
 Medical and surgical history 
 Concurrent medications 
 Neurologic Disease history (month and year of symptom onset, month and 
year of diagnosis, family history of neurologic disease) 
Whenever possible, the medical history will be confirmed by medical records. 
Physical Examination  
A complete physical examination will be conducted at the screening visit. Clinically 
significant changes from screening will be recorded as adverse events for the relevant 
study period. 
Neurological Examination  
A neurological examination will be performed at the screening visit to evaluate cranial 
nerves, gait, sensory, and motor function, coordination and tendon reflexes.  The 
investigator is to look for these specific signs: 
 Pyramidal signs (plantar extension reflex, Achilles tendon clonus); 
 Extrapyramidal signs (rigidity, wrist cogwheel phenomena, involuntary 
movements); and 
 Myoclonus. 
MRI 
MRI, including both volumetric and standard clinical sequences will be obtained.  The 
MRI sequences and acquisition parameters will be described in a separate document.  If a 
comparable MRI has been performed within the last six months, for the screening MRI, 
and an electronic copy of the images is available for submission, it should be discussed 
with the sponsor whether the MRI need not be repeated. 
A sub-set of subjects in the Exploratory Phase may have the option to have a rsfMRI in 
addition to the volumetric and standard clinical sequences at both the screening MRI and 
follow-up MRIs. 
Electronic copies of MRI scans will be submitted to Avid or designated imaging core lab. 
Vital Signs  
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Vital signs (pulse rate, respiratory rate, supine blood pressure) will be taken at the 
following time points: 
 Screening visit 
 Florbetapir F18 Imaging Day 
o immediately prior to injection of florbetapir F 18 
 
18F-AV-1451 Imaging Day  
o Immediately prior to the administration of 18F-AV-1451 Injection 
o Within 5 minutes after completion of injection of 18F-AV-1451 Injection  
o After the completion of imaging prior to discharge   
Temperature will be obtained at the following time points: 
 
18F-AV-1451 Imaging Day  
o Immediately prior to the administration of 18F-AV-1451 Injection 
o After the completion of imaging prior to discharge   
Height and Weight 
At both the screening and imaging visits body weight will be measured, lightly clothed.   
Height will be measured at screening. 
Electrocardiogram 
A resting 12-lead electrocardiogram will be recorded at screening.  At the 18F-AV -1451 
imaging visits the ECGs will be taken at the following time points: 
 Two ECGs will be taken at approximately 5 minutes apart immediately prior 
(within approximately 10 minutes) to 18F-AV-1451 Injection administration. 
 One ECG will be taken immediately (within approximately five minutes) after 
completion of 18F-AV -1451 injection.  
 One ECG will be taken after completion of the PET scan prior to discharge. 
Clinical Laboratory Tests  
Clinical laboratory evaluation will be performed at screening, on imaging day: prior to 
administration of 18F-AV-1451 Injection, and after completion of 18F-AV-1451 imaging. 
Tests will include: 
 Hematology (5 mL EDTA):  hemoglobin, hematocrit, RBC, WBC, MCH, 
MCHC, neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, 
platelets, morphology, MCV, and RBC morphology.  
 Chemistry (6 mL blood):  total bilirubin, alkaline phosphatase, ALT (SGPT), 
AST (SGOT), urea nitrogen, creatinine, glucose, uric acid, calcium, 
phosphorus, total protein, albumin, total cholesterol, triglycerides, sodium, 
potassium, bicarbonate, chloride, magnesium, globulin, GGT. 
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 Urinalysis (10 mL, urine):  Samples will be used to assess glucose, RBC, 
WBC, specific gravity, pH, protein, ketones, urobilinogen, blood, nitrite, 
microscopic, color, bilirubin, casts, epithelial cells, leukocyte, esterase, and 
bacteria.  
 ApoE Genotyping (10 mL, blood) will be performed at the initial 18F-AV-
1451 imaging session for those subjects whose ApoE results are unknown. 
Genetic Samples 
A one-time blood collection (10 mL, blood) will be performed on the day of the initial 
18F-AV-1451 imaging session for genetic analysis. Where local regulations allow, 
samples will be stored and analysis may be performed on genetic variants thought to play 
a role in dementia or related diseases. Samples will only be used for investigations related 
to disease and drug or class of drugs under study in the context of this clinical program. 
They will not be used for broad exploratory unspecified disease or population genetic 
analysis.  
Samples will be identified by the patient number and stored for up to 15 years after the 
last patient visit for the study at a facility selected by the sponsor. The sample and any 
data generated from it can only be linked back to the patient by investigator-site 
personnel. Subjects may opt out of participation. 
Pregnancy Testing  
 Serum beta hCG, qualitative:  performed at screening for females of 
childbearing potential who are not surgically sterile.  A serum pregnancy test 
may also be obtained prior to injection at the Imaging Visit if required by the 
local site. 
 Urine beta hCG: performed at both the 18F-AV-1451 and florbetapir F 18 
imaging visit(s) prior to injection for females of childbearing potential 
(defined as pre-menopausal, less than 2 years post-menopausal or not 
surgically sterile). 
Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-ID) 
Tau pathology can be associated with Traumatic Brain Injury (TBI), therefore the OSU 
TBI-ID (Corrigan and Bogner 2007) short version will be used to screen for a history of 
traumatic brain injury. It is the briefest version that still provides several summary indices 
on which the original version was validated. To shorten the instrument, TBIs resulting in 
loss of consciousness are emphasized over less severe injuries. 
Mini-Mental State Examination (MMSE)  
The MMSE (Folstein et al., 1975) is a brief instrument used to assess cognitive function 
in elderly patients.  The instrument is divided into 2 sections.  The first section measures 
orientation, memory, and attention.  The maximum score for the first section is 21.  The 
second section tests the ability of the patient to name objects, follow verbal and written 
commands, write a sentence, and copy figures.  The maximum score for the second 
section is 9.  The range for the total MMSE score is 0 to 30. 
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Alzheimer’s Disease Assessment Scale—Cognitive subscale (ADAS-Cog 11)  
The ADAS (ADAS-Cog; Rosen et al. 1984) was designed to assess the severity of the 
dysfunction in the cognitive and noncognitive behaviors characteristic of persons with 
AD.  The cognitive subscale of the ADAS, the ADAS-Cog11, consists of 11 items 
assessing areas of function most typically impaired in AD:  orientation, verbal memory, 
language, and praxis.  The scale ranges from 0 to 70, with higher scores indicating greater 
disease severity.   
Digit Symbol Substitution Test (DSST) 
The DSST (Wechsler Adult Intelligence Scale F Revised, 1981) is a paper test of 
psychomotor performance in which the subject is given a key of numbers and matching 
symbols and a test section with numbers and empty boxes. Under each number the 
subject should write down the corresponding symbol as fast as possible. The score is the 
number of correct number-symbol matches made within the allowed time (90 seconds).  
The strategy to solve the DSST consists of sequential encoding and retrieval of numbers 
and corresponding symbols.  Incidental memory, visuo-motor coordination, perceptual 
organization, and selective attention are key factors that determine the final score 
(Wechsler Adult Intelligence ScaleFRevised, 1981).  The ability to sort out irrelevant 
information (e.g., symbols that may look alike) also impacts performance. This test has 
high test–retest reliability (Matarazzo and Herman, 1984).  
Digit span forward and backward (Wechsler Memory Scale-Revised (WMS-R)) 
Digit Span is composed of two tasks administered independently of each other: Digits 
Forward and Digits Backward. On both tasks, the examiner reads a series of number 
sequences to the subject. For each Digits Forward item, the subject is required to repeat 
the number sequence in the same order as presented. For Digits Backward, the subject is 
required to repeat the number sequence in the reverse order.  
Trail Making A and B 
The trail making test (Reitan and Wolfson, 1985) is a test of executive function. Part A 
consists of 25 circles numbered 1 through 25 distributed over a sheet of paper. The 
subject is instructed to connect the circles by drawing a line as quickly as possible in 
ascending numerical order. Part B consists of 25 circles containing either numbers (1 
through 13) or letters (A-L).  The subject is instructed to connect the circles while 
alternating between numbers and letters in ascending order. The subject is timed. The 
time to complete Part A is a 150 second maximum and Part B is a 300 second maximum. 
Testing is stopped if the maximum time is reached.  
Logical Memory Test, Immediate and Delayed Recall, Story A (WMS-R) 
The logical memory test (Wechsler D. 1987) assesses the ability to recall a short story. 
Subjects are read a story and asked to recall the story immediately and after a delay. 
Animal list generation 
The animal list generation (Morris et al. 1989) is used to measure verbal fluency. The 
subject is asked to name as many animals as possible in 60 seconds.  
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Boston Naming Test (BNT) (30 item) 
The 30 item Boston Naming Test (Kaplan, et al. 1983) is a measure of the ability to 
orally label 30 line drawings of objects. The objects are presented to the subject in order 
of frequency, from most frequent to least frequent. 
American National Adult Reading Test (ANART) 
ANART (Grober and Sliwinski 1991) is a measure for estimating premorbid verbal 
intelligence. The subject is presented with a word list and asked to pronounce the words.    
Clock drawing test 
The clock drawing test (Goodglass and Kaplan 1983) has two components: a command 
condition and a copy condition. In the command condition, the subject draws a clock 
according to verbal instructions. In the copy condition, the subject copies a model clock 
drawn at the top of a form.  
Judgment of Line Orientation Test (JOLO) 
The JOLO (Benton 1978) is a non-motor measure of visual perceptual ability where there 
is no time demand. The task asks subjects to match two lines by their angel of orientation 
to a test set of lines presented below the stimulus lines.  
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.” FAQ was developed to assess instrumental activities of daily 
living involving higher level functional skills such as shopping alone, writing checks, 
remembering appointments..etc. FAQ asks informant to rate 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 = 1The sum scores ranges from 0-30. 
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 global rating of dementia can be 
generated from the domain scores. A CDR Sum of Boxes can be generated from the total 
across domains.  
Physician Visit 
A physician must see the subject at screening, at baseline, prior to drug administration 
and at study end, prior to discharge from both the 18F-AV-1451 and florbetapir F 18 
imaging sessions.  At this time, the physician should review all safety data and briefly 
examine/query the subject regarding potential adverse events or other treatment issues.  A 
physician or physician designee can administer these assessments on the day of imaging 
for the florbetapir F 18 imaging session only. 
Optional Cerebrospinal fluid (CSF) collection  
Depending on site participation, subjects in the Exploratory Phase will be offered to 
consent for optional CSF collection by LP. Aβ, phospho-tau, and total tau will be 
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measured. 20 mL of CSF will be collected from each subject and divided into 1 ml 
conical vials. Samples will be shipped to a facility designated by the Sponsor. Samples 
will be identified by the patient number and stored for up to 15 years after the last patient 
visit for the study at a facility selected by the sponsor  
7.3. 
Protocol for Image Collection 
The sponsor will prepare and distribute a PET Imaging Manual for 18F-AV-1451 and 
florbetapir F 18. MRI image acquisition parameters and transmission procedures will be 
outlined in an MRI procedures manual.   
7.4. 
Good Clinical Practice and Monitoring 
All clinical studies performed under the direction of Avid/CRO will be conducted in 
accordance with applicable regulatory requirements and International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) and Avid/CRO Standard Operating 
Procedures (SOP).  
This includes: 
1. IRB/IEC approval:  An investigation will be initiated at a study site only after the 
IRB/IEC for that study site has given their written approval of the protocol and 
informed consent;    
2. Informed Consent:  Study procedures will not be initiated until the subject and/or 
their   legally authorized representative (as appropriate) signs the informed 
consent form;   
3. Recording and monitoring of adverse events as outlined in Section 7.7.3 including 
the notification of study site clinical investigators, local IRBs and the FDA 
regarding serious adverse event; 
4. Avid RP’s obligation to monitor the participating center on a regular basis; and 
5. The termination of a center or the trial if conditions apply, as outlined in Section 
5.6. 
7.5. 
Informed Consent and Subject Information 
Potential subjects, or their legally authorized representative (as appropriate), will be 
allowed to read a written informed consent form.  The principal investigator or designee 
will explain all study procedures, risks, and alternative therapies.  The subject and legally 
authorized representative will have an opportunity to have all questions answered by a 
physician.  The subject will then sign and date the informed consent form, indicating 
willingness to participate in the study. 
Subjects with AD are potentially a vulnerable population with compromised mental 
capacity.  Investigators should take extra care to evaluate a patient’s ability to give 
consent.  If the subject is capable of giving informed consent then the subject should sign 
on the consent line of the informed consent form.  When applicable the legally authorized 
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representative should sign as well, indicating that they have witnessed the subject’s 
consent, and further agree to participate as an informant. 
If the subject is not capable of giving consent, consent may be given by a legally 
authorized representative.  However, it is expected that all subjects entering this study 
should at least have the capacity to understand that they are engaging in a research study 
and should affirm that they do not object to participating, by signing on the Subject 
Assent line of the consent form.  If the legal guardian is also the informant, the guardian 
must still sign the informant line of the form, indicating their own willingness to 
participate as an informant. 
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB).  No study related procedures shall be 
performed prior to completion of the informed consent process, and signing of the 
consent form.  A copy of the signed informed consent should be given to the patient 
and/or their legally authorized representative for their records. 
7.6. 
Documentation 
18F-AV-1451 and florbetapir F 18 PET scans, as well as MRI scans, will be saved in an 
appropriate electronic format as specified in the imaging manuals.  A copy of all scans 
will be saved at the site/imaging center and a copy of each will be forwarded to the 
sponsor or to the designated imaging core lab as described in the imaging manuals.  All 
other data required by the protocol will be recorded in the CRF.  All data in the CRF will 
be substantiated by “source documents,” which consist of the subject’s medical files, 
laboratory result sheets, ECG tracings, etc.  All source documentation must be available 
to Avid and designees.  Completed source documents and CRFs may need to be made 
available and complete for an audit by the FDA or other international regulatory 
authorities or Avid at any time.  A ballpoint pen should be used to ensure that all copies 
are legible.  CRFs and all other records must be filed in accordance with applicable laws 
and regulations (see Section 10.6) 
7.7. 
Adverse Events (AE) 
Avid’s standards for recording and reporting adverse events (AEs) are to be followed 
regardless of applicable regulatory requirements that may be less stringent.  All AEs must 
be fully recorded on the Adverse Event Page of the eCRF. Investigators will be instructed 
to report to Avid or its designee their assessment of the potential relatedness of each AE 
to investigational product or protocol procedure via electronic data entry.  If a patient’s 
treatment is discontinued as a result of an AE, study site personnel must clearly report to 
Avid or its designee via electronic data entry the circumstances and data leading to any 
such discontinuation of treatment. In cases where the investigator notices an 
unanticipated benefit to the patient, study site personnel should report “unexpected 
benefit” with the actual event term to Avid or its designee (for example, the complete 
actual term would be “unexpected benefit- sleeping longer”). 
Laboratory test abnormalities considered by the Investigator to be clinically relevant 
should be reported on the Adverse Event Page of the eCRF.  Signs and symptoms of each 
AE should be described in detail (e.g., start and stop dates/time, severity/intensity, 
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relationship to investigational product, action taken, and outcome).  Additionally, any 
clinically significant findings from laboratory evaluations, vital sign measurements, or 
other study procedures including those that result in a diagnosis should be reported as an 
AE to Avid or its designee.  
7.7.1. 
Adverse Event Monitoring 
Each patient must be carefully monitored for adverse events.  This includes clinical 
laboratory test variables.  An assessment must be made of the severity/intensity and 
relationship to the administration of the trial medication. 
7.7.2. 
Adverse Event Definitions 
Adverse Events 
For reporting purposes, Avid will distinguish among pre-existing conditions, treatment -
emergent adverse events and trial-emergent adverse events.  Pre-existing conditions (i.e., 
undesirable experiences, signs or symptoms that begin prior to the Screening Visit) will 
be recorded on the medical history and/or physical exam eCRF pages.  Signs and 
symptoms that are believed to be due to the pre-existing condition (started prior to dose 
of study medication) do not have to be recorded in the AEs section of the eCRF, unless 
there is an increase in frequency or severity.  Additionally, signs or symptoms or changes 
in pre-exisiting conditions that occur outside the trial defined adverse event reporting 
period (e.g., between the end of the baseline/cross-sectional imaging period and the 9 
month follow-up imaging period) will be recorded in medical history. 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. For the purposes of this study, untoward 
medical occurrences will be considered associated with the use of 18F-AV-1451, and thus 
be reported as adverse events, if they occur within 48 hours after 18F-AV-1451 
administration, either at baseline or at the 9 or 18 month imaging visit. Untoward medical 
occurrences will be considered associated with the use of Florbetapir F 18 injection, if 
they occur within 48 hours after Florbetapir F 18 injection administration.  Adverse 
events associated with the use of 18F-AV-1451 or Florbetapir F 18 injection will be 
recorded as treatment emergent relative to the respective drug.  Adverse experiences that 
occur after administration of either drug but outside the 48 hour reporting window will 
not be reported unless the investigator believes they are attributable to the drug. 
In order to capture possible adverse effects of trial participation, trial-emergent adverse 
events will also be reported as any untoward medical occurrences occurring, during the 
baseline/cross-sectional imaging period but not during the 48 hour windows following 
the administration of 18F-AV-1451 or Florbetapir F 18 injection.  For this purpose, the 
baseline/cross-sectional imaging period will be defined as beginning with the signing of 
consent and ending 48 hours after the last of the screening/baseline procedures described 
in sections 7.1.1 – 7.1.3, including (but not limited to) neuropsychological testing, MRI, 
18F-AV-1451 or Florbetapir F 18 injection PET scanning and lumbar puncture. 
The end of study for the purpose of adverse event reporting is defined as 48 hours after 
the last administration (i.e., 18 month visit or early termination visit) of 18F-AV-1451. 
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Serious Adverse Event (SAE) 
An SAE is an AE that results in one of the following outcomes or constitutes one of the 
following events: 
 Death; 
 Initial or prolonged inpatient hospitalization (other than that required by 
protocol; “social hospitalization” or any hospitalization for non-medical 
reasons does not constitute an SAE); 
 A life-threatening experience (that is, immediate risk of dying); 
 Persistent or significant disability/incapacity; 
 Congenital anomaly/birth defect; 
 Considered significant by the investigator for any other reason. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
Unexpected Adverse Event 
An unexpected adverse event is an adverse event not previously reported or an adverse 
event that occurs with specificity, severity or frequency that is not consistent with the 
current investigator’s brochure. 
Relationship to Investigational Product 
Investigators will be instructed to report their assessment of the potential relatedness of 
each adverse event to protocol procedure, concomitant medication and/or investigational 
product.  The assessment of the relationship of an adverse event to the administration of 
the investigational product is a clinical decision based on all available information at the 
time of the completion of the eCRF. 
Intensity/Severity of an Adverse Event 
In addition to assessing the relationship of the administration of the investigational 
product to adverse events, an assessment is required of the intensity (severity) of the 
event.  
The following classifications should be used: 
Mild:   
A mild adverse event is an adverse event, usually transient in nature and generally not 
interfering with normal activities. 
Moderate:   
A moderate adverse event is an adverse event that is sufficiently discomforting to 
interfere with normal activities. 
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Severe:   
A severe adverse event is an adverse event that incapacitates the subject and prevents 
normal activities.   Note that a severe event is not necessarily a serious event.  Nor must a 
serious event necessarily be severe. 
7.7.3. 
Adverse Event Documentation 
All adverse events must be fully recorded on the Adverse Event Page via the Electronic 
Data Capture (EDC) system.  Documentation must be supported by an entry in the 
subject file.  Laboratory test, vital signs and ECG abnormalities considered by the 
Investigator to be clinically relevant should be reported on the Adverse Event page of the 
eCRF.  Signs and symptoms of each AE should be described in detail (e.g., start and stop 
dates, severity/intensity, relationship to investigational product, action taken, and 
outcome). 
Adverse events and laboratory test abnormalities fulfilling the definition of a serious 
adverse event should, in addition, be reported on the Serious Adverse Event Reporting 
Form. 
7.7.4. 
Reporting of Serious Adverse Events  
Study site personnel must alert Eli Lilly or its designee of any SAE within 24 hours of 
their awareness of the event via a sponsor-approved method.  Alerts issued via telephone 
are to be immediately followed with official notification on study-specific SAE forms.  
Serious adverse events occurring after a subject receive a dose of investigational product 
will be collected until 48 hours after the  dosing of the investigational product, regardless 
of the investigator’s opinion of causation.  Therefore, SAEs that occur later than 48 hours 
after the dosing of the investigational product are not required to be reported unless the 
investigator feels the events were related to either investigational product or a protocol 
procedure. 
If a patient experiences an SAE after signing informed consent, but prior to receiving 
investigational product, the event will NOT be reported unless the investigator feels the 
event may have been caused by a protocol procedure.  Previously planned (prior to 
signing the ICF) surgeries should not be reported as SAEs unless the underlying medical 
condition has worsened during the course of the study. 
8. 
STATISTICAL ANALYSIS  
8.1. 
General Statistical Considerations 
All statistical analyses will be performed using SAS® version 8.2 or higher. 
Data will be summarized using descriptive statistics (number of subjects [N], mean, 
standard deviation [SD], median, quartiles, minimum, and maximum) for continuous 
variables and using frequency count and percentage for discrete variables.  The 
demographic and baseline characteristics data will be summarized according to clinical 
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group (healthy volunteers and subjects with cognitive impairment) at recruitment for all 
subjects in the safety population.  Safety data will be summarized for all patients. 
Subject listings of all data from the electronic case report forms (eCRFs) as well as any 
derived variables will be presented.  
Additional details concerning statistical analyses will be included in the Statistical 
Analysis Plan (SAP). 
8.1.1. 
Sample Size Estimation 
8.1.1.1. 
Exploratory Phase 
A total of 230 subjects (80 cognitively healthy volunteers, 80 MCI and 70 AD) will be 
enrolled in the Exploratory Phase study.   To explore the 18F-AV-1451 SUVR values 
across age strata among cognitively healthy subjects, these subjects will be divided into 5 
age groups as 20-40 years old, 50-59 years old, 60-69 years old, 70-79 years old and 80 
years old or above. There will be 15 subjects in each of the 50 or older age groups and 
about 20 subjects from age group 20-40 years old. From a preliminary analysis of study 
T807000, the standard deviation (SD) of SUVR from combination ROI was 0.06 for 
subjects with low probability of AD. Therefore assuming a 0.06 SD, a sample of 15 
subjects will give an approximately 90% probability to observe a 95% confidence 
interval (CI) as accurate as +/-0.04 around the point estimation.  
From previous studies, the amyloid positive rate is approximately 50% among MCI 
patients and approximately 80% from AD subjects. Therefore 80 MCIs and 70 ADs will 
likely result in 40 amyloid positive MCIs and 56 amyloid positive ADs. Also from study 
T807000, the combination ROI SUVR difference between CN and AD was 0.39, with a 
pooled SD of 0.27. Assume a pooled SD of 0.30, a sample of 60 CNs and 56 amyloid 
positive ADs will give a 90% power to detect a 0.18 difference between the CN and AD 
groups.  
8.1.1.2. 
Confirmatory Phase 
 
