Cause or Effect: Untangling the Relationship With Amyloid and Tau Deposits to Cognitive Decline and Alzheimer's Disease in the Dallas Lifespan Brain Study
Phase: PHASE2
Conditions: Alzheimer Disease, Cognitive Decline
Sponsor: Neil M Rofsky, MD, MHA

Study Protocol and Statistical Analysis Plan 
 
 
Cognitive Decline and Alzheimer's Disease in the Dallas Lifespan Brain Study 
 
 
NCT04080544 
 
Document approval date: November 18, 2021 

 
University of Texas Southwestern Medical Center IND# 143884  
[18F]AV-1451 
November 2021 
 
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6. PROTOCOL 
PROTOCOL Version 6 
PROTOCOL TITLE 
Cause or effect? Untangling the relationship with amyloid and tau deposits to cognitive 
decline and Alzheimer’s disease in the Dallas Lifespan Brain Study 
 
Phase II, Investigational Drug, Alzheimer’s Disease 
 
Principal Investigator: 
 
Denise Park, Ph.D. 
 
 
 
 
 
University Regents Research Scholar 
University Distinguished Chair in Behavioral and 
Brain Sciences 
University of Texas Dallas 
Center for Vital Longevity 
1600 Viceroy Drive, Ste. 800, Dallas, TX, 75235 
(Phone): 214-470-8673 
(Fax): 972-883-3250 
Email: Denise@utdallas.edu  
 
 
Co-Principal Investigator(s)  
 Neil M. Rofsky, M.D. 
or Lead Sub-Investigator(s): 
 Professor and Chair,  Radiology 
 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
 
 
5323 Harry Hines Blvd 
Dallas, Texas 75390 - 8896 
(Phone): 214-648-7702 
(Fax): 214-648-7782 
 Email: Neil.Rofsky@utsouthwestern.edu  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carol Tamminga, MD 
 
 
 
 
 
Professor and Chair of Psychiatry 
 
 
 
 
 
University of Texas Southwestern 
 
 
 
 
 
Dallas, Texas 
 
 
 
 
 
(Phone): 214-404-2284 
 
 
 
 
 
(Fax): 214-645-2786 
 
 
 
 
 
 
Email: Carol.Tamminga@utsouthwestern.edu  

 
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[18F]AV-1451 
November 2021 
 
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Protocol Version: v6 2 
 
 
Study Drug: 
 
 
[18F]AV-1451 
 
IND/IDE Number: 
 
Serial Number 143884 
 
IND/IDE Holder Name:  
Neil M. Rofsky, M.D. 
 
Funding Source:   
 
National Institute of Aging 
 
 
 
 
 
(RF1 AG006265-32A1, RF1 AG006265-32A1S1) 
 
 Version:  
 
 
November 18, 2021 
 
 
 
 
 
 
UT Southwestern Medical Center 
Department of Radiology 
5323 Harry Hines Blvd. MC 8896 
Dallas, Texas 75390-8896 
Phone: 214-648-7770; Fax: 214-648-7785 
 

 
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[18F]AV-1451 
November 2021 
 
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6.1. LIST OF ABBREVIATIONS 
AD 
Alzheimer's Disease 
AE 
Adverse Event 
AVID 
Advancement Via Individual Determination 
BOLD 
Blood Oxygen-Level Dependent 
CFR 
Code of Federal Regulations 
COI 
Conflict of Interest 
CSF 
Cerebrospinal Fluid  
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBS 
The Dallas Lifespan Brain Study 
DSMB 
Data and Safety Monitoring Board 
FDA 
The Food and Drug Administration 
GCP 
Good Clinical Practice 
hERG 
Human ether-a-go-go related gene 
HHS 
Health and Human Services 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPP 
Human Research Protection Program 
ICH 
International Conference of Harmonization  
IND 
Investigational New Drug 
IRB 
The Institutional Review Board 
IV or iv 
Intravenously 
MHD 
Maximum Human Mass Dose 
MMSE 
Mini-Mental State Examination  
MPRage 
Magnetization-prepared radio-frequency pulses and rapid 
gradient-echo 
MRI 
Magnetic Resonance Image  
NCI 
National Cancer Institute 
NOAEL 
No-Observed-Adverse-Effect-Level 