The final hypothesis and endpoint measurements for the Confirmatory Phase are yet to be 
determined and will depend on the discoveries from Exploratory Phase data. However the 
primary objective of the confirmatory phase is to validate the accuracy of 18F-AV-1451 
scans to predict clinically significant disease progression within 18 months from scan 
(e.g., cognitive function deterioration as measured by endpoints based on Exploratory 
Phase results).  For the purpose of sample size calculation, we assumed that the target 
success criteria would be at least 70% sensitivity and at least 70% specificity for 18F-AV-
1451 scans to detect this deterioration, with the lower bound of 95% confidence intervals 
(CI) above 50% for both sensitivity and specificity. Preliminary analysis of the 
exploratory phase cohort data showed that clinical assessments may have a relatively 
large variance. It is important to ensure that enough subjects will be in each group for 
sensitivity and specificity calculation (i.e., the subjects with or without a significant 
disease progression).  To that end, we assume at least 20% of the subjects will be in each 
group at the 18 month follow up.  With this assumption, a 5% two-sided type I error rate, 
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and that 95% CI will be calculated using Wilson score method, a sample of 115 subjects 
will provide an over 90% probability to observe lower bound of 95% CI above 50%, for 
both sensitivity and specificity.    Also assuming an approximate 20% drop out rate over 
the 18 months follow up, this study will aim to enroll 150 subjects in total.    
 
8.1.2. 
Exploratory Phase, Cross-sectional Component 
8.1.2.1. 
Primary Objective Analysis 
ANOVA analysis will be applied to detect the difference between clinical diagnosis 
groups. If an overall difference is detected, pair-wised comparisons will be conducted. If 
the pre-requisites of ANOVA test are not met, Kruskal Wallis and Wilcoxon rank sum 
test will be conducted instead. 
8.1.2.2. 
Secondary Objective Analysis 
Descriptive statistics will be applied to describe the tau SUVR distribution across age 
groups among cognitive healthy subjects. These data will also be graphically displayed.  
8.1.2.3. 
Exploratory Objective Analyses 
Correlation analysis will be conducted to determine whether greater degrees of cognitive 
impairment are associated with higher 18F-AV-1451 uptake in subjects with an amyloid 
positive status.  
Correlation analysis will be conducted to assess the relationship between regional tau 
deposition measurements with cognitive function measurements and other collected 
biomarkers.  
The association between baseline values in 18F-AV-1451 uptake in brain and clinical 
function measures, as well as, biomarkers of neurodegeneration and neurological disease 
will be explored using the methods described below in 8.1.3.2.  
Subgroup and/or covariate analyses will also be planned accordingly by amyloid beta 
status, age groups, and etc. The specific analyses to address these objectives will be 
described in the Statistical Analysis Plan (SAP) 
8.1.3. 
Exploratory Phase, Longitudinal Component 
8.1.3.1. 
Primary Objective Analysis 
The primary objective of longitudinal component is to assess the rate of change of tau 
deposition as measured by 18F-AV-1451 over time. The tau measurement change from 
baseline at each follow up visit will be estimated using Mixed Model Repeated Measures 
(MMRM). The MMRM model will include the following fixed effects: baseline value, 
clinical group, visit, clinical group by visit interaction, and baseline age. Visit will be 
considered as a categorical variable. An unstructured covariance matrix will be used to 
model the within-subject correlation. Least squared means (LSM) and standard error for 
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the tau value change from baseline will be calculated for each clinical group at every 
follow up visit.  
8.1.3.2. 
Exploratory objective analyses 
The association between change and/or baseline values in 18F-AV-1451 uptake in brain 
and clinical function measures, as well as, biomarkers of neurodegeneration and 
neurological disease (CSF markers including tau, phosphor-tau and beta-amyloid (Aβ), 
genetic markers, PET amyloid imaging, brain atrophy assessed by volumetric MRI, and 
resting connectivity assessed with rsfMRI) will also be assessed using MMRM analyses. 
Marginal logistic regression and time to event analyses will also applied when 
appropriate, such as to investigate the odds ratio of ADAS score change over 4 with the 
tau deposition change over time. The details of these statistical analyses will be provided 
in SAP.    
8.1.4. 
Confirmatory Phase 
Longitudinal data from the exploratory study phase will be assessed periodically to 
determine the relationships between various 18F-AV-1451 imaging parameters (e.g., 
composite and regional SUVr, voxel based statistics and visual interpretation) and the 
change from baseline in the various cognitive and functional assessments.  These data 
will be used to generate hypotheses regarding the relationship between 18F-AV-1451 PET 
tau imaging and cognitive/functional change that will be formally incorporated into an 
analysis plan and tested in the confirmatory stage of the study.     
Based on discoveries using data from Exploratory Phase, a disease progression 
measurement will be chosen as truth standard (TS), and the accuracy of 18F-AV-1451 
PET scans to detect this TS within 18 months of scan will be evaluated.  Hypothesis 
testing and detailed analyses will be described in a statistical analysis plan (SAP), which 
will be finalized prior to database lock. Possible analyses include calculation of accuracy 
measures such as sensitivity, specificity, and two sided 95% confidence intervals (CI) 
around these rates. Other analyses may include Mixed-Effect Model Repeated Measures 
(MMRM) analysis, risk ratio analysis, and time to event analysis.   
8.2. 
Safety Analysis 
Safety laboratory test results and vital signs measurements will be summarized by subject 
and by evaluation time point.  Change from baseline (pre-dose time point) values will be 
determined and summarized.   Subjects whose laboratory values are outside the pre-
determined upper and lower limits of normal will be identified and tabulated.  
Adverse events including injection site reactions will be summarized in terms of number 
and percentage of subjects experiencing an AE.  The summary will be further broken 
down by system organ class (SOC) and preferred term using Medical Dictionary for 
Regulatory Activities (MedDRA) terms.  Adverse events will also be presented by 
severity, relationship to treatment and seriousness.  All subjects who experience SAEs or 
who discontinue due to AEs will be summarized. 
Discontinuation  
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All subjects who discontinued participation prior to completing the study will be listed 
and their discontinuation reasons will be tabulated. 
Laboratory Data 
Changes in laboratory data from Baseline will be summarized.  Subjects whose 
laboratory values are outside threshold values will be identified and tabulated. 
Vital Signs 
Changes in vital signs from baseline will be summarized. 
ECG 
Mean changes in ECG parameters will be summarized.  The average of the two ECG 
collected prior to administration of 18F-AV-1451 on imaging day (-10 and -5 min prior to 
the administration of 18F-AV-1451), will be used for the baseline estimate.  Any subjects 
showing QTc > 500 or change from baseline of more than 60 msec will be highlighted. 
8.3. 
18F-AV-1451 Image Analysis 
All 18F-AV-1451 PET images obtained at baseline and follow-up starting at 80 minutes 
post injection will be analyzed. 18F-AV-1451 PET images starting at 110 minutes post 
injection, for those subjects in which they were acquired, will also be analyzed. The 18F-
AV-1451 PET images will be spatially normalized to standard stereotactic atlas space 
using MNI brain atlas. The uptake in tau protein rich brain regions will be assessed with 
regions of interest (ROI, designed in MNI brain atlas) in terms for standard uptake value 
ratio (SUVr, normalized by cerebellar uptake). The spatially normalized images and the 
measured SUVr values will be used to accordingly to accomplish the study objectives.  
Exploratory analysis will include co-registration of MRI to the 18F-AV-1451 PET images 
for ROI creation and/or partial volume correction of 18F-AV-1451 PET images using 
anatomical information from MRI data. 
Additional analyses may explore various voxel and threshold based approaches.   
The final primary method image analysis for the confirmatory phase will be chosen based 
on results from the exploratory phase before any of the confirmatory phase images are 
analyzed. 
9.
USE OF DATA AND PUBLICATION
Avid adheres to the Pharmaceutical Research and Manufacturers of America (PhRMA) 
Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results. A 
complete copy of these principles is available from Avid and can also be found at the 
PhRMA website (http://www.phrma.org).  Our policy is briefly summarized below: 

We commit to timely communication of meaningful results of controlled
clinical trials, regardless of outcome.

As a sponsor, we may recommend that the Investigator(s) delay or decline
publication in cases where the study design, conduct, or data are insufficient
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to allow meaningful interpretation.  Avid and the Investigator(s) will discuss 
the study design and data in advance of the study, and again after completion, 
and will strive, through appropriate scientific debate, to reach a consensus 
regarding the potential merits of publication. 
 Avid retains the right to review any manuscripts, presentations, or abstracts 
before they are submitted for publication. Where differences of opinion or 
interpretation exist regarding data planned for publication, the parties (Avid 
and the Investigator) should try to resolve them through appropriate scientific 
debate.  Avid retains the right to delay publication for up to 60 days to protect 
intellectual property.  
 Anyone who provides substantial contributions should receive appropriate 
recognition as an author or contributor when the manuscript is published.  
This is a multi-center study. The primary analysis will include data from all centers.  A 
multicenter publication, reporting the primary analysis data set, with authorship from all 
contributing centers, should precede any other publications. 
10. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
All clinical work conducted under this protocol is subject to Good Clinical Practice 
regulations; this may include an inspection by Avid and/or Health Authority 
representatives (FDA, EMA or international regulatory authorities) at any time. 
10.1. 
Institutional Review Board (IRB) 
The intent of the research program, the trial protocol, the patient information/informed 
consent form and any advertising material used to recruit subjects must be submitted to 
the clinical investigator’s local IRB/IEC and its approval must be obtained prior to its 
use.  A copy of the approval must be forwarded to Avid.  When necessary, an extension 
or renewal of IRB/IEC approval must be obtained and also forwarded to Avid. 
10.2. 
 Informed Consent 
A signed, written informed consent must be obtained from each patient.  A copy of the 
signed informed consent should be given to the patient for their records.  A copy of the 
local IRB/IEC’s approved version of the informed consent form must be forwarded to 
Avid or designee for review prior to being used to obtain patient consent. 
10.3. 
 Protocol Adherence 
The protocol must be read thoroughly and the instructions must be followed exactly.  
Where a deviation occurs, it must be documented, the sponsor/monitor informed, and a 
course of action agreed upon. 
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10.4. 
 Documents Necessary for Initiation of the Trial 
Avid must be provided with the following documents prior to the enrollment of any 
subjects: 
 Original signed and dated Statement of Agreement page; 
 Copy of the IRB/IEC and radiation safety committee approval (if applicable); 
 Copy of the IRB/IEC stamped approved consent form; 
 Name and location of the laboratory utilized for laboratory assays, and other 
facilities conducting tests, including laboratory certification number and date 
of certification if available.  Avid may be responsible for supplying these to 
the investigator if a central laboratory is used;  
 List of reference range laboratory values.  Avid may be responsible for this if 
a central laboratory is used; and 
 Any additional licenses required in order to order to use florbetapir F 18 or 
18F-AV-1451. 
10.5. 
Investigational Product Control 
The receipt of clinical supplies (i.e. starting material for 18F-AV-1451) must be 
documented at the site. 
All drug supplies for this trial should be retained in a safe and secure place at all times 
during the trial.  18F-AV-1451 Injection and Florbetapir F18 Injection should be prepared 
by a qualified PET manufacturing site and administered by a qualified individual under 
the investigator’s supervision.  An up-to-date drug inventory/dispensing record must be 
maintained.  All drug supplies must be accounted for.  After completion of the trial, all 
remaining clinical supplies must be returned to the sponsor or their representative.   
10.6. 
Data Collection 
Electronic case report forms (eCRFs) will be used for this trial.  Individual patient files 
should include appropriate source documents, including but not limited to patient’s 
medical records and laboratory test results.  The files should include information such as 
visit dates, records of medical history, examinations administered, laboratory, 
concomitant treatment, any adverse event encountered and other notes as appropriate.  
These constitute “source data”.  All entries on the eCRFs must be backed up by source 
data.  Original electronic versions of imaging studies are also considered source data and 
should be kept on file by the site/imaging center, and appropriate copies should be 
forwarded to Avid or a designated Imaging Core Lab as specified in the Imaging Manual.   
Each patient’s source file should include an original signed informed consent form.  
When the trial is completed, the informed consent form should be kept on file with other 
trial related records. 
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All original laboratory reports must be available for review in each patient’s file.  It is 
important that the original reports be available for review because of the possibility of 
inaccuracies or errors in transcribing data from original records to the eCRF. 
The eCRFs must be kept in order and up-to-date so that they always reflect the latest 
observations on the subjects that are enrolled in the trial.  The eCRFs must be completed 
for each patient enrolled in the trial and signed by the investigator.  This should be done 
as soon as possible after completion of the patient’s participation in the trial.  A monitor 
will verify the source data for all information on the eCRF. 
10.7. 
Adverse Events 
All adverse events encountered during the clinical trial must be documented on the eCRF, 
whether or not considered drug-related. 
Eli Lilly must be notified immediately (as soon as possible, and in all cases within 24 
hours) of a drug experience, condition, development, or event, which is considered 
serious. Eli Lilly must be notified immediately of any findings with the use of the drug 
that may suggest significant hazards, contraindications, adverse drug reactions (ADRs) 
and precautions pertinent to the safety of the drug.  The investigator will be requested to 
complete a separate report form in addition to the information on the CRF.  See section 
7.7.4 for reporting serious adverse events 
If an SAE is determined to be unexpected (not previously reported or described by Avid), 
and study drug-related, Eli Lilly will notify the investigator in writing.  The investigator 
should forward this notification to the IRB/IEC within 24 hours of receipt. 
10.8. 
Records Retention 
All correspondence (e.g., with Avid, IRB/IEC, etc.) relating to this clinical trial should be 
kept in appropriate file folders.  Records of subjects, source documents, and drug 
inventory sheets pertaining to the trial must be kept on file.  Records must be retained 
until the date a marketing application (NDA) is approved for the drug for the indication 
for which it is being investigated, or until 3 years following the date of clinical trial 
termination or completion, whichever is later.   If no application is to be filed or if the 
application is not approved for such indication, records should be kept until 3 years 
following the date of clinical trial termination or completion. 
If an investigator moves, withdraws from an investigation, or retires, the responsibility 
for maintaining the records may be transferred to another person who will accept the 
responsibility.  Notice of transfer must be made to and agreed upon by Avid. 
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11. 
APPENDICES 
11.1. 
References 
Albert, M. S., DeKosky, S. T., Dickson, D., et al. “The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging and Alzheimer’s Association workgroup.”  The Alzheimer’s Association. 
Alzheimer’s and Dementia, 1-10, 2011. 
Burack, M.A., Hartlein, J., Flores, H.P., Taylor-Reinwald, L., Perlmutter, J.S., Cairns, 
N.J. “In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia”. 
Neurology. 2010;74(1):77-84. 
Chien, D.T., Bahri, S., Szardenings, A.K., Walsh, J.C., Mu, F., Su, M.Y., Shankle, W.R., 
Elizarov, A., Kolb, H.C., “Early clinical PET imaging results with the novel PHF-tau 
radioligand [18F]-T807.” J Alzheimers Dis, 2013 Jan 1l34(2):467-68 
Clark, C.M., Pontecorvo, M.J., Beach, T.G., Bedell, B.J., Coleman, R.E., Doraiswamy, 
P.M., Fleisher, A.S., Reiman, P.E.M., Sabbagh, M.N., Sadowsky, C.H., Schneider, J.A., 
Arora, A.,  Carpenter, A.P., Flitter. M.L., Joshi, A.D., Krautkramer, M.J., Lu, M., 
Mintun, M.A., Skovronsky, D.M.  “Florbetapir PET for Detection of Amyloid Neuritic 
Plaques, Comparison to Neuropathology at Autopsy: A Prospective Cohort Study.”  The 
Lancet Neurology, 2012; 11: 669–78. 
Clark, C.M., Schneider, J.A., Bedell, B.J., et al. “Use of florbetapir-PET for imaging 
beta-amyloid pathology”. JAMA. 2011;305(3):275-283. 
Dickson, T.C., Saunder, H.L., Vickers, J.C.  “Relationship between apolipoprotein E and 
the amyloid deposits and dystrophic neuritis of Alzheimer’s disease.”  Neuropathol Appl 
Neurobiol.  1997; (23):483-491.  
Dubois, B., Feldman, H.H., Jacova, C., et al.  “Research criteria for the diagnosis of 
Alzheimer’s disease: revising the NINCDS-ADRDA criteria.”  Lancet Neurol. 6:734-46 
Review, 2007. 
Dubois B., Feldman H.H., Jacova C., et al. “Revising the definition of Alzheimer's 
disease: a new lexicon”. Lancet Neurol. 2010;9(11):1118-1127.   
Duyckaerts, C., Brion, J.P., Hauw, J.J., Flament-Durand, J.  “Quantitative assessment of 
the density of neurofibrillary tangles and senile plaques in senile dementia of the 
Alzheimer type.  Comparison of immunocytochemistry with a specific antibody and 
Bodian’s protargol method.”  Acta Neuropathol. 1987;(7):129-135. 
Folstein, M.R., Folstein, S.E., and McHugh, P.R. “Mini Mental State: A practical method 
for grading the cognitive status of patients for the clinician.”  Journal of Psychiatric 
Research, 12: 189-198, 1975.  
Hyman, B.T., Phelps, C.H., Beach, T.G., et al. “National Institute on Aging-Alzheimer's 
Association guidelines for the neuropathologic assessment of Alzheimer's disease”. 
Alzheimers Dement. 2012;8(1):1-13. 
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Jack, C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., 
Petersen, R.C., Trojanowski, J.Q.  “Hypothetical model of dynamic biomarkers of the 
Alzheimer’s pathological cascade.”  Lancet Neurol 9:119-128, 2010. 
Kantarci, K., Lowe, V.J., Boeve, B.F., Weigand, S.D., Senjem, M.L., Przybelski, S.A., et 
al. “Multimodality imaging characteristics of dementia with Lewy bodies”. Neurobiol 
Aging 2011: Oct 20. [Epub ahead of print]. 
Leinonen, V., Alafuzoff, I., Aalto S., Suotunen, T., Savolainen, S., Nagren, K., et al. 
“Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron 
emission tomography with carbon 11-labeled Pittsburgh Compound B”. Arch Neurol 
2008; 65(10):1304–1309. 
McKhann, G.M., Knopman, D.S., Chertkow, H., et al. “The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease”. Alzheimers 
Dement. May 2011;7(3):263-269.    
Price, J.L., Morris, J.C. ”Tangles and plaques in nondemented aging and “preclinical”  
Alzheimer’s disease.” Ann Neurol 45:358–368, 1999. 
Sojkova J., Driscoll I., Iacono D., Zhou Y., Codispoti K., Kraut M., et al. “In vivo 
fibrillar beta-amyloid detected using [11C] PiB positron emission tomography and 
neuropathologic assessment in older adults”. Arch Neurol 2011;68(2):232–240. 
Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., 
Iwatsubo, T., Jack, C.R., Jr., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, 
C.C., Siemers, E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, M., 
Wagster, M.V., Phelps, C.H. 2011. “Toward defining the preclinical stages of 
Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease”. Alzheimers 
Dement 7(3), 280-92.  
Wechsler Adult Intelligence ScaleFRevised. San Antonio, TX: Psychological 
Corporation, 1981. 
Wong, D.F., Rosenberg, P.B., Zhou, Y., et al. “In vivo imaging of amyloid deposition in 
Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)”. J 
Nucl Med. 2010;51(6):913-920. 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent for 
Alzheimer’s disease,” Alzheimers Dement. 2013, 1-11 
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11.2. 
Trial Flow Chart 
Exploratory Phase and Confirmatory Phase Cohorts 
 
a. 
Screening may take place over several days.  All assessments must be performed within 30 days of the first 18F-AV-1451 
imaging session (with the exception of the MRI if previously performed). 
b. 
The 18F-AV-1451 and florbetapir F 18 imaging sessions must be performed at least 48 hours apart, but the order of the scans is 
interchangeable. 
c. 
Two ECGs will be taken approximately 5 minutes apart immediately prior to (within approximately 10 minutes) 18F-AV-1451 
Injection administration.  One will be taken within 5 minutes after completion of injection.   
d. 
Screening vital signs include pulse rate, respiratory rate, supine blood pressure, height and weight  
e. 
Vital signs (pulse rate, respiratory rate, supine blood pressure, weight) will be taken immediately prior to injection of florbetapir 
F 18.  
f. 
Pulse, respiratory rate, supine blood pressure, temperature and weight  will be taken immediately prior to administration of 18F-
AV-1451.  Pulse, respiratory rate, and supine blood pressure within 5 minutes after completion of injection of 18F-AV-1451 
Injection.  
g. 
Pulse, respiratory rate, supine blood pressure, temperature 
h. 
Blood and urine samples will be collected prior to administration of 18F-AV-1451 Injection.  
i. 
Serum beta-hCG pregnancy test at screening (for females of childbearing potential defined as pre-menopausal or less than 2 
years post-menopausal and not surgically sterile. 
j. 
For women of childbearing potential, a negative urine pregnancy test must be obtained within 24 hours prior to florbetapir F 18 
injection and within 24 hours prior to 18F-AV-1451 injection. 
k. 
Including CDR for subjects tin the Confirmatory Cohort. 
l. 
CSF collection may occur after the subject has passed screening procedures for subjects in the Exploratory Cohort only 
m. 
A physician or physician designee  
 
Evaluations 
 
Screening 
Visita 
Florbetapir 
F 18 
Imaging 
Visitb 
End of 
Florbetapi
r F 18 
Imaging 
(prior to 
discharge) 
Follow-up 
Phone Call 
18F-AV- 
1451 
Imaging 
Visitb 
End of 18F-AV- 
1451 Imaging 
(prior to 
discharge) 
Follow-up 
Phone Call 
Signed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical 
History/Neurologic 
Disease History 
X 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
 
 
X 
 
 
Physical Exam/ 
Neurological Exam 
X 
 
 
 
 
 
 
ECG  
X 
 
  
 
Xc 
X 
 
Vital Signs    
Xd 
Xe 
 
 
X f 
Xg 
 
Safety Labs  
X 
 
  
 
Xh 
X 
 
Serum beta-hCG i 
X 
 
 
 
 
 
 
Urine Pregnancy testj 
 
X 
 
 
X 
 
 
OSU TBI-ID 
X 
 
 
 
 
 
 
MMSE 
X 
 
 
 
  
 
 
ADAS-Cog 11 
X 
 
 
 
 
 
 
Neuropsych batteryk 
X 
 
 
 
 
 
 
MRI of the brain 
X 
 
 
 
  
 
 
PET Brain Scan 
 
X 
 
 
X 
 
 
ApoE 
 
 
 
 
X 
 
 
Genetic sample 
 
 
 
 
X 
 
 
Optional CSF 
Xl 
 
 
 
 
 
 
Evaluation by a physician   
X 
Xm 
Xm 
 
X  
X 
 
Adverse Events  
X  
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
 X 
X 
X 
X 
X 
X 
X 
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Longitudinal Component 
 
Exploratory Phase Cohorts ONLY 
 
 
 
 
 
 
The First and Second Longitudinal Follow-up Visits will be performed over several days.  
n. 
Two ECGs will be taken approximately 5 minutes apart immediately prior to (within approximately 10 minutes) 18F-AV-1451 
Injection administration. One will be taken within 5 minutes after completion of injection. One will be obtained at the end of 
imaging day 
o. 
Vital signs include pulse rate, respiratory rate, supine blood pressure, temperature and weight 
p. 
Blood and urine samples will be collected prior to administration of 18F-AV-1451 Injection and at the end of the imaging day.  
q. 
For women of childbearing potential, a negative urine pregnancy test must be obtained within 24 hours prior to 18F-AV-1451 
injection. 
r. 
ADAS-Cog 11, Neuropsych battery, and MRI can be performed +/- 30 days of the 18F-AV-1451 scan and within 30 days of each 
other. Assessments should be performed within the specified window of 9 (+/-2) months or 18 (+/-2) months.  
s. 
Between 2 or 3 business days of the imaging day 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluations 
5 Month 
Follow-up 
Phone Call 
9 (+/-2) Months 
First 
Longitudinal 
Follow-up Visit 
14 Month Follow-up 
Phone Call 
18 (+/-2) Months, 
Second Longitudinal 
Follow-up Visit 
Updated Medical History 
X 
X 
X 
X 
Updated Concomitant Meds 
X 
X 
X 
X 
ECG  
 
Xn 
 
Xn 
Vital Signs    
 
Xo 
 
Xo 
Safety Labs  
 
Xp 
 
Xp 
Urine Pregnancy testq 
 
X 
 
X 
MMSE 
 
X 
 
X 
ADAS-Cog 11r 
 
X 
 
X 
Neuropsych battery, including 
CDRr 
 
X 
 
X 
MRI of the brainr 
 
 X 
 
 X 
PET Brain Scan 
 
X 
 
X 
Follow-up Phone Calls  
 
X 
 
X 
Evaluation by a physician   
 
X  
 
X  
Adverse Events  
 
X 
 
X 
Serious Adverse Events 
 
X 
 
X 
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Confirmatory Phase Cohort ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluations 
5 Month 
Follow-up 
Phone Call 
9 (+/-2) Months, 
First 
Longitudinal 
Follow-up Visit 
14 Month Follow-up 
Phone Call 
18 (+/-2) Months, 
Second Longitudinal 
Follow-up Visit 
Updated Medical History 
X 
X 
X 
X 
Updated Concomitant Meds 
X 
X 
X 
X 
MMSE 
 
X 
 
X 
ADAS-Cog 11 
 
X 
 
X 
Neuropsych battery, including 
CDR 
 
X 
 
X 
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INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol:  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 
 
 
 
 
Date and Version: 07 August 2015, Amendment 2 
 
 
I agree to conduct the study according to this protocol and to comply with its obligations, 
subject to ethical and safety considerations and all applicable regulations (ICH, CFR). 
 
I shall not disclose the confidential information contained in this protocol or any results 
obtained from the study, except for publication in accordance with Section 9 of this 
protocol, without written authorization from Avid. 
 