 
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OHRP 
Office of Human Research Protections 
PET 
Positron Emission Tomography 
PHF 
Paired Helical Filaments 
PI 
Principal Investigator 
SCCC 
Simmons Comprehensive Cancer Center 
SUVr 
Standardized Uptake Value Ratio 
TBI 
Traumatic Brain Injury 
TdP 
Torsades de Pointes 
UPIRSO 
Unanticipated Problems Involving Risks to Subjects or Others 
UTD 
University of Texas at Dallas 
UTSW 
University of Texas Southwestern Medical Center 
 
 

 
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6.2. STUDY SCHEMA FOR WAVE 3 MODIFICATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day of Visit. Pre-dose Procedures: 
Informed consent, HIPAA consent, MMSE (if 
not completed at screening), Vital Signs, 
Pregnancy Test 
Pre-Visit. Phone screening for eligibility 
Verbal waiver of consent 
Inclusion/Exclusion Criteria, Medical History, 
Concomitant Medications, MMSE (unless 
planned for Day of Visit), Physician Review of 
eligibility via email 
Day of Visit. Agent Administration: 
[18F]AV-1451; a single IV bolus 
administration of up to a target dose of 370 
MBq (10 mCi) 
Adverse Event Assessment 
PET Scan 
 
Day of Visit. Post-dose Evaluation:  
Vital Signs, Adverse Event Assessment, 
Physician Visit prior to discharge 
2-3 days Post-Injection: 
Adverse Event Assessment. 

 
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6.3. STUDY SUMMARY 
Title 
Cause or effect? Untangling the relationship with amyloid and tau 
deposits to cognitive decline and Alzheimer’s disease in the Dallas 
Lifespan Brain Study 
Protocol Number 
Version 6 
Phase 
Phase II 
Methodology 
Open label 
Study Duration 
5/1/2019 - 6/30/2022 
Study Center(s) 
Single-center 
Objectives 
We will conduct tau PET scans on up to 125 adults using the 
radiopharmaceutical AV-1451. This will allow us to determine tau 
deposition across adults of different ages and assess the relationship 
of current tau burden to cognitive function and amyloid deposition 
collected over the previous 10-year interval.  
Number of Subjects 
Up to 125 
Diagnosis 
and 
Main 
Inclusion Criteria 
Eight- to ten-year follow-up Dallas Lifespan Brain Study 
participants who were cognitively normal at the time of enrollment 
from 2008 to 2014.  
Study Product(s), Dose, 
Route, Regimen 
[18F]AV-1451 
(7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-
b]indole) for Injection, a single intravenous (IV) bolus 
administration of up to a target dose of 370 MBq (10 mCi) 
Duration of 
administration 
Single dose 
Reference therapy 
Not applicable 
Statistical Methodology 
Tau deposition will be examined via estimating the mean 
standardized uptake value ratio (SUVr) of [18F]AV-1451 in six 
temporal brain regions of interest in both the left and right 
hemispheres. Linear mixed-model analysis will use the Tau SUVr 
values to examine relationships with changes in other Alzheimer’s 
Disease pathology and changes in decline of cognitive function in 
brain changes associated with typical aging. 
 
 

 
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6.4. BACKGROUND AND RATIONALE 
6.4.1. Disease Background 
Alzheimer’s disease (AD) is a highly prevalent disorder of dementia in older adults. AD 
neuropathology is marked by the presence of amyloid plaques and tau neurofibrillary 
tangles (Khachaturian, 1985). Autopsy studies (Trojanowski et al., 1997), as well as 
magnetic resonance imaging (MRI) studies (Jack et al., 1997; Convit et al., 1993; Killiany 
et al., 1993) in living persons, have established that the neurodegenerative changes in AD 
begin in medial temporal lobe structures and later progress to adjacent temporal, parietal 
and frontal neocortical regions (Braak & Braak, 1991; Price et al., 2001). Magnetic 
resonance image studies of AD consistently reveal volumetric loss in the hippocampus 
using both cross-sectional and longitudinal approaches (Jack et al., 1997; Convit et al., 
1993; Killiany et al., 1993). The primary symptom of early-stage AD is memory 
impairment (Mohs et al., 1998; Storandt et al., 2002) possibly accompanied by deficits in 
attentional control (Balota & Faust, 2001). Normal aging, however, is also marked by 
cognitive decline (Park et al., 2009; Park et al., 2014), as well as structural brain changes 
(Raz & Rodrigue, 2006). Autopsy data had shown in the past that about 30% of older adults 
with no obvious cognitive impairment show some degree of the neuropathology typically 
associated with dementia at autopsy (Bennett et al., 2006; Kemper, 1994).  
Importantly, the recent ability to image b-amyloid and tau deposits in vivo using 
positron emission tomography (PET) scanning has revolutionized our understanding of 
early stages of AD. Evidence suggests that amyloid deposits may be detected 10 - 15 years 
before memory symptoms appear. These findings are leading to the ability to diagnose AD 
years before symptoms begin (see Jack et al., 2013 for a review). Much less is known about 
the impact and developmental course of tau deposition because the ligand to image tau was 
only recently invented. There is increasing evidence that tau is particularly toxic to the 
brain and is a later precursor of AD than amyloid deposits. Additional research on b-
amyloid and tau deposition in aging is crucial, as much work suggests that treatment of AD 
may be most effective when implemented early in the time course of the disease (Sperling 
et al., 2011). Understanding the impact of tau deposits and its interactions with amyloid 
deposition allows us to see the development of early markers of AD, which are important 
in understanding the trajectory of the disease. An important approach to understand the 
amyloid/tau puzzle and its relationship to AD is a large-scale longitudinal study of normal 
aging that integrates extensive neuroimaging and cognitive assessments along with tau 
imaging. A key aspect in separating normal from pathological aging is the inclusion of 
adults across the lifespan, establishing baselines from a sufficiently early stage to detect 
the very beginnings of pathological decline. 
The Dallas Lifespan Brain Study (DLBS) began in 2008 and was designed to utilize the 
new in vivo imaging techniques to address uncertainty regarding how AD pathology relates 

 
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to the developmental process of aging and cognition, fueled in part by the partial overlap 
of pathological markers and decline in mnemonic function observed in a substantial 
proportion of ‘normal’ aged individuals (Mohs et al., 1998; Whalley, 2002). As shown in 
Figure 1, a total of 296 participants were recruited for Wave 1 from 2008 to 2014 to the 
DLBS and they received cognitive testing, structural and functional MRI, as well as a scan 
for beta amyloid using the radioligand AV-45 (florbetapir F 18, also known as “[18F]AV-
45”).  A total of 183 returning participants were tested four years later in Wave 2, and they 
received the same battery (shown in Figure 2) as in Wave 1. In addition, 60 of these were 
also scanned with Flortaucipir F 18 (also known as “[18F]AV-1451”). [18F]AV-1451 is a 
newly-developed Phase II ligand that measures tau deposit in the human brain and this drug 
was provided to the DLBS by Avid Radiopharmaceuticals.   
The objective of the current project is to manufacture [18F]AV-1451 (Flortaucipir F 18) 
at the University of Texas Southwestern Medical Center (UTSW) for use in Wave 3 of the 
DLBS. We will offer an AV-1451 PET scan to past Wave 1 and 2 participants. We will 
first contact those who completed Waves 1 and 2, followed by those who completed only 
Wave 1 until we have used the 125 doses we were allocated. Figure 3 shows the specific 
procedures associated with this protocol for the up to 125 participants who will receive tau 
imaging in Wave 3. The inclusion of tau imaging in Wave 3 will allow us to relate tau 
deposition in the brain to the 10-year history of amyloid deposition and cognitive decline 
in the DLBS participants and understand the independent and joint contributions of tau to 
cognitive decline and early AD at different ages.   
 
 

 
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Figure 1. Dallas Lifespan Brain Study Overview and Timeline 
The DLBS is an ongoing, comprehensive study of the relationship between brain 
structure and function to decline in cognition across the lifespan. The focus of this protocol 
is noted in, “DLBS Wave 3.” 
 