 
 
________________________________________________________________________ 
Printed Name                                                                    Date 
 
 
 
______________________________________ 
Signature 
 
 
LY3191748

SAP_001.pdf: 
18F-AV-1451-A05 SAP Confirmatory v1.0 
 
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 
 
NCT02016560 
Approval date: 05 Jan 2018


Avid Radiopharmaceuticals                                                                                               
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Protocol No. 18F-Flortaucipir-A05  
 
An open label, multicenter study, evaluating the safety and imaging characteristics of 
flortaucipir in cognitively healthy volunteers, subjects with Mild Cognitive Impairment, 
and subjects with Alzheimer’s Disease 
 
Confirmatory (Second Phase)  
Statistical Analysis Plan 
 
Prepared for: 
Avid Radiopharmaceuticals, Inc 
 
Version 1.0 Date 05Jan2018 
 
 
Prepared by: 
 
Chiltern International Inc. 
Revision History 
Version 
Date 
Revision Author 
Comments 
1.0 
05Jan2018 
 
 
This document is the confidential information of Avid Radiopharmaceuticals. It may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of Avid Radiopharmaceuticals. 
 




Avid Radiopharmaceuticals                                                                                               
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Table of Contents 
 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................ 5 
2 
INTRODUCTION ........................................................................................................................................ 7 
3 
STUDY OBJECTIVES ................................................................................................................................ 8 
3.1 
CONFIRMATORY PHASE, LONGITUDINAL OBJECTIVES ............................................................................ 8 
4 
STUDY DESIGN .......................................................................................................................................... 9 
4.1 
GENERAL DESIGN .................................................................................................................................... 9 
4.2 
DISCUSSION OF STUDY DESIGN ............................................................................................................. 10 
4.3 
METHOD OF ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS ........................................................ 11 
4.4 
BLINDING .............................................................................................................................................. 11 
4.5 
DETERMINATION OF SAMPLE SIZE ......................................................................................................... 11 
5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ............................... 13 
5.1 
CHANGES IN THE CONDUCT OF THE STUDY ........................................................................................... 13 
5.2 
CHANGES FROM THE ANALYSES PLANNED IN THE PROTOCOL/CIP ....................................................... 13 
6 
BASELINE, EFFICACY AND SAFETY EVALUATIONS ................................................................... 14 
6.1 
SCHEDULE OF EVALUATIONS ................................................................................................................ 14 
6.2 
TIME POINT ALGORITHMS ..................................................................................................................... 17 
6.2.1 
Relative Day ................................................................................................................................. 17 
6.2.2 
Windows ....................................................................................................................................... 17 
6.3 
SCREENING AND BASELINE ASSESSMENTS ............................................................................................ 17 
6.4 
EFFICACY VARIABLES ........................................................................................................................... 19 
6.4.1 
Primary Efficacy Variable(s) ........................................................................................................ 19 
6.4.1.1 
Tau Status Based on flortaucipir ..................................................................................................................... 19 
6.4.1.2 
Clinical Dementia Rating (CDR) Scale (Berg, 1988) ................................................................................... 19 
6.4.2 
Additional Efficacy Variables ....................................................................................................... 20 
6.4.2.1 
Amyloid Beta Status Based on Florbetapir .................................................................................................... 20 
6.4.2.2 
Cognitive Assessments .................................................................................................................................... 20 
Mini-Mental State Examination (MMSE) ........................................................................................................................ 20 
Pfeffer Functional Activities Questionnaire (FAQ), (Pfeffer et al. 1982) ...................................................................... 21 
6.4.2.3 
Clinically Meaningful Progress ...................................................................................................................... 23 
6.4.2.4 
ApoE Genotyping ............................................................................................................................................ 24 
6.4.2.5 
Genetic Samples .............................................................................................................................................. 24 
6.4.2.6 
MRI Scan of the Brain ..................................................................................................................................... 24 
6.5 
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETIC PARAMETERS ............................... 24 
6.5.1 
Handling of Pharmacokinetic Parameter Outliers ....................................................................... 24 
6.6 
SAFETY ASSESSMENTS .......................................................................................................................... 25 
6.6.1 
Extent of Exposure and Compliance to Study Treatment.............................................................. 25 
6.6.2 
Adverse Events .............................................................................................................................. 25 
6.6.3 
Clinical Laboratory Evaluations .................................................................................................. 26 
6.6.4 
Other Observations Related to Safety ........................................................................................... 27 
6.6.4.1 
Vital Signs ........................................................................................................................................................ 27 
6.6.4.2 
Electrocardiogram (ECG) ............................................................................................................................... 28 
6.7 
PHARMACODYNAMICS PARAMETERS .................................................................................................... 28 


Avid Radiopharmaceuticals                                                                                               
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7 
STATISTICAL METHODS ...................................................................................................................... 28 
7.1 
GENERAL METHODOLOGY .................................................................................................................... 28 
7.2 
ADJUSTMENTS FOR COVARIATES .......................................................................................................... 28 
7.3 
HANDLING OF DROPOUTS OR MISSING DATA ........................................................................................ 29 
7.4 
INTERIM ANALYSES AND DATA MONITORING ....................................................................................... 29 
7.5 
MULTI-CENTER STUDIES AND POOLING OF CENTERS ............................................................................ 29 
7.6 
MULTIPLE COMPARISONS/MULTIPLICITY .............................................................................................. 29 
7.7 
USE OF AN “EFFICACY SUBSET” OF SUBJECTS ....................................................................................... 30 
7.8 
ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE .......................................................... 30 
7.9 
EXAMINATION OF SUBGROUPS .............................................................................................................. 30 
8 
STATISTICAL ANALYSIS ...................................................................................................................... 30 
8.1 
DISPOSITION OF SUBJECTS ..................................................................................................................... 30 
8.2 
PROTOCOL DEVIATIONS/VIOLATIONS ................................................................................................... 30 
8.3 
ANALYSIS POPULATIONS ....................................................................................................................... 30 
8.3.1 
Enrolled Population...................................................................................................................... 31 
8.3.2 
Safety Population for flortaucipir ................................................................................................. 31 
8.3.3 
Safety Population for florbetapir .................................................................................................. 31 
8.3.4 
Safety Population for Study .......................................................................................................... 31 
8.3.5 
Efficacy Population ...................................................................................................................... 31 
8.4 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................................................... 31 
8.5 
PRIOR AND CONCOMITANT THERAPY .................................................................................................... 32 
8.6 
ANALYSIS OF EFFICACY PARAMETERS .................................................................................................. 32 
8.6.1 
Confirmatory Phase, Longitudinal Analysis ................................................................................. 32 
8.6.1.1 
Analysis of Primary Efficacy Variable .......................................................................................................... 32 
8.6.1.2 
Analysis of Secondary Efficacy Variable ...................................................................................................... 33 
8.6.1.3 
Exploratory Analysis ....................................................................................................................................... 34 
8.6.1.4 
Additional Efficacy Analysis ........................................................................................................................ 38 
8.6.1.5 
Subgroup Analyses .......................................................................................................................................... 38 
8.7 
ANALYSIS OF SAFETY ............................................................................................................................ 39 
8.7.1 
Extent of Exposure and Compliance to Study Treatment.............................................................. 39 
8.7.2 
Adverse Events .............................................................................................................................. 39 
8.7.3 
Clinical Laboratory Evaluations .................................................................................................. 40 
8.7.4 
Other Observations Related to Safety ........................................................................................... 40 
8.7.4.1 
Vital Signs ........................................................................................................................................................ 40 
8.7.4.2 
Electrocardiogram............................................................................................................................................ 40 
8.8 
PHARMACODYNAMICS ........................................................................................................................... 41 
9 
COMPUTER SOFTWARE ....................................................................................................................... 41 
10 REFERENCES ........................................................................................................................................... 41 
11 
APPENDICES............................................................................................................................................. 44 
11.1 
APPENDIX 1 - DERIVATION OF CLINICAL DEMENTIA RATING SCORE .................................................... 44 
11.2 
APPENDIX 2 – LABORATORY RESULTS – POTENTIALLY CLINICALLY SIGNIFICANT CRITERIA ............... 45 
11.3 
APPENDIX 3 – VITAL SIGNS AND ECGS – POTENTIALLY CLINICALLY SIGNIFICANT CRITERIA ............. 48 
 


Avid Radiopharmaceuticals                                                                                               
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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 
AE 
adverse event 
ANART 
American National Adult Reading Test 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BNT 
Boston Naming Test 
C 
Celsius 
cm 
centimeters 
CNS  
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DBP 
diastolic blood pressure 
DSST 
digit symbol substitution test 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
eCRF 
electronic case report form 
FAQ 
Pfeffer Functional Activities Questionnaire 
FDG 
18F- flurodeoxyglucose 
H 
high 
hCG 
human chorionic gonadotropin 
IND 
investigational new drug 
IV 
intravenous 
JOLO 
Benton Judgment of Line Orientation Test 
Kd 
dissociation constant 
kg 
kilograms 
L 
low 
LOC 
loss of consciousness 
LS 
least squares 
max 
maximum 
MBq 
megabecquerel 
mCi 
millicuries 
MCI 
mild cognitive impairment 


Avid Radiopharmaceuticals                                                                                               
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MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
mSv 
millisievert 
n 
number of subjects 
N 
normal 
nM 
nanomolar 
OSU TBI-ID 
Ohio State University Traumatic Brain Injury Identification Method 
PET 
positron emission tomography 
ROI 
region of interest 
RR 
respiration rate 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
SUVr 
standardized uptake value ratio 
TBI 
Traumatic Brain Injury 
TEAE 
treatment-emergent adverse event 
TEMP 
temperature 
WHO 
World Health Organization 
 
 
 


Avid Radiopharmaceuticals                                                                                               
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2 
INTRODUCTION 
 
Molecular imaging biomarkers have the potential to aid in the diagnosis of patients with 
cognitive impairment who are being evaluated for Alzheimer’s disease (AD) (Dubois, 2010; 
McKhann, 2011). Positron emission tomography (PET) ligands such as florbetapir F 18 
(Wong, 2010) may provide a minimally invasive estimate of cortical beta amyloid-β (Aβ) 
neuritic plaque deposition, a hallmark pathology, and a required element for the evaluation of 
AD neuropathologic diagnosis (Hyman, 2012). Multiple studies comparing amyloid PET 
scans to histopathologic assessment of amyloid burden, in subjects for whom biopsy samples 
were available or who came to autopsy after receiving a PET amyloid scan, support the 
relationship between PET amyloid imaging results and cortical neuritic plaque density 
(Clark, 2011, 2012; Leinonen, 2008; Sojkova, 2011; Kantarci, 2011; Burack, 2010). The 
largest of these studies (Clark, 2012) demonstrated a high sensitivity and specificity for 
florbetapir PET to discriminate subjects with subsequent autopsy findings of no or sparse 
neuritic plaques (amyloid negative) from those with moderate to frequent plaques (amyloid 
positive).  
 
The ability to image brain amyloid with compounds such as florbetapir is an important 
advance for diagnosis of neurological disease. An amyloid negative florbetapir PET scan 
indicates the absence of a hallmark pathology and is inconsistent with a diagnosis of AD. 
However, because amyloid is believed to accumulate very early in the disease process (Jack 
et al., 2010) and may be present in other diseases or in clinically normal elderly subjects 
(Sperling et al. 2011; Price and Morris, 1999), the density or distribution of amyloid in 
subjects with a positive scan is not associated with Alzheimer’s disease severity, has not been 
established to predict rate of future deterioration and has not been established as a tool to 
predict or monitor response to therapy.  
 
In contrast to Aβ neuritic plaques, the density and distribution of phosphorylated tau, 
aggregated in neurofibrillary tangles, increases with AD-related cognitive impairment and 
correlates with neurodegeneration (Dickson et al., 1997; Duyckaerts et a., 1987). Thus, a PET 
imaging agent that binds to phosphorylated tau has potential application as a biomarker for 
disease severity/neurodegeneration and may be useful both for selecting patients for therapy 
and for monitoring disease progression in therapeutic trials.  
 
Flortaucipir F 18 (originally named [F-18]T807 by Siemens Molecular Imaging Biomarker 
Research group) has been developed as a positron emitting radiopharmaceutical for in vivo 
imaging of tau protein aggregates (Xia et al., 2013). Autoradiography results using tissue 
sections from human brains showed a strong signal in the grey matter of cortical slices from 
tau positive brains but weak or no binding in tau negative, Aβ positive, or tau and Aβ 
negative tissue.  
 


Avid Radiopharmaceuticals                                                                                               
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The overarching goal of this protocol is to further investigate the spectrum of PET imaging 
results with flortaucipir in patients with cognitive decline and healthy controls. To 
accomplish this goal, the protocol will investigate flortaucipir results in younger and older 
controls and patients with cognitive complaints ranging from mild cognitive impairment 
(MCI) to mild and moderate Alzheimer’s disease (AD). Additionally, this protocol will 
investigate correlations between 18F-AV1451 PET imaging and other biomarkers associated 
with AD and will test the relationship between flortaucipir PET imaging and cognitive 
decline over the 18 month study period.  
 
3 STUDY OBJECTIVES 
 
The A05 study will be conducted in two phases, an exploratory phase and a confirmatory 
phase. This statistical analysis plan (SAP) is for the confirmatory phase of this study. 
 
3.1 Confirmatory Phase, Longitudinal Objectives 
 
The confirmatory (second) phase of the study is designed to provide independent validation 
of the relationships observed in the exploratory analyses of the first phase. In particular, the 
goal of the second phase is to confirm the relationship between flortaucipir uptake in the 
brain as measured by PET and the subsequent rate of cognitive decline observed over 
longitudinal follow up. 
 
The primary objective of the confirmatory (second) phase longitudinal component is: 
• To assess whether or not the baseline tau positivity according to a flortaucipir scan 
visual read predicts a higher 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 
 
The secondary objective of the confirmatory (second) phase longitudinal component is: 
• To assess the diagnostic performance of  baseline tau positivity according to a 
flortaucipir scan visual read, for predicting  subjects’ clinically meaningful cognitive 
and functional deterioration within 18 months of scan, as measured by the  CDR-SB 
scales 
 
The exploratory objectives of the confirmatory (second) phase longitudinal component are: 
• To evaluate whether or not the baseline brain tau level assessed by flortaucipir scan 
predicts subjects’ cognitive and functional deterioration including the measurements 
from these tests: MMSE, ADAS Cog-11, FAQ, CDR-SB, CDR global, and 
Neuropsychological tests (DSST, logical memory). Analyses will also include the 
exploration of associations between flortaucipir and biomarkers of neurodegeneration 


Avid Radiopharmaceuticals                                                                                               
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and neurological disease such as amyloid level according to florbetapir scan; brain 
atrophy assessed by volumetric magnetic resonance imaging (MRI).  
• To expand the flortaucipir safety database 
 
4 STUDY DESIGN 
 
4.1 General Design 
 
This study is an open label, multicenter Phase II/III study. This study is conducted in two 
phases, an exploratory (first) phase (phase II part) and confirmatory (second) phase (phase III 
part).  
 
The confirmatory (second) phase, for which this SAP is designed, will enroll subjects ≥ 50 
years of age with cognitive impairment (MCI or demented subjects with a suspected 
neurodegenerative cause (AD)) and an MMSE ≥ 20 and ≤ 27. For the purposes of ensuring a 
distribution of disease severity, a target of at least 1/3 of the enrolled subjects will have 
dementia. Approximately 150 subjects will be enrolled in the confirmatory (second) phase of 
the study. 
 
All subjects will provide informed consent before starting any study procedures.  
 
Screening assessments may take place over several days and will include demographic 
information, cognitive testing, safety assessment, and MRI, including both volumetric and 
standard clinical sequences. Subjects who qualify for the study will undergo both a 
florbetapir F 18 PET imaging session and a flortaucipir PET imaging session. The imaging 
sessions must be performed at least 48 hours apart, but not more than 60 days apart. The 
order of the scans is interchangeable. 
 
Subjects will return for follow-up visits at 9 (+/-2) and 18 (+/-2) months following the initial 
flortaucipir scan. Cognitive assessments and updates to concomitant medications and medical 
history will be collected at each follow-up visit. 
 
Florbetapir F 18 PET Imaging Session:  
 
For the florbetapir F 18 PET imaging session, an intravenous (IV) catheter will be placed for 
administration of the florbetapir F 18 injection. Subjects will receive a single IV bolus 
injection target dose of 370 MBq (10 mCi) of florbetapir F 18 injection followed by a saline 
flush. At approximately 50 minutes following the injection, a continuous 10-minute brain 
scan (2 acquisitions of 5 minute duration) will begin.  
 