 
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Figure 2. Sequence of Wave 3 Assessments 
 
 
 
 

 
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Figure 3. PET-Tau Imaging Procedures  
 
 
 
 
 

 
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6.4.2. Study Agent Background and Associated Known Toxicities 
A PET/CT tau imaging agent, [18F]AV-1451, was developed by Avid 
Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company. For this 
study, Avid and UT Southwestern have signed a clinical agreement that allows UTSW to 
produce this imaging agent, [18F]AV-1451, which is in Phase II clinical trials, and a focus 
of the present IND. It has been extensively evaluated by various in vitro and in vivo 
methods, including human brain sections, and human PET/CT imaging, as well as in 
animal models of Alzheimer’s disease (Chien et al., 2013; Declercq et al., 2016; Schöll et 
al., 2016; Xia et al., 2013). It has been shown to have a high affinity for tau tangles. Based 
on studies in humans, it is estimated that the dose of radiation from [18F]AV-1451, 
averaged over the entire human body, is comparable to the range of other approved brain 
imaging agents, such as an agent [18F]FDG (1.0 rem) and [18F]florbetapir ([18F]AV-45) 
(1.3 rem) (see Appendix V). In completed studies with a total of 273 subjects the following 
adverse events were reported in at least 1% of subjects and were not thought by the 
investigator to be related to study procedures, or otherwise thought by the investigator to 
be related to flortaucipir: diarrhea, headache, muscle spam, dysgeusia, injection site pain 
(see Appendix V). 
In vitro autoradiography results showed that [18F]AV-1451 bound with high affinity to 
aggregated tau protein and with preferential selectivity for aggregated tau vs. β-amyloid 
positive sections (Xia et al., 2013). The Kd calculated for [18F]AV-1451 binding to 
aggregated tau protein in human brain slices was measured to be approximately 15 nM. In 
that study, the dissociation constant (Kd) could not be calculated for [18F]AV-1451 binding 
to PHF-tau purified from the human brain samples because at lower ligand concentrations 
(< 200 nM) autoradiographic signals were indistinguishable from noise, and at high 
concentrations binding was nonspecific and random. They also compared a competitive 
binding assay versus a panel of 72 common central nervous system targets, observing no 
clinically relevant inhibition for [18F]AV-1451. [18F]AV-1451 has demonstrated rapid 
uptake in vivo in mouse, rat, and monkey brains followed by moderate clearance (Appendix 
V; Declercq et al., 2016; Xia et al., 2013). 
Preclinical toxicity studies of [18F]AV-1451 showed a good safety profile with no 
observable effects at high multiples of the intended maximum human dose (Appendix V). 
With respect to risk for genotoxicity, positive results in the in vitro Ames test and 
chromosomal aberration studies did not manifest in the in vivo rat micronucleus study at 
doses greater than 750 times the intended human dose. [18F]AV-1451 was positive in the 
in vitro hERG assay. However, the cardiovascular assessments performed during the dog 
toxicology studies showed no evidence that [18F]AV-1451 prolongs the QT interval at high 
multiples of relevant clinical doses, and therefore risk of QT prolongation is not included 
in the risk profile. Out of an abundance of caution, and in consideration of previous 

 
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exclusionary criteria, this study will exclude participants with a history of risk factors for 
Torsades de Pointes and participants taking drugs known to increase QT intervals.  
Human dosimetry has been obtained for nine participants (Appendix V). The radiotracer 
distribution was consistent among the participants and showed rapid hepatobiliary 
clearance. The organs of the gastrointestinal tract (upper large intestine, small intestine and 
liver) received the greatest exposure. The whole-body effective dose for a 10 mCi (370 
MBq) injection of [18F]AV-1451 was calculated to be 8.92 mSv. This is comparable to the 
effective doses of approved 18F-labeled compounds such as [18F]florbetapir and 
[18F]fluorodeoxyglucose.  
The distribution of the imaging agent in the brain closely matches the expected pattern of 
deposits. Considering the well supported specificity of [18F]AV-1451 to tau tangles and its 
robust clinical safety record, this imaging agent should allow us to effectively meet the 
objectives of this research project. Avid Radiopharmaceuticals has signed a clinical 
agreement allowing UT Southwestern to produce up to 125 doses of this tau imaging agent 
([18F]AV-1451) for the current DLBS Wave 3.  
6.4.3. Other Agents 
6.4.3.1. 
Florbetapir F 18 
The inclusion of florbetapir F 18 allows us to get a complete picture of the two major 
markers of AD pathology – tau and amyloid – in healthy adults. Florbetapir F 18 is an 
FDA-approved radiopharmaceutical that can be commercially obtained and is used to 
assess amyloid burden in the brain.  It is known that amyloid accumulates long before 
behavioral and cognitive changes manifest. Better characterization of where and when 
amyloid accrues and its relationship to tau burden and cognitive changes will provide 
critical knowledge to help assess Alzheimer’s disease, treat patients, and develop therapies. 
To meet this objective, all participants in the study will have undergone Florbetapir F 18 
PET scans at three different times approximately 4 years apart over the last 10 years. See 
Figure 1. The third Florbetapir F 18 PET scan will be acquired prior to acquisition of the 
third Tau PET scan under a UTSW IRB approved protocol.  
6.4.3.2. 
Florbetapir F 18 mechanism of action 
Florbetapir F 18 is an FDA approved radiopharmaceutical compound containing the 
radionuclide fluorine-18 bound to the compound florbetapir, a molecule that binds with 
high affinity to beta amyloid plaque, a peptide that plays a key role in Alzheimer's Disease 
pathogenesis. The radionuclide fluorine-18 was chosen as it has a half-life of 110 minutes 
allowing it to accumulate sufficiently in the brain before undergoing positron emission 
decay. In in vitro binding studies using postmortem human brain homogenates containing 

 
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β-amyloid plaques, the Kd for florbetapir F 18 was 3.7 ± 0.3 nM. The binding of florbetapir 
F 18 to β-amyloid aggregates was demonstrated in postmortem human brain sections using 
autoradiographic methods, thioflavin S and traditional silver staining correlation studies as 
well as monoclonal antibody β-amyloid-specific correlation studies. Florbetapir F 18 
binding to tau protein and a battery of neuroreceptors was not detected in in vitro studies 
(Eli Lily 2012).  
6.4.3.3. 
Florbetapir F 18 safety issues 
In clinical studies, 555 patients were exposed to Florbetapir F 18. Florbetapir F 18 
caused no serious adverse reactions in the studies and the reported adverse reactions were 
predominantly mild to moderate in severity. The most common reported adverse reaction 
was headache, occurring in 2% of patients, followed by musculoskeletal pain, blood 
pressure increased, fatigue, nausea, and injection site reaction, all occurring in < 1% of 
patients (Eli Lily 2012).  
6.4.4. Rationale 
Tau pathology is a primary feature of Alzheimer’s disease, and can now be measured in 
vivo using the recently developed PET radiotracer [18F]AV-1451. Autopsy studies have 
long established that many older adults who exhibited no signs of cognitive impairment in 
life are found at autopsy to possess the neuropathological hallmarks of Alzheimer’s 
disease: amyloid plaques and neurofibrillary tau tangles. In the previous decade, PET 
imaging tracers made it possible to image amyloid plaques but not tau tangles in the living 
brain, providing substantial insight into the cascade of events leading from a healthy to a 
diseased brain. However, these studies have also indicated that amyloid has a limited direct 
effect on the neurodegeneration and cognitive decline indicative of incipient dementia. One 
prevailing theory, supported by in vivo measures of amyloid and tau, is that amyloid 
induces tau tangle pathology, and it is tau that directly connects to neurodegeneration and 
cognitive decline. The recent development of tau imaging ligands, including [18F]AV-
1451, provides an opportunity to better understand the joint influence of tau and amyloid 
on neurodegeneration and cognition, as well as insight into the neurological cascade from 
health to dementia of the Alzheimer’s type. An understanding of this cascade is critical for 
therapeutic and intervention trials.  
The main objective of the present project is to assess evidence for neurofibrillary tau 
pathology in the brains of adults who are participants in Wave 3 in a larger project — the 
DLBS. This is a longitudinal observational study and tau imaging will be open-label. The 
DLBS protocol includes structural MRI, diffusion tensor, functional MRI, and a 
comprehensive cognitive and psychosocial battery as well as amyloid PET imaging. The 
DLBS participants (current age range: 38 - 96) allows us to address directly the role of tau 
deposition in declining cognition in a sample that was cognitively normal at the start of the 