Avid Radiopharmaceuticals                                                                                               
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Adverse events will be continuously monitored during the florbetapir F 18 PET imaging 
session. A physician or physician designee must evaluate the subject for AEs prior to 
injection and prior to discharge from the imaging center. Subjects who experience an AE will 
not be discharged from the imaging center until the event has resolved or stabilized.  
 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days of the post-injection of florbetapir F 18, but not before 48 hours 
post-injection, to confirm subject well-being and to collect information about any new 
adverse events. If both of these days are not business days, the follow-up phone call can 
occur the following business day.  
 
Flortaucipir PET Imaging Session:  
 
For the flortaucipir PET imaging session, an IV catheter will be placed for administration of 
flortaucipir injection. Subjects will receive a single IV bolus injection target dose of 370 
MBq (10 mCi) of flortaucipir injection followed by a saline flush. At approximately 80 
minutes post dose, a continuous 20-minute brain scan (4 acquisitions of 5-minute duration) 
will be obtained. If at any point during the imaging session it is determined that the subject is 
not able to continue, or that it is not in the best interest of the subject to continue, imaging 
will be discontinued. The image data that has been collected up to that point will be analyzed. 
Clinical laboratory tests will be obtained prior to injection and upon completion of each 
imaging session. Adverse events will be monitored continuously during the imaging session. 
Subjects who experience any AE during an imaging session will not be discharged until the 
event has resolved or stabilized.  
 
A follow-up phone call to the subject, or designated decision maker, will be conducted 
between 2 or 3 business days of the imaging day, but not before 48 hours post-injection, to 
confirm subject well-being and to collect information about any new adverse events. If both 
of these days are not business days, the follow-up phone call can occur the following 
business day. 
 
4.2 
Discussion of Study Design 
 
This trial is designed to evaluate the brain tau protein imaging properties and safety of 
flortaucipir to be used in subjects with cognitive impairment (first and second phases) and 
healthy volunteers (first phase only). Another goal of this protocol is to establish a 
relationship between flortaucipir imaging results and cognitive assessments. Allowing all 
subjects to complete various cognitive assessments, with MMSE being the primary 
assessment for the second phase, will provide evidence whether greater degrees of cognitive 
impairment will be correlated with higher levels of flortaucipir uptake. This relationship is 


Avid Radiopharmaceuticals                                                                                               
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important in this protocol in order to determine the utility and predictive power of flortaucipir 
on the severity of cognitive impairment. 
 
4.3 
Method of Assignment of Subjects to Treatment Groups 
 
Florbetapir F 18:  
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) of 
florbetapir F 18 injection.  
 
Flortaucipir:  
All subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) of 
flortaucipir injection. 
 
4.4 
Blinding 
 
A blinded design was not used for this trial, because all subjects will receive the same 
medication.  
 
Raters administering the cognitive testing will be blinded to the flortaucipir scans 
information. 
 
For the confirmatory (second) phase, Avid personnel will be blinded to all clinical 
assessments data, including cognitive assessments.  Avid personnel will also remain blinded 
to the PET scans (both florbetapir and flortaucipir) performed on subjects enrolled in the 
confirmatory (second) phase with the exception of periodic quality assurance (QA) 
assessment of a random subset of image data (not to exceed 20% unless issues identified that 
warrant additional review). Avid staff performing the PET scan QA assessment will not be 
aware of diagnostic group or cognitive test scores for the subjects/images being reviewed. 
Database will be locked as scheduled when all clinical assessments and both flortaucipir and 
florbetapir scan visual reading process are done. Avid will remain blinded to all clinical data 
and scan results until this time.  After database is formally locked, flortaucipir scans will be 
transferred to Avid to allow for a quantitative analysis conducted by Avid’s imaging science 
group. The quantitative analysis results (SUVR values) of flortaucipir scans will be included 
to exploratory analyses, which are detailed in addendum of this SAP, and the outputs will be 
included in clinical study report (CSR) for this study. 
 
4.5 
Determination of Sample Size 
 
The primary objective of the confirmatory (second) phase is to assess the hazard ratio of 
subjects with flortaucipir scan rated as likely to progress (i.e., AD++) vs. subjects with scan 
rated as non-AD++ (i.e., patterns other than likely to progress) in progressing to a clinically 


Avid Radiopharmaceuticals                                                                                               
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meaningful event (CDR-SB with 1 point or more increase) within 18 months of scan. 
According to A05 exploratory data, 75% (15/20) AD++ subjects had an event and 27% 
(7/26) non-AD++ subjects experienced an event. Assuming a similar AD++ rate, and a 
similar event rate will be observed in this confirmatory cohort, a sample of 120 subjects in 
total will give a close to 90% power to detect a risk ratio of at least 2, under a two sided type 
I error rate of 5%.   
 
The key secondary objective is to validate the accuracy of flortaucipir scans to predict 
clinically significant disease progression within 18 months from scan (e.g., cognitive 
function deterioration as measured by endpoints based on Exploratory Phase results at the 
time of protocol finalization). For the purpose of sample size calculation, we assumed that 
the target success criteria would be at least 70% sensitivity and at least 70% specificity for 
flortaucipir scans to detect this deterioration, with the lower bound of 95% confidence 
intervals (CI) above 50% for both sensitivity and specificity. Preliminary analysis of the 
exploratory phase data showed that clinical assessments may have a relatively large variance. 
It is important to ensure that enough subjects will be in each group for sensitivity and 
specificity calculation (i.e., the subjects with or without a significant disease progression). To 
that end, we assumed at least 20% of the subjects will be in each group at the 18 month 
follow up. With this assumption, a 5% two-sided type I error rate, and that 95% CI will be 
calculated using Wilson score method, a sample of 115 subjects will provide an over 90% 
probability to observe lower bound of 95% CI above 50%, for both sensitivity and 
specificity. Also assuming an approximate 20% drop out rate over the 18 months follow up, 
this study will aim to enroll 150 subjects in total for the confirmatory (second) phase. 
 
The exploratory cohort (first phase) data showed that for AD/MCI subjects with a baseline 
MMSE between 20-27, those who had flortaucipir scans classified as AD++ had an average 
of 4.4 point decrease in MMSE (SD=3.8), while those classified as non-AD++ had an 
average of 0.7 points decrease in MMSE (SD =2.5). The ratio of AD++ vs. non-AD++ was 
2:3. Assuming the same ratio of AD++ ends up in this confirmatory cohort, with similar 
values of SD for mean changes, a total of 100 completers will give an over 90% power to 
detect a 2.5 points or larger difference in MMSE change from baseline values between the 
AD++ and non-AD++ groups, under a 5% two sided type I error rate.   
 
A subgroup of subjects from A05 confirmatory cohort will be selected and their flortaucipir 
scans will be read twice in a random sequence, for the intra-reader reliability evaluation of 
scan interpretation. According to A05 exploratory cohort data, the AD++  rate is 47% among 
AD/MCI subjects with baseline MMSE 20-27.  Assuming this will be the rate of AD++ from 
confirmatory cohort, a simulation showed that a sample size with 20 random selected cases 
will have an approximately 95% probability to have the AD++ rate in the range from 30% to 


Avid Radiopharmaceuticals                                                                                               
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70% for the selected cases. This relative balance AD++ rate will ensure a meaningful kappa 
statistics calculation for assessing the intra-reader reliability assessment.   
 
   
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. 
 
5.2 
Changes from the Analyses Planned in the Protocol/CIP 
 
The protocol was amended (version 07 August 2015, Amendment 2). In this amendment the 
study was divided into two phases, exploratory (first) phase and confirmatory (second) phase. 
Currently, this SAP provides the planned analyses for the confirmatory (second) phase of the 
study.


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6 
BASELINE, EFFICACY AND SAFETY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Exploratory (First) Phase and Confirmatory (Second) Phase: 
 
 
 


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 Confirmatory (Second) Phase Only: 
 
 
 


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6.2 Time Point Algorithms 
 
6.2.1 Relative Day 
 
The date of first dose of study drug (flortaucipir) will be considered relative day 1, and 
the day before the first dose of study drug will be relative day -1.  Relative days will be 
calculated as follows only when the full assessment date is known (i.e., partial dates will 
have missing relative days): 
 
For days on or after the first dose of study drug: 
Date of Assessment – Date of First Dose of Study Drug + 1. 
 
For days before the first dose of study drug: 
Date of Assessment – Date of First Dose of Study Drug. 
 
6.2.2 Windows 
 
For all analyses, results will be summarized at the planned study visit they were obtained 
(screening/baseline, or 9 or 18 months post baseline).  
 
6.3 Screening and Baseline Assessments 
 
Screening may take place over several days. All screening assessments should be 
performed within 30 days of the initial flortaucipir PET imaging session. Screening 
assessments will include:  
• Informed consent;  
• Demographics (age, gender, race, ethnicity, education, alcohol, drug use, and 
smoking);  
• Medical history, physical and neurological exams, concomitant medications;  
• Disease history (date/months since symptom onset, date/months since diagnosis, 
family history of neurologic disease) for cognitively impaired subjects;  
• Ohio State University Traumatic Brain Injury Identification Method (OSU TBI-
ID);  
• Mini Mental State Exam (MMSE);  
• Safety assessments: Vital signs (pulse rate, respiratory rate, supine blood pressure, 
height and weight), ECG, safety labs (hematology, chemistry, and urinalysis);  
• Serum beta human chorionic gonadotropin (hCG) test (for females of childbearing 
potential defined as pre-menopausal or less than 2 years post-menopausal and not 
surgically sterile);  
• MRI imaging including standard clinical sequences and volumetric MRI;  
• A physician will see the patient during the screening visit.  
 


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Baseline assessments may be performed at the screening visit or +/- 30 days of the initial 
flortaucipir Imaging Visit. Raters administering the MMSE and baseline assessments 
described below will be blinded to the flortaucipir scans for subjects in the confirmatory 
(second) phase.  
Baseline assessments will include:  
• Alzheimer’s Disease Assessment Scale- Cognitive subscale (ADAS-Cog11);  
• Neuropsychological test battery (Digit Symbol Substitution Test (DSST), Digit 
span forward and backward, Trail Making A and B, Logical Memory Test, 
Immediate and Delayed Recall Story A, Animal list generation, Boston Naming 
Test (BNT) (30 item), American National Adult Reading Test (ANART), Clock 
Drawing Test, Benton Judgment of Line Orientation test);  
• Clinical Dementia Rating (CDR) Sum of Boxes Scale; 
• Pfeffer Functional Activities Questionnaire (FAQ).   
 
Tau pathology can be associated with Traumatic Brain Injury (TBI), therefore the OSU 
TBI-ID (Corrigan and Bogner 2007) short version will be used to screen for a history of 
traumatic brain injury. It is the briefest version that still provides several summary indices 
on which the original version was validated. To shorten the instrument, TBIs resulting in 
loss of consciousness (LOC) are emphasized over less severe injuries. Classifying worst 
injury based on the OSU TBI-ID will all be displayed. The following classifies worst 
injury: 
• 1= Improbable TBI- if interview data reports all questions numbered 1-5 are all 
‘no’ or if response to question 6, interview data reports never having LOC, being 
dazed or having memory lapses. 
• 2= Possible Mild TBI without LOC- if in response to question 6, interview data 
reports being dazed or having memory lapse. 
• 3= Mild TBI with LOC- if in response to question 6, interview data reports LOC 
does not exceed 30 minutes for any injury. 
• 4= Moderate TBI-  if in response to question 6 , interview data reports LOC for 
one injury is between 30 minutes and 24 hours. 
• 5= Severe TBI- if in response to question 6, interview data reports LOC for any 
one injury exceeds 24 hours. 
 
Weight will be displayed in kilograms (kg), height will be displayed in centimeters (cm), 
and temperature will be displayed in Celsius (C). Weights, heights, or temperatures 
recorded in alternate units will be converted to the units being displayed using standard 
conversion formulas. Body mass index (BMI) will be calculated as weight (kg) divided 
by height squared (cm2). 
 
Each subject’s age (years) will be calculated based on his/her date of informed consent 
and will be truncated to a whole number.  Because only year of birth is collected, January 
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months between the date of informed consent and the imputed birthdate.  Divide the 
result by 12 and round down to the nearest integer to get the age of the subject. 
 
The number of years of education for a subject will be calculated for individuals who 
have specified the level of schooling he/she has obtained. The years of education will be 
calculated as follows: elementary school = 6 years, middle school = 8 years, high school 
= 12 years, college/university = 16 years, graduate/master’s degree = 18 years, 
PhD/multiple graduate degrees/medical degree = 20 years. Otherwise, if a subject 
specified the number of years of education, then this number will be used.  
 
For efficacy measurements, baseline is defined as the assessments recorded at screening 
visit. Baseline for safety assessments, including vital signs and labs are defined as last 
assessments prior to flortaucipir injection. For ECG safety assessments during the 
flortaucipir scan session, baseline value will be calculated as the average of the two 
ECGs administered prior to flortaucipir administration. If only one ECG was 
administered prior to flortaucipir administration, the baseline will be defined as the 
singular ECG administered prior to flortaucipir administration.   
 
6.4 Efficacy Variables 
 
6.4.1 Primary Efficacy Variable(s) 
 
6.4.1.1 Tau Status Based on flortaucipir 
 
Flortaucipir images will be assessed by 5 independent readers blinded to any clinical 
information of the subjects. The images will be classified as either AD++ (AD pattern, 
likely to progress), AD + (AD pattern, but unlikely to progress; tau limited to 
temporal/occipital lobe) or AD- (Inconsistent with an AD pattern) by each reader, 
following the pre-specified reading method (see imaging reading manual for details). The 
majority reading results derived from the 5 readers will be used to determine the tau 
status for each subject for primary objective analysis.  For the purposes of study analyses 
images will be considered positive for progression if they are rated AD ++ and negative 
for progression if they are rated non-AD++ (AD- or AD+ but not AD++). 
 
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 global rating of dementia can be 
generated from the domain scores. A CDR Sum of Boxes (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 will be performed at 
screening or baseline, 9 months, and 18 months post-baseline. CDR-SB will be used as a 
continuous scale in exploratory objective analysis, when assessing the average change 
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The detailed derivation of CDR global score is defined in Appendix 1 of this SAP. 
 
For primary and secondary analysis, the CDR-SB score change from baseline will be 
dichotomized in two groups: CDR-SB score change 1 point or more at 18 months, or 
otherwise. 
 
 
  
 
 
 
6.4.2 Additional Efficacy Variables 
 
 
 
6.4.2.1 Amyloid Beta Status Based on Florbetapir 
 
Florbetapir F 18 images will be assessed by an expert reader blinded to all clinical related 
information for the subjects. The images will then be classified as either AB+ (amyloid 
positive) or AB- (amyloid negative).   
 
 
6.4.2.2 Cognitive Assessments 
 
Cognitive assessments will be performed at screening or baseline. Some of the cognitive 
assessments will be evaluated at follow-up visits (9 (+/- 2) months, and 18 (+/- 2) 
months) during the study. These cognitive assessments include the following:   
 
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 will be performed at 
screening or baseline, 9 months, and 18 months post-baseline. The score on a continuous 
scale will be used for primary objective analysis, when assessing the average change 
from baseline by tau status.  
 
Alzheimer’s Disease Assessment Scale—Cognitive subscale (ADAS-Cog11)  
 
The ADAS (ADAS-Cog; Rosen et al. 1984) was designed to assess the severity of the 
dysfunction in the cognitive and noncognitive behaviors characteristic of persons with 
AD. The cognitive subscale of the ADAS, the ADAS-Cog11, consists of 11 items 
assessing areas of function most typically impaired in AD: orientation, verbal memory, 


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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 exploratory analysis, to assess the average change from baseline by tau status.  
 
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 will be performed at screening 
or baseline, 9 months, and 18 months post-baseline. FAQ sum score will be used as a 
continuous variable in secondary objective analysis, when assessing the average change 
from baseline by tau status.  
 
Digit Symbol Substitution Test (DSST)  
 
The DSST (Wechsler Adult Intelligence Scale F Revised, 1981) is a paper test of 
psychomotor performance in which the subject is given a key of numbers and matching 
symbols and a test section with numbers and empty boxes. Under each number the 
subject should write down the corresponding symbol as fast as possible. The score is the 
number of correct number-symbol matches made within the allowed time (90 seconds). 
The strategy to solve the DSST consists of sequential encoding and retrieval of numbers 
and corresponding symbols. Incidental memory, visuo-motor coordination, perceptual 
organization, and selective attention are key factors that determine the final score 
(Wechsler Adult Intelligence Scale Revised, 1981). The ability to sort out irrelevant 
information (e.g., symbols that may look alike) also impacts performance. This test has 
high test–retest reliability (Matarazzo and Herman, 1984). One point is given for each 
symbol correctly drawn during the ninety seconds, with the maximum score of 93. 
Greater totals denote lower disease severity. DSST total score will be used as a 
continuous variable for the exploratory analysis, to assess the average change from 
baseline by tau status. 
 
Digit span forward and backward (from Wechsler Memory Scale-Revised (WMS-R))  
 
Digit Span is composed of two tasks administered independently of each other: Digits 
Forward and Digits Backward. On both tasks, the examiner reads a series of number 
sequences to the subject. For each Digits Forward item, the subject is required to repeat 
the number sequence in the same order as presented. For Digits Backward, the subject is 


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required to repeat the number sequence in the reverse order. The score ranges from 0-24, 
a maximum score of 12 for digit span forward and a maximum score of 12 for digit span 
backward, with lower scores indicating greater disease severity. Total score from this test 
will be used as a continuous variable for the exploratory analysis, to assess the average 
change from baseline by tau status. 
 
Trail Making A and B  
 
The trail making test (Reitan and Wolfson, 1985) is a test of executive function. Part A 
consists of 25 circles numbered 1 through 25 distributed over a sheet of paper. The 
subject is instructed to connect the circles by drawing a line as quickly as possible in 
ascending numerical order. Part B consists of 25 circles containing either numbers (1 
through 13) or letters (A-L). The subject is instructed to connect the circles while 
alternating between numbers and letters in ascending order. The subject is timed. The 
total score is the time to complete Part A, with a maximum of 150 seconds and Part B 
with a maximum of 300 seconds. Timing is not stopped while correcting errors. Testing 
is stopped if the maximum time is reached. The total score is the number of seconds to 
complete both trails, where higher scores indicate greater disease severity. Total score 
will be used as a continuous variable for the exploratory analysis, to assess the average 
change from baseline by tau status. 
 
Logical Memory Test, Immediate and Delayed Recall, Story A (WMS-R)  
 
The logical memory test (Wechsler D. 1987) assesses the ability to recall a short story. 
Subjects are read a story and asked to recall the story immediately and after a delay. The 
maximum score is 25, and each point is obtained based on how much of the story is 
correct. Higher scores indicate better cognition. The immediate recall total as well as 
delayed recall total score will be used as continuous variables for the exploratory 
analysis, to assess the average change from baseline by tau status. 
 
Animal List Generation  
 
The animal list generation (Morris et al. 1989) is used to measure verbal fluency. The 
subject is asked to name as many animals as possible in 60 seconds. The total score is the 
count of all admissible words, where lower scores denote greater cognitive impairment. 
The total score will be used as a continuous variable for the exploratory analysis, to 
assess the average change from baseline by tau status. 
 
Boston Naming Test (BNT) (30 item)  
 
The 30 item Boston Naming Test (Kaplan, et al. 1983) is a measure of the ability to 
orally label 30 line drawings of objects. The objects are presented to the subject in order 
of frequency, from most frequent to least frequent. The maximum score is 30, where 


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higher scores indicate better cognition, obtained from the number of spontaneously given 
correct responses in addition to the number of correct responses following a stimulus cue. 
The total score will be used as a continuous variable for the exploratory analysis, to 
assess the average change from baseline by tau status. 
 
American National Adult Reading Test (ANART)  
 
ANART (Grober and Sliwinski 1991) is a measure for estimating premorbid verbal 
intelligence. The subject is presented with a word list and asked to pronounce the words. 
One point is given for each correctly pronounced word, with a maximum score of 45, 
where lower scores indicate greater disease severity. As an indicator of cognition reserve, 
baseline ANART score will be used as an adjusting variable in all the multivariate 
models.  
 
Clock Drawing Test  
 
The clock drawing test (Goodglass and Kaplan 1983) has two components: a command 
condition and a copy condition. In the command condition, the subject draws a clock 
according to verbal instructions. In the copy condition, the subjects copy a model clock 
drawn at the top of a form. The score ranges from 0-5 where a point is obtained for 
approximately circular face, symmetry of number placement, correctness of numbers, 
presence of two hands, and presence of two hands set to the correct time. Higher scores 
suggest better cognition. The total score will be used as a continuous variable for the 
exploratory analysis, to assess the average change from baseline by tau status. 
 
Benton Judgment of Line Orientation Test (JOLO)  
 
The JOLO (Benton 1978) is a non-motor measure of visual perceptual ability where there 
is no time demand. The task asks subjects to match two lines by their angle of orientation 
to a test set of lines presented below the stimulus lines. Each correct response is given 
one point and the maximum score is 30, where higher scores denote lesser disease 
severity. . The total score will be used as a continuous variable for the exploratory 
analysis, to assess the average change from baseline by tau status. 
 
6.4.2.3 Clinically Meaningful Progress 
 
The following cognitive/functional assessments will be dichotomized or categorized, to 
allow for the assessment of risk to progress to a clinically significant change. Subjects 
within each diagnostic group will be categorized to these groups by the criteria 
accordingly. 
 
MMSE: clinically significant progress is defined as MMSE has a 3 points or more 
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FAQ:   clinically significant progress is defined as FAQ has a 3 points or more increase 
from baseline.  
   
ADAS Cog-11:   clinically significant progress is defined as ADAS Cog-11 has a 4 
points or more increase from baseline.  
 
CDR Global:   CDR global change from baseline will be categorized into 3 groups such 
as >0, = 0 and <0.  
 
 
6.4.2.4 ApoE Genotyping 
 
ApoE genotyping will be performed at the initial flortaucipir imaging session for those 
subjects whose ApoE is unknown.  For analysis purposes, subjects will be categorized as 
ApoE ε4 positive (ε4+) if at least one allele is an ε4 allele and ApoE ε4 negative (ε4-) if 
neither allele is an ε4 allele.   
 
6.4.2.5 Genetic Samples 
 
A one-time blood collection (10 mL, blood) will be performed on the day of the initial 
flortaucipir imaging session for genetic analysis. Where local regulations allow, samples 
will be stored and analysis may be performed on genetic variants thought to play a role in 
dementia or related diseases. Samples will only be used for investigations related to 
disease and drug or class of drugs under study in the context of this clinical program. 
They will not be used for broad exploratory unspecified disease or population genetic 
analysis. No prospective analyses will be performed using this data. 
 
 
 
6.4.2.6 MRI Scan of the Brain 
 
MRI, including both volumetric and standard clinical sequences, will be conducted 
during Screening. A MRI will be performed on the whole brain, ventricle, and 
hippocampus. Normalized volumetric measurements, including whole brain, total gray 
region, ventricle, and hippocampal volumes will be conducted, and used for correlation 
analysis with cognition changes or corresponding flortaucipir imaging uptake values. 
 
6.5 Drug Concentration Measurements and Pharmacokinetic Parameters 
 
6.5.1 Handling of Pharmacokinetic Parameter Outliers 
 
No pharmacokinetic parameters or drug concentration measurements will be collected 
during this study. 


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6.6 Safety Assessments 
 
6.6.1 Extent of Exposure and Compliance to Study Treatment 
 
During the florbetapir F 18 imaging session, subjects will receive a single IV bolus 
administration target dose of 370 MBq (10 mCi) of florbetapir F 18 injection followed by 
a 10 minute PET brain scan (2 acquisitions of 5 minute duration) at 50 minutes post 
injection. During the flortaucipir imaging session, all subjects will receive a single IV 
bolus administration target dose of 370 MBq (10 mCi) of flortaucipir injection. At 
approximately 80 minutes post dose, scanning will begin. Four 5-minute acquisitions will 
be taken. Exposure to study drug will be summarized as the total administered dose for 
both florbetapir F 18 injection and for flortaucipir exposures.  
 
6.6.2 Adverse Events 
 
The investigator’s verbatim term of both serious and non-AEs will be mapped to system 
organ class (SOC) and preferred terms using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). 
 
Treatment-emergent AEs (TEAEs) are undesirable experiences, signs, or symptoms that 
begin or worsen in intensity or frequency at the time of or after the administration of 
study drug, and prior to 48 hours post dose injection of each scan sessions.  Trial-
emergent AEs are undesirable experiences, signs or symptoms between enrollment and 
any of the baseline scan sessions, or between the baseline florbetapir and baseline 
flortaucipir scan sessions but not within the 48 hours window post dose injection of each 
scan session. These events will be recorded on the AE page of the electronic case report 
form (eCRF). During the trial, any events happening outside the TEAE or trial-emergent 
AE window as defined above will be collected in medical history form, unless the site 
physicians consider it a study drug related event.  
 
Serious AEs (SAEs) are events that result in one of the following outcomes or constitute 
one of the following events: 
• Death 
• Initial or prolonged hospitalization (other than that required by protocol; “social 
hospitalization” or any hospitalization for non-medical reasons does not constitute 
an SAE) 
• A life-threatening experience (that is, immediate risk of dying) 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Considered significant by the investigator for any other reason 
 


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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
 
For the summarization of TEAEs by seriousness, events recorded with missing 
seriousness will be summarized as serious. 
 
Investigators will be instructed to report their assessment of the potential relatedness of 
each AE to protocol procedure, concomitant medication, and/or investigational product. 
The assessment of the relationship of an AE to the administration of the investigational 
product is a clinical decision based on all available information at the time of the 
completion of the eCRF. For the summarization of TEAEs by relationship to study drug 
or protocol procedure, events recorded with missing relationship will be summarized as 
Related. 
 
In addition to assessing the relationship of the administration of the investigational 
product to AEs, an assessment is required of the severity of the event. The following 
classifications should be used: 
 
Mild: 
A mild AE is an AE, usually transient in nature and generally not interfering with normal 
activities. 
 
Moderate: 
A moderate AE is an AE that is sufficiently discomforting to interfere with normal 
activities. 
 
Severe: 
A severe AE is an AE that incapacitates the subject and prevents normal activities. Note 
that a severe event is not necessarily a serious event. Nor must a serious event necessarily 
be severe. 
 
For the summarization of TEAEs by intensity, events recorded with missing intensity will 
be summarized as Severe. 
 
6.6.3 Clinical Laboratory Evaluations 
 
Clinical laboratory evaluation will be performed at screening, prior to administration of 
flortaucipir injection, and after completion of flortaucipir imaging. Tests will include: 
• Hematology (5 mL EDTA): hemoglobin, hematocrit, RBC, WBC, MCH, MCHC, 
neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils, platelets, 
morphology, MCV, and RBC morphology. 


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• Chemistry (6 mL blood): total bilirubin, alkaline phosphatase, ALT (SGPT), AST 
(SGOT), urea nitrogen, creatinine, glucose, uric acid, calcium, phosphorus, total 
protein, albumin, total cholesterol, triglycerides, sodium, potassium, bicarbonate, 
chloride, magnesium, globulin, GGT. 
• Urinalysis (10 mL, urine): Samples will be used to assess glucose, RBC, WBC, 
specific gravity, pH, protein, ketones, urobilinogen, blood, nitrite, microscopic, 
color, bilirubin, casts, epithelial cells, leukocyte, esterase, and bacteria. 
• Serum beta hCG, qualitative: performed at screening for females of childbearing 
potential who are not surgically sterile. A serum pregnancy test may also be 
obtained prior to injection at the Imaging Visit if required by the local site. 
• Urine beta hCG:  performed at the imaging visit(s) prior to injection for females 
of childbearing potential (defined as pre-menopausal, less than 2 years post-
menopausal or not surgically sterile). 
• ApoE Genotyping (10mL, blood): will be performed at the initial flortaucipir 
imaging session for those subjects whose ApoE results are unknown. 
 
Baseline for clinical laboratory evaluations will be calculated as described in section 6.3.  
Change from baseline for continuous post-baseline assessments will be calculated as the 
result at the visit minus the baseline value.  For applicable laboratory tests, laboratory 
values will be defined as low, normal, or high relative to the normal reference ranges for 
each subject’s age and sex.  Criteria for potentially clinically significant laboratory results 
are defined in Appendix 2 of the SAP.  A result will be considered potentially clinically 
significant if the result occurs post-baseline and no test results at or prior to baseline for 
the parameter in question meet the same criteria for potential clinical significance. 
 
6.6.4 Other Observations Related to Safety 
 
6.6.4.1 Vital Signs 
 
Vital signs (pulse rate, respiratory rate, and supine blood pressure) will be taken at the 
following time points:  
• Screening visit  
• Florbetapir F18 Imaging Day  
• immediately prior to injection of florbetapir F 18  
• Flortaucipir Imaging Day  
• Immediately prior to the administration of flortaucipir injection  
• Within 5 minutes after completion of injection of flortaucipir injection  
• After the completion of imaging prior to discharge  
 
Temperature will be obtained at the following time points:  
• Flortaucipir Imaging Day  
• Immediately prior to the administration of flortaucipir injection  


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• After the completion of imaging prior to discharge  
 
Baseline for vital signs will be calculated as described in Section 6.3.  Change from 
baseline for post-baseline assessments will be calculated as the result at the visit minus 
the baseline value.  Criteria for potentially clinically significant vital sign results are 
defined in Appendix 3 of this SAP.  A measurement will be considered potentially 
clinically significant if the measurement occurs post-baseline and no measurements at or 
prior to baseline for the parameter in question meet the same criteria for potential clinical 
significance. 
 
6.6.4.2 Electrocardiogram (ECG) 
 
A resting 12-lead electrocardiogram will be recorded at screening. At the 
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imaging visits the ECGs will be taken at the following time points:  
• Two ECGs will be taken at approximately 5 minutes apart immediately prior 
(within approximately 10 minutes) to flortaucipir injection administration.  
• One ECG will be taken immediately (within approximately five minutes) after 
completion of flortaucipir injection.  
• One ECG will be taken after completion of the PET scan prior to discharge.  
 
Baseline for ECGs will be calculated as described in section 6.3.  Change from baseline 
for post-baseline assessments will be calculated as the result at the visit minus the 
baseline value.  Criteria for potentially clinically significant ECG results are defined in 
Appendix 3 of this SAP.  A result will be considered potentially clinically significant if 
the result occurs post-baseline and the baseline result for the parameter in question does 
not meet the same criteria for potential clinical significance. 
 
6.7 Pharmacodynamics Parameters 
 
No pharmacodynamics parameters will be collected during this study. 
 
7 STATISTICAL METHODS 
 
7.1 General Methodology 
 
 Frequency distributions including counts and percentages will be included for all 
categorical outcomes. Summary statistics including mean, standard deviation, median, 
minimum and maximum values will be presented for all continuous outcomes. Unless 
otherwise specified, hypothesis testing will be two-sided with type I error rate of 0.05. 
 
All statistical analyses will be performed using SAS® version 9.3 or higher.  
 
7.2 Adjustments for Covariates 
 


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For multivariate model analyses using cognitive or function assessments as dependent 
variables, the models will be adjusted for baseline age and baseline American national 
adult reading test (ANART) score. 
 
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. 
 
A likelihood-based mixed effects model for repeated measures will be used to handle 
missing data.  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.  
 
 
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 
 
This study will be conducted in approximately 30 centers. The data from all centers will 
be pooled. The pooled data will be analyzed and presented.  
   
7.6 
Multiple Comparisons/Multiplicity 
 
To control the overall type I error rate at 0.05, a gate keeper methodology will be 
employed (Marcus, et. al., 1976). Hypotheses will be tested in the following order:  
 
1.  Testing of hypothesis for primary objective analysis; 
2.  Testing of hypothesis for secondary objective analysis.  
 
Hypothesis testing will begin testing (1) at the 0.05 level. If the p-value is less than or 
equal to 0.05, the second hypothesis will be tested.  These hypotheses will be marked in 
the table as having passed or failed the multiple comparisons testing. All p-values will be 
displayed regardless of passing or failing the multiple comparisons testing. 
 


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7.7 
Use of an “Efficacy Subset” of Subjects 
 
Invalid PET images will be excluded from analysis. An image will be considered invalid 
if it is missing, cannot be reconstructed or is irretrievably missing key identifying 
information as determined by the Expert Review Process document. All scans that pass 
Quality Control and the Expert Review Process will be read for the purposes of the 
primary and secondary endpoints.   The contracted independent imaging readers will be 
able to rate scans as evaluable or unevaluable.  Regardless of reader rating of technical 
adequacy (i.e., evaluable vs. unevaluable), all readers will be asked to record their scan 
interpretation and this result will be used for study endpoints analyses. If 3 or greater of 
the 5 readers rate a scan as unevaluable, additional sensitivity 
analyses for key primary and secondary endpoints will be conducted excluding these 
scans.  All analyses involving flortaucipir imaging outcomes will be based on the efficacy 
population. 
 