 
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study eight years earlier. This population of subjects is critical to study because pathology 
for Alzheimer’s disease starts long before clinically observable effects develop. The timing 
of tau development relative to amyloid is not well understood. The Wave 3 data will 
provide us the ability to relate tau aggregation in Wave 3 to magnitude of amyloid 
deposition both during Wave 3 and across the previous 8 - 10 years. We can also connect 
tau deposition in Wave 3 to present cognitive function and magnitude of decline over 8 - 
10 years. 
While [18F]AV-1451 was not available and no tau scanning was done for Wave 1 in the 
DLBS, we were able to conduct 60 [18F]AV-1451 PET scans in DLBS on 60 Wave 2 
participants as part of a clinical trial by Avid Radiopharmaceuticals. During Wave 3 (the 
focus of the present protocol), we propose to manufacture [18F]AV-1451 via the UTSW 
Cyclotron and Radiochemistry Program. We will administer one dose to up to 125 
participants in Wave 3. This portion of the study is important because it will allow us to 
assess longitudinal changes in [18F]AV-1451 in the 60 previously tested Wave 2 
participants, and its relationship to growth in amyloid and decline in cognition. Secondly, 
we can see whether it increases more rapidly as a function of age. Finally, it will allow us 
to add to the information on [18F]AV-1451’s safety profile. These data, in combination 
with DLBS behavioral data and MRI scanning and amyloid imaging, will provide a 
comprehensive picture of the aging mind over a period of years, allowing us a window into 
maintenance of cognitive health and, for some subjects, transition towards dementia.  
Key neurological endpoints for this study include estimation of amyloid and tau 
deposition in participants at Wave 3. Tau deposition will be examined via estimating the 
standardized uptake value ratio (SUVr) of [18F]AV-1451 in temporal regions (both left and 
right) of interest: (1) inferior temporal gyrus, (2) middle temporal gyrus, (3) superior 
temporal gyrus, (4) entorhinal cortex, (5) parahippocampal gyrus, and (6) fusiform gyrus. 
SUVr of [18F]AV-1451 in these regions is elevated in those with mild cognitive impairment 
or Alzheimer’s disease (Johnson et al., 2016; Scholl et al., 2016). There are sometimes 
hemispheric-specific effects, so left and right hemispheres will be analyzed separately. We 
also note that Wave 3 amyloid deposition will be measured across eight cortical regions: 
dorsal lateral prefrontal cortex, orbitofrontal cortex, lateral parietal cortex, posterior 
cingulate cortex, anterior cingulate cortex, precuneus, lateral temporal cortex, and occipital 
lobe and then averaged.  
Key cognitive endpoints for this study include measures of processing speed, episodic 
memory, working memory, and executive function. Processing speed tasks measure 
participants’ ability to quickly do simple mental tasks, such as comparing two strings of 
numbers. Episodic memory tasks measure their ability to remember contextual 
information, such as remembering the details of a story. Working memory tasks measure 
their ability to store and manipulate long strings of information in memory; a common task 
has participants repeating a list of numbers back to the experimenter in reverse order (n-

 
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back task). Executive function tasks measure participants’ ability to solve simple problems. 
A wide range of research has shown that these cognitive functions typically decline in 
healthy aging and often decline more sharply in those with AD pathology, particularly 
memory (Amieva et al., 2005; Epelbaum et al., 2017; Mortamais et al., 2017). The current 
study is one of the first to be able to examine how in vivo measures of tau deposition relate 
with declines in these cognitive functions. 
 