7.8 
Active-Control Studies Intended to Show Equivalence 
 
Not applicable to this study. 
 
7.9 
Examination of Subgroups 
 
Not applicable to the confirmatory phase of this study. 
 
8 
STATISTICAL ANALYSIS 
 
8.1 
Disposition of Subjects 
 
The number and percentage of subjects who were treated, who completed the study, and 
who discontinued from the study, as well as the reasons for discontinuing, will be 
summarized.  
 
Data on screening failures (subjects who signed informed consent but were not entered 
into the trial) were not collected on the CRF, are not included in the database and will not 
be presented. 
 
8.2 
Protocol Deviations/Violations 
 
Subjects who entered the study even though they did not satisfy one or more of the 
inclusion/exclusion criteria will be listed.  Deviations/violations from the protocol will be 
documented, the Avid/contract research organization (CRO) monitor will then be 
informed and a course of action will be agreed upon. 
 
8.3 
Analysis Populations 
 


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8.3.1 Enrolled Population 
 
The enrolled population will consist of all subjects in the clinical database.  Disposition 
information will be summarized using the safety population. 
 
8.3.2 Safety Population for flortaucipir 
 
The safety population for investigational drug will consist of all subjects that received an 
injection of flortaucipir. All baseline, efficacy endpoints, and safety endpoints for 
flortaucipir will be summarized and listed using the safety population for flortaucipir. 
 
8.3.3 Safety Population for florbetapir 
 
The safety population for investigational drug will consist of all subjects that received an 
injection of florbetacipir. All safety endpoints for florbetapir will be summarized and 
listed using the safety population for florbetapir. 
 
 
8.3.4 Safety Population for Study  
 
The safety population for study will consist of all subjects that received an injection of 
flortaucipir and/or an injection of florbetapir 18 F.  The disposition summary will be 
based on the safety population for study. 
 
8.3.5 Efficacy Population 
 
The efficacy population will include all subjects with a valid, interpretable PET images 
and at least one clinical/cognitive assessment. The primary/secondary efficacy population 
will include all subjects with a valid, interpretable PET images and the relevant 
clinical/cognitive assessment post flortaucipir scan.      
 
8.4 
Demographic and Other Baseline Characteristics 
 
All baseline summaries will be based on the safety population. 
 
Frequency distributions and summary statistics for demographic and baseline variables 
will be presented by enrolling diagnosis groups, and for all subjects combined. Key 
demographic and baseline characteristics to be summarized include: age, gender, race, 
ethnicity, height, weight, BMI, education, alcohol history, recreational drug use history, 
smoking history, medical history, family disease history, cognitive assessments, worst 
brain injury history, physical examination, and neurological examination.  
 
All demographic and baseline characteristics data will be presented in listings. 


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8.5 
Prior and Concomitant Therapy  
 
A current version of the World Health Organization (WHO) Drug Dictionary will be used 
to classify medications by preferred term and WHO Anatomical Therapeutic Chemical 
(ATC) classification of ingredients. ATC classification level 3 will be used. If level 3 is 
missing, then level 2 will be used. If level 2 is missing, then level 1 will be used. Any 
medication given before the day of administration of study drug is considered a prior 
medication. Any medication given on or after the day of administration of study drug is 
considered a concomitant medication. A medication can be considered both prior and 
concomitant. The most conservative algorithms will be implemented in case a medication 
has partial start/stop date information. 
 
Descriptive statistics, such as frequency counts and percentages will be provided to 
summarize the use of medications other than the study drug reported throughout the 
study.  The number and percentage of subjects who received other treatment will be 
shown by WHO classification of ingredients and by preferred term.  No statistical tests 
will be performed on prior and concomitant medications.  All prior and concomitant 
medications data will be presented in listings. 
 
8.6 
Analysis of Efficacy Parameters 
 
8.6.1 Confirmatory Phase, Longitudinal Analysis 
 
8.6.1.1 Analysis of Primary Efficacy Variable 
 
8.6.1.1.1 Hazard Ratio of AD++ vs. Non-AD++ Subjects in Progression to Clinically 
Meaningful Changes Evaluated by CDR-SB   
 
As described in section 6.4.1.2, the primary efficacy variable will be the dichotomized 
CDR-SB score change from baseline (1 point or more increase vs. otherwise). Time to 
first occurrence of this clinically meaningful event will be modeled using a Cox 
proportional hazard model by baseline tau status as determined by majority flortaucipir 
scan visual reading results from the 5 independent imaging physicians, and the hazard 
ratio of AD++ rated subjects progressing to the event over non-AD++ rated subjects 
along with the 95% confidence interval will be provided. The Cox proportional hazard 
model will be adjusted for baseline age, ANART, and baseline CDR-SB score.  
 
The specific hypothesis for testing is that the hazard of progressing to this clinically 
meaningful event as determined by CDR-SB value change within 18 months will be 
significantly greater for subjects with flortaucipir scans rated as AD++, as comparing to 
those with scans rated as non-AD++ (otherwise, including AD- and AD+ but not AD++ 
reading).   


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8.6.1.2  Analysis of Secondary Efficacy Variable 
 
8.6.1.2.1 Diagnostic Performance of Baseline Tau Status in Predicting Clinically 
Meaningful Changes Evaluated by CDR-SB   
 
This Analysis will use dichotomized CDR-SB Change (1 point or more increase vs. 
otherwise) as a truth standard (TS) to assess the diagnostic performance of baseline tau 
status as determined by flortaucipir scan. The assessments will be conducted for each of 
the 5 independent imaging readers. Sensitivity, specificity, negative predictive value 
(NPV), positive predictive value (PPV), positive likelihood ratio (LR+), negative 
likelihood ratio (LR-) will be calculated, with details as below: 
 
 
 
 
Clinically Meaningful Change
 Change +
Change-
AD++
  A
   B
Non-
AD++ 
   C
  D
 
Sensitivity = A/(A+C) 
 
Specificity = D/(B+D) 
 
Accuracy = (A+D)/(A+B+C+D) 
 
PPV=A/(A+B) 
 
NPV = D/(C+D) 
 
LR+ = Sensitivity/ (1-Specificity) 
 
LR- = (1-Sensitivity) /Specificity 
 


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The confidence intervals around sensitivity, specificity, accuracy, NPV, and PPV will be 
calculated by Wilson score method.  
 
The hypothesis for testing is that, of the 5 independent imaging physicians, at least the 
same 3 will have the lower bounds of two-sided 95% CIs ≥ 50%, for both sensitivity and 
specificity.  
 
 
8.6.1.3  Exploratory Analysis 
 
8.6.1.3.1 CDR Clinically Meaningful Deterioration 
 
The CDR global score change from baseline will be categorized into 3 groups: <0, = 0 
and >0.  
A Cochran-Armitage trend test will be applied to compare the groups of CDR global 
score change from baseline  by baseline tau scan groups at 9 months and 18 months 
respectively.  
 
8.6.1.3.2 
Mixed Model Repeated Measures for Comparison of MMSE over time as 
a function of Tau scan visual interpretation 
 
Descriptive summary statistics for the MMSE cognitive scale at baseline, 9 months, and 
18 months will be provided by all subjects. The change from baseline to 9 months and 18 
months will be summarized in the same corresponding table. 
 
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 
exploratory analysis will test that hypothesis using change from baseline MMSE as the 
indicator of cognitive deterioration. The flortaucipir scans will be visually interpreted by 
5 imaging physicians independently, and the majority classification from their 
interpretations will be used to decide if the scan is AD++ (predicts cognition likely to 
progress) or non-AD++ (not likely to progress over 18 months).  The specific hypothesis 
for testing is that the MMSE change (worsening) from baseline to month 18 will be 
significantly larger for AD++ group, as comparing to non-AD++ group.  The hypothesis 
will be tested using an MMRM analysis method. MMSE change from baseline (at 9 and 
18 months visit) will be used as a dependent variable, and the model will include the 
fixed effects of tau status (AD++ or non-AD++), visit (categorical covariate), tau status-
by-visit interaction, baseline MMSE score, baseline age, and baseline ANART score as 
continuous covariates.  The null hypothesis is that the least squared mean contrast 
between AD++ and non-AD++ groups at month 18 visit equals zero. 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 convergence, the following 
tests will be used in sequence: heterogeneous Toeplitz covariance structure, 
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structure. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom.  
 
 
LS Mean change will also be graphed as the change in MMSE score across time by 
AD++ and non-AD++ groups. 
 
8.6.1.3.3 Mixed Model Repeated Measures for Comparison of CDR-SB over time as a 
function of Tau scan visual interpretation   
 
The same analyses will be performed as described in Section 8.6.1.3.2 with the 
substitution of CDR-SB for MMSE.  
 
8.6.1.3.4 Mixed Model Repeated Measures for Comparison of FAQ over time as a 
function of Tau scan visual interpretation   
 
The same analyses will be performed as described in Section 8.6.1.3.2 with the 
substitution of FAQ for MMSE.  
 
8.6.1.3.5 Mixed Model Repeated Measures for Comparison of ADAS Cog-11 Score over 
time as a function of Tau scan visual interpretation   
 
The same analyses will be performed as described in Section 8.6.1.3.2 with the 
substitution of ADAS Cog-11 for MMSE.  
 
 
 
8.6.1.3.6 Mixed Model Repeated Measures for Comparison of DSST over time as a 
function of Tau scan visual interpretation   
 
The same analyses will be performed as described in Section 8.6.1.3.2 with the 
substitution of Digital Symbol Substitute Test (DSST) for MMSE.  
 
8.6.1.3.7 Mixed Model Repeated Measures for Comparison of Logical Memory Test-
Delayed Recall over time as a function of Tau scan visual interpretation   
 
The same analyses will be performed as described in Section 8.6.1.3.2 with the 
substitution of logical memory test-delayed recall score for MMSE.  
 
8.6.1.3.8 Mixed Model Repeated Measures for Comparison of Logical Memory Test-
Immediate Recall over time as a function of Tau scan visual interpretation   
 
The same analyses will be performed as described in Section 8.6.1.3.2 with the 
substitution of logical memory test-immediate recall score for MMSE.  


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8.6.1.3.9 MMSE Clinically Meaningful Changes 
 
 A 3 point drop in MMSE at follow up visits will be considered as clinically meaningful 
change for this analysis.  Time to first occurrence of this clinically meaningful event will 
be modeled using a Cox proportional hazard model by tau status as determined by 
flortaucipir scan, and the hazard ratio of AD++ rated subjects progressing to the event 
over non-AD++ rated subjects along with the 95% confidence interval will be provided. 
The Cox proportional hazard model will be adjusted for baseline age, ANART, and 
baseline MMSE score.  
 
 
8.6.1.3.10 FAQ Clinically Meaningful Deterioration  
 
The same analysis will be performed as described in Section 8.6.1.3.9 for FAQ. 
However, a change from baseline in FAQ score >= 3 will be used instead of the MMSE 
evaluation. 
 
 
8.6.1.3.11 ADAS Clinically Meaningful Deterioration  
 
The same analysis will be performed as described in Section 8.6.1.3.9 for ADAS Cog-11. 
However, a change from baseline in ADAS Cog-11 total score >= 4 will be used instead 
of the MMSE evaluation. 
 
8.6.1.3.12 Prognostic Value of the Classification According to Amyloid and Tau Scans  
 
Subjects will be sorted to these 3 groups, according to their flortaucipir and florbetapir 
scan visual reading results: AB+ AD++, AB+ AD+ (but not AD++) or AB+ AD-, and 
AB-. Then analyses as described in section 8.6.1.3.2 to 8.6.1.3.5 will be repeated, by 
replacing flortaucipir scan reading results with this 3-level group variable.  
 
8.6.1.3.13 Relationship of Amnestic MCI and Tau among MCI Subjects 
 
MCI subjects will be classified as amnestic MCI vs. non-amnestic MCI according to their 
logical memory delayed recall score: MCI subjects with baseline logical memory delayed 
recall score 8 or less (approximately 1 SD below mean value at baseline according to the 
exploratory cohort data) will be classified as amnestic MCI, otherwise will be classified 
as non-amnestic MCI. An MMRM model will be applied to explore the relationship of 
amnestic MCI and tau among MCI subjects, on the global cognitive and functional 
assessments including MMSE, CDR-SB, ADAS Cog-11 and FAQ. The model will have 
change from baseline in cognitive/functional assessments as dependent variable, and the 
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(amnestic + or amnestic -), visit (categorical covariate), amnestic-by-tau status 
interaction, amnestic-by-tau status-by-visit interaction, baseline assessment score, 
baseline age, and baseline ANART score as continuous covariates. The model building 
will follow details as described in section 8.6.1.3.2. The contrast will be set up to 
compare the MMSE change at 18 months between AD++, amnestic + vs. AD++, 
amnestic -; between AD++, amnestic + vs. non-AD++, amnestic +; between –non-AD++, 
amnestic + vs. –non-AD++, amnestic -; between AD++, amnestic - vs. –non-AD++, 
amnestic -.  
 
LS Mean change will also be graphed as the change in MMSE score across time by these 
4 groups (AD++amnestic+, AD++amnestic-, non-AD++amnestic+, and non-AD++ 
amnestic-). 
 
8.6.1.3.14 Prognostic Value of Baseline Clinical Evaluations versus Tau Scan 
 
Relevant baseline clinical and demographic information that are commonly used in 
clinical practice for patient’s clinical stage assessment, including diagnosis (MCI or 
dementia), MMSE, age, education, and APOE E4 allele carrying status will be included 
in the following analyses to evaluate the prognostic values of these information in regards 
to the progression in CDR-SB values. Two sets of analyses will be performed: 
 
8.6.1.3.14.1 Multivariate Regression Model 
 
For this analysis, the CDR-SB change from baseline at 18 months will be used as 
dependent variable, and the baseline clinical/demographic information (diagnosis, 
MMSE, age, years of education, and E4 carrying vs. not) will be included as predictors. 
The partial R-squares from each predictor, associated F and P-value will be reported.  
 
A separate model will be run by including majority tau scan visual reads (AD++ vs. non-
AD++, as described in section 6.4.1.1), in addition to all those baseline 
clinical/demographic information. An identical analysis as above will be performed to 
assess the contribution of the majority tau scan visual reads, in addition to the baseline 
information.    
 
8.6.1.3.14.2 Receiver Operating Characteristic Analysis 
 
For this analysis, CDR-SB change at 18 months will be dichotomized as CDR-SB change 
1 point or more vs. otherwise (described in section 6.4.1.2), and will be used as a 
dependent variable in a logistic regression model. Baseline clinical/demographic 
information as described in section 8.6.1.14.1 will be included in this logistic regression 
as predictors, along with the majority tau scan visual reads. Two receiver operating 
characteristic (ROC) curves will be generated from this model, and will be displayed in 
the same figure: ROC curve for model including all baseline clinical/demographic 


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information; ROC curve for model including both baseline clinical/demographic 
information and majority tau scan visual reads. Area under curve (AUC) values from 
both models will be contrasted, and the associated p-value for comparison will be 
reported.  In addition, the sensitivity and specificity of majority tau scan visual reads 
alone will be determined, and its relative data point (sensitivity, 1-specificity) will be 
displayed along with the other two ROC curves in the same figure.  
 
8.6.1.4 Additional Efficacy Analysis 
 
8.6.1.4.1 Inter-rater Agreement 
 
A Fleiss’ kappa will also be calculated to assess the overall inter-reader agreement across 
all 5 readers for visual classification of flortaucipir scans. The Cohen’s kappa coefficients 
to show pair-wise agreement between readers will also be calculated.  
The P value testing will be presented if a nonzero correlation is observed. 
 
8.6.1.4.2 Intra-rater Agreement 
 
Twenty scans from the confirmatory cohort will be randomly selected for the evaluation 
of intra-rater agreement. These 20 scans will be assigned with two unique randomization 
codes each, and randomized into the reading sequence along with all other scans in order 
to  be read twice by the same readers in a random sequence. To assess the intra-rater 
agreement, a Cohen’s kappa statistics will be applied. A point estimation along with 95% 
CI will be reported for each reader.    
 
     
 
 
8.6.1.5 Subgroup Analyses 
 
 
 
8.6.1.5.1 Age group: Subjects will be grouped as age <=75 years or >75 years.  
 
Primary and secondary analyses as described in section 8.6.1.1.1 and 8.6.1.2.1 will be 
repeated according to the age groups. 
 
8.6.1.5.2 Sex 
 
Primary and secondary analyses as described in section 8.6.1.1.1 and 8.6.1.2.1 will be 
repeated according to sex. 
 
8.6.1.5.3 Diagnosis 
 


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Primary and secondary analyses as described in section 8.6.1.1.1 and 8.6.1.2.1 will be 
repeated according to enrollment diagnosis, that is, demented or MCI. 
 
8.6.1.5.4 CDR Global Score Group 
 
Subjects will be grouped to two groups according to baseline CDR global score: CDR 
global score > 1, and otherwise. Primary and secondary analyses as described in section 
8.6.1.1.1 and 8.6.1.2.1 will be repeated according to this baseline CDR global score 
group. 
 
 
8.7 
Analysis of Safety 
 
8.7.1 Extent of Exposure and Compliance to Study Treatment 
 
The total dose administered (mCi) of flortaucipir and florbetapir F 18 will be summarized 
using descriptive statistics (n, mean, SD, median, min, max, 25th, and 75th pct).  All 
exposure data will be presented in listings. 
 
Because this is a study with only one bolus of study medication per imaging agent, 
compliance will not be summarized.   
 
8.7.2 Adverse Events 
 
All AE summaries will be based on the set of TEAEs only.  TEAEs will be summarized 
alphabetically by SOC and preferred term; a subject will only be counted once per SOC 
and once per preferred term.  Subject counts and percentages will be presented for the 
following summaries: 
 
1. All TEAEs by system organ class (SOC) and preferred term; 
2. All TEAEs by preferred term (in order of descending frequency); 
3. All TEAEs by relationship to study drug, SOC, and preferred term; 
4. All TEAEs by relationship to protocol procedure, SOC and preferred term; 
5. All TEAEs by severity, SOC and preferred term 
 
For the summary of TEAEs by severity, if a subject has multiple events occurring in the 
same SOC or same preferred term, the event with the highest severity will be counted.   
 
TEAEs by relationship to study drug and protocol procedure will be summarized as 
Related vs. Not Related.  If a subject has multiple events occurring in the same SOC or 
same preferred term, the related event will be summarized.   
 
Listings will be presented by subject for all TEAEs as well as for Serious TEAEs, TEAEs 
associated with death, and TEAEs associated with study discontinuation. Listings will 


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also present adverse events relative to the first dose and relative to the flortaucipir 
injection. 
 
8.7.3 Clinical Laboratory Evaluations 
 
Laboratory test values from the flortaucipir imaging session at each time point and for 
change from baseline to end of study will be displayed using summary statistics (n, mean, 
SD, median, min, max, 25th pct, and 75th pct).  This will be calculated within each 
diagnostic group and on all subjects.  Potentially clinically significant laboratory results 
will be displayed using frequency and percentage of subjects with the result. 
 
All clinical laboratory data will be presented in listings.  Within each listing, laboratory 
values outside the normal ranges will be flagged as either high (H) or low (L).  In 
addition, shift tables will be presented to display the shift in the normal range categories 
(L, normal (N), H) from baseline to the final evaluation.  Baseline is defined in section 
6.3.   
 
8.7.4 Other Observations Related to Safety 
8.7.4.1 Vital Signs 
 
Observed vital sign measurements as well as changes from baseline will be summarized 
using descriptive statistics (n, mean, SD, median, min, max, 25th pct, and 75th pct) for 
each time point across all subjects and by diagnostic group. At each post-baseline 
assessment, a paired t-test will be used to test the hypothesis that the change from 
baseline is not statistically different than zero, for all subjects summary only. Clinically 
significant vital signs will be highlighted.  
 
All vital signs data will be presented in listings.  Baseline is defined in section 6.3.   
 
8.7.4.2 Electrocardiogram 
 
The ECG measures (QTc-B, QTc-F, QT, RR, PR, and QRS) from the flortaucipir 
imaging session will be listed and summarized with descriptive statistics (n, mean, SD, 
median, min, max, 25th pct, 75th pct) at each time point by diagnostic group. At each 
post-baseline assessment, a paired t-test will be used to test the hypothesis that the change 
from baseline is not statistically different than zero.  This will be calculated within each 
diagnostic group and on all subjects.  Potentially clinically significant ECG results will be 
displayed using frequency and percentage of subjects with the result. 
The number and percentage of subjects with normal and abnormal ECG results, as judged 
by the investigator, will be displayed and ECG changes from screening will be 
calculated. 
 


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8.8 Pharmacodynamics 
 
No pharmacodynamics analyses are planned for this study. 
 
9 COMPUTER SOFTWARE 
 
All analyses will be performed by Chiltern International Inc. using Version 9.3 or later of 
SAS software.  All summary tables and data listings will be prepared utilizing SAS 
software. 
 
For continuous variables, descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum, maximum, 25th pct, and 75
th pct) will be generated.  
The standard operating procedures (SOPs) of Chiltern International Inc. will be followed 
in the creation and quality control of all data displays and analyses. 
 
 
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beta-amyloid detected using [11C] PiB positron emission tomography and neuropathologic 
assessment in older adults”. Arch Neurol 2011;68(2):232–240.  
 
Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., Fagan, A.M., Iwatsubo, 
T., Jack, C.R., Jr., Kaye, J., Montine, T.J., Park, D.C., Reiman, E.M., Rowe, C.C., Siemers, 
E., Stern, Y., Yaffe, K., Carrillo, M.C., Thies, B., Morrison-Bogorad, M., Wagster, M.V.,  
Phelps, C.H. 2011. “Toward defining the preclinical stages of Alzheimer's disease: 
Recommendations from the National Institute on Aging-Alzheimer's Association workgroups 
on diagnostic guidelines for Alzheimer's disease”. Alzheimers Dement 7(3), 280-92.  
 
Wechsler Adult Intelligence ScaleFRevised. San Antonio, TX: Psychological 
Corporation, 1981. 
 
Wong, D.F., Rosenberg, P.B., Zhou, Y., et al. “In vivo imaging of amyloid deposition in 
Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)”. J Nucl 
Med. 2010;51(6):913-920.  
 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent for 
Alzheimer’s disease,” Alzheimers Dement. 2013, 1-11 


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11 APPENDICES 
 
11.1 Appendix 1 - Derivation of Clinical Dementia Rating Score 
 
The global CDR was derived from the scores in each of 6 categories ("box scores"). Memory (M) was considered the primary 
category and all others were secondary. 
• CDR = M if at least 3 secondary categories were given the same score as M. 
• Whenever 3 or more secondary categories were given a score greater or less than M, CDR equaled the score of the majority of 
secondary categories on whichever side of M had the greater number of secondary categories. 
• When 3 secondary categories were scored on one side of M and 2 secondary categories were scored on the other side of M, 
CDR = M. 
• When M = 0.5, CDR = 1 if at least 3 of the other categories were scored 1 or greater. If M = 0.5, CDR could not be 0; it could 
only be 0.5 or 1. If M = 0, CDR = 0, unless there was impairment (0.5 or greater) in 2 or more secondary categories, in which 
case CDR = 0.5. 
 
Although applicable to most AD situations, these rules do not cover all possible scoring 
combinations. Unusual circumstances occur occasionally in AD and may be expected in 
non-Alzheimer’s dementia as well. These circumstances were scored as follows: 
• With ties in the secondary categories on one side of M, the tied scores closest to M for CDR were chosen (eg, M and another 
secondary category = 3, 2 secondary categories = 2, and 2 secondary categories = 1; CDR = 2). 
• When only 1 or 2 secondary categories were given the same score as M, CDR = M as long as no more than 2 secondary 
categories were on either side of M. 
• When M = 1 or greater, CDR could not be 0; in this circumstance, CDR = 0.5 when the majority of secondary categories were 
0. 
 
 


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11.2 Appendix 2 – Laboratory Results – Potentially Clinically Significant Criteria 
Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
Unit 
Low  
High 
SI 
Unit 
Conversion  
Factor 
Hematology 
 
 
 
 
 
 
 
Hematocrit 
HCT  
% 
Male ≤ 
37% 
Female 
≤ 32% 
NA 
L/L 
0.01 
Hemoglobin 
Hgb  
g/dL 
Male ≤ 
11.5 
Female 
≤ 9.5 
NA 
g/L 
10 
White blood cell 
WBC  
10^3/mm3 
≤2.8 
≥16.0 
GI/L 
1 
Platelets 
PLT  
10^3/mm3 
≤ 75 
≥ 700 
GI/L 
1 
Mean corpuscular 
hemoglobin 
MCH  
pg/cell  
NA 
NA 
pg/cell  
1 
Mean corpuscular 
hemoglobin 
concentration 
MCHC  
g/dL 
NA 
NA 
g/L 
10 
Mean corpuscular 
volume 
MCV  
fl 
NA 
NA 
fl 
1 
Red blood cell 
RBC  
10^6/mm3 
≤ 3.5 
NA 
TI/L 
1 
 
 
 
 
 
 
 
Differential 
 
 
 
 
 
 
Bands or (Band 
neutrophil (stab)) 
BAND  
% 
NA 
≥ 10% 
% 
1 
Basophil (absolute)  
Baso.  
10^3/mm3  
NA 
≥ 0.4 
GI/L 
1 
Basophil (%) 
Baso.  
% 
NA 
≥ 5% 
% 
1 
Lymphocytes 
(absolute) 
lymphs  
10^3/mm3 
≤ 0.5 
≥ 4.5 
GI/L 
1 
Lymphocytes (%)  
lymphs  
% 
≤ 10% 
≥ 80% 
% 
1 
Monocytes (absolute)  
MONO  
10^3/mm3  
NA 
≥ 1.5 
GI/L 
1 
Monocytes (%) 
MONO  
% 
NA 
≥ 20% 
% 
1 
Neutrophils 
(absolute) 
NEUT  
10^3/mm3 
≤ 1.0 
NA 
GI/L 
1 


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Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
nit 
Low   
igh 
SI 
nit 
Conversion  
Factor 
SI 
Low 
SI 
igh 
Neutrophils ( ) 
NE T   
 
 15   
 90  
 
1 
 15   
 90  
Eosinoph
ils 
(absolute) 
EOS   
103/mm3   
NA 
0. 
GI/L  
1 
NA 
0. 
Eosinoph
ils ( ) 
EOS   
 
NA 
 10  
 
1 
NA 
 10  
 
 
 
 
 
 
 
 
 
Chemistry 
 
 
 
 
 
 
 
 
eart Function 
 
 
 
 
 
 
 
 
Aspartate 
transaminase 
AST   
I/L 
NA 
3 x LN 
/L 
1 
NA 
3 x LN 
Lactic 
dehydrogenase 
LD   
/L 
NA 
3 x LN 
/L 
1 
NA 
3 x LN 
 
 
 
 
 
 
 
 
 
Liver Function 
 
 
 
 
 
 
 
 
Alkaline 
Phosphatase 
ALP   
I/L 
NA 
 3 x LN 
/L 
1 
NA 
 3 x LN 
Alanine 
transaminase 
ALT   
I/L 
NA 
3 x LN 
/L 
1 
NA 
3 x LN 
Total Bilirubin 
TBili   
mg/dL   
NA 
 2.0 
umol/L   
1.1   
NA 
34.2 
Gamma-
glutamyltransferase 
GGT   
I/L 
NA 
 3 x LN 
/L 
1 
NA 
 3 x LN 
Total Protein 
TPRO   
g/dL 
 4.5  
 9.0 
g/L 
10 
 45  
 90 
Albumin 
ALB   
g/dL 
 2.5  
 6.5 
g/L 
10 
 25  
 65 
 
 
 
 
 
 
 
 
 
Renal Function 
 
 
 
 
 
 
 
 
Blood urea nitrogen   
B N   
mg/dL   
NA 
 30 
mmol/L   
0.35   
NA 
10. 
Creatinine 
CREAT   
mg/dL   
NA 
 2.0 
mol/L   
88.4   
NA 
16.8 
 
 
 
 
 
 
 
 
 
Lipid Chemistry 
 
 
 
 
 
 
 
 
Total cholesterol  
chol   
mg/dL   
NA 
 300 
mmol/L   
0.0259   
NA 
 .  
Triglycerides 
TG  
mg/dL   
NA 
 300 
mmol/L   
0.0113   
NA 
3.39 
 
 
 
 
 
 
 
 
 
Electrolytes 
 
 
 
 
 
 
 
 
Chloride 
Cl 
E/L 
 90  
 112 
mmol/L   
1 
 90  
 112 


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Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
nit 
Low   
igh 
SI 
nit 
Conversion  
Factor 
SI 
Low 
SI 
igh 
Potassium 
 
MEqL 
 3.0  
≥ 5.8 
mmolL   
1 
 3.0  
≥ 5.8 
Sodium 
Na  
MEqL 
 130  
≥ 150 
mmolL   
1 
 130  
≥ 150 
icarbonate 
icarb   
MEqL   
NA 
NA 
mmolL   
1 
NA 
NA 
Magnesium 
M   
mgdL   
<1.0  
>4.4 
mmolL   
0.411   
<0.41   
>1.81 
 
 
 
 
 
 
 
 
 
Metabolic 
 
 
 
 
 
 
 
 
Calcium 
Ca  
mgdL 
 .0  
≥ 15.5 
mmolL   
0.25 
1.5  
≥3.88 
Phosphorous 
P 
mgdL   
<1.0  
>10.0  
mmolL   
0.323   
<0.32   
>3.23 
lood lucose 
L   
mgdL 
 50 
(fasting) 
≥ 180 
(fasting) 
mmolL   
0.0555 
2.8 
(fasting) 
≥10.0 
(fasting) 
ric Acid 
RICA   
mgdL   
NA 
Male ≥ 
10.5 
Female ≥ 
8.5 
molL   
59.48   
NA 
Male ≥ 
624 
Female ≥ 
505 
 
 
 
 
 
 
 
 
 
rinalysis 
 
 
 
 
 
 
 
 
(rine) protein 
PROT   
0 to 3+   
NA 
Change≥2 
0 to 3+   
1 
NA 
Change≥2 
(rine) glucose 
L   
0 to 3+   
NA 
Change≥2 
0 to 3+   
1 
NA 
Change≥2 
(rine) hemoglobin   
gb   
0 to 3+   
NA 
Change≥2 
0 to 3+   
1 
NA 
Change≥2 
(rine) white blood 
cells 
W C   
0 to 3+   
NA 
Change≥2 
0 to 3+   
1 
NA 
Change≥2 
(rine) white blood 
cells (M
icroscop
ic 
test) 
W C   
W Chpf   
NA 
≥20 
W Chpf   
1 
NA 
≥20 
(rine) red blood 
cells 
R C   
0 to 3+   
NA 
Change≥2 
0 to 3+   
1 
NA 
Change≥2 
(rine) red blood 
cells (M
icroscop
ic 
test) 
R C   
R Chpf   
NA 
≥10 
R Chpf   
1 
NA 
≥10 
Specific gravity 
Sp   
0 to 3+   
NA 
NA 
0 to 3+   
1 
NA 
NA 
Specific gravity 
(M
icroscopic test) 
Sp   
 
 1.005 
NA 
 
 
 1.005 
NA 


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11.3 Appendix 3  Vital Signs and ECGs  Potentially Clinically Significant Criteria 
 
 
Parameter 
(Full Names) 
Parameter 
(Short 
Names) 
 
Reporting 
nit 
 
Reporting 
Format 
Potentially Clinically Significant 
Criteria 
Low 
High 
Vital Sign 
 
 
 
 
 
Systolic blood 
pressure 
SBP   
mmHg   
3.0 
 0 and 
 20 decrease 
 180 and 
 20 increase 
Diastolic blood 
pressure 
DBP   
mmHg   
3.0 
 50 and 
 15 decrease 
105 and 
 15 increase 
Pulse rate 
P LSE   
bpm   
3.0 
 50 and 
 15 decrease 
 120 and 
 15 increase 
Body Temperature   
TEMP 
C 
3.1 
NA 
 1.11 C 
increase 
 2 F  increase 
Respiration rate 
RESP   
min   
3.1 
 10 
-- 
Weight 
WEIGHT   
kg   
4.1 
  decrease  
  increase 
 
 
 
 
 
 
QTcB 
 
 
 
  
> 500 msec or 
CfB > 60 msec 
QTcF 
 
 
 
  
> 500 msec or 
CfB > 60 msec 
 
Cfb=Change from Baseline