6.5. STUDY OBJECTIVES  
6.5.1. Primary Objectives 
6.5.1.1. 
To determine the time course of tau deposition with age and assess its 
relationship to changes in cognitive function over a 10-year interval by 
conducting tau PET scans on up to 125 adults from previous waves of the 
DLBS using the tau tracer [18F]AV-1451. 
6.5.2. Secondary Objectives 
6.5.2.1. 
To assess the relationship of tau burden to hippocampal volume and 
cortical thickness and their contributions to predicting decline in memory and 
other cognitive functions. 
6.5.2.2. 
To determine whether rate of amyloid accumulation over the past 8 - 10-
year interval predicts tau deposition.  
6.5.2.3. 
To examine the detrimental effect of tau deposits, as well as the joint 
effect of tau and amyloid, on changes in brain activity and cognitive function.  
6.5.2.4. 
To examine differences in cognitive, structural, and functional decline 
between those with and without amyloid and tau pathology. 
6.5.3. Exploratory Objectives 
6.5.3.1. 
As findings are made while pursuing these secondary objectives, we will 
sometimes conduct additional follow-up analyses to better understand these 
findings. For example, a sufficient number of subjects vary in their 
socioeconomic status (SES), we will likely examine if SES is related to the 
time course of tau deposition. 
6.5.4. Primary Endpoints 

 
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6.5.4.1. 
The primary objective will involve completion of up to 125 [18F]AV-1451 
PET scans on returning Wave 1 and 2  DLBS participants. Once these data are 
collected, data collection will stop. 
6.5.5. Secondary Endpoints 
Tau deposition will be examined via estimating the SUVr of [18F]AV-1451 in 
temporal regions (both left and right) of interest: (1) inferior temporal gyrus, (2) 
middle temporal gyrus, (3) superior temporal gyrus, (4) entorhinal cortex, (5) 
parahippocampal gyrus, and (6) fusiform gyrus. Amyloid accumulation will be 
measured continuously as the SUVr value averaged across eight cortical regions: 
dorsal lateral prefrontal cortex, orbitofrontal cortex, lateral parietal cortex, 
posterior cingulate cortex, anterior cingulate cortex, precuneus, lateral temporal 
cortex, and occipital lobe.  
6.5.5.1. 
Hippocampal volume and regional cortical thickness will be estimated 
using FreeSurfer (ver. 5.3), with surface parcellation manually edited, when 
necessary, by our team of experts.  
6.5.5.2. 
Longitudinal declines in brain structures will be measured using linear 
mixed models with estimated cortical thickness and white matter volumes from 
waves 1, 2, and 3 as our primary structural measures, BOLD signal from a 
subsequent memory task, a semantic judgment task, and resting state as our 
functional measures, and time of scanning entered as an interaction term.  
6.5.5.3. 
Joint effects of tau and amyloid will be examined by including them as an 
interaction term in a linear mixed-model analysis. 
6.5.5.4. 
Cognitive decline will be assessed using the following constructs: 
processing speed, episodic memory, working memory, and executive function. 
Scores on these constructs will be averaged across relevant DLBS tasks and 
standardized based on performance at the beginning of this longitudinal study 
(Wave 1).  
 
6.6. SUBJECT ELIGIBILITY 
Participants will be  eligible to volunteer for this scan if they participated in Waves 1 or 
2 of the DLBS. To determine medical eligibility for the scan by the study physician, 
those who volunteer when contacted  will be asked for verbal consent to provide medical 
information needed for the physician review. At the subsequent PET scanning visit, all 
participants must sign the consent form to be eligible for the PET study. 

 
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6.6.1. Inclusion Criteria 
6.6.1.1. 
Participated in Waves 1 or 2 of the DLBS  
6.6.1.2. 
Adults aged 38 to 96 years old.  
6.6.1.3. 
Subjects must indicate that they are not currently pregnant if they are 
women of child-bearing potential. Women of child-bearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry, for the duration of study participation, 
and for 90 days following completion of therapy. Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
 
A female of child-bearing potential is any woman (regardless of 
sexual orientation, having undergone a tubal ligation, or remaining 
celibate by choice) who meets the following criteria: 
• Has not undergone a hysterectomy or bilateral oophorectomy; or 
• Has not been naturally post-menopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 consecutive 
months). 
6.6.1.4. 
Volumetric Brain MRI Image (T-1 Weighted MPRage) collected as part of 
DLBS Wave 1, 2, or 3 protocol. 
6.6.1.5. 
Completed at least 9 years of formal education, or the equivalent of 
freshman year of high school. 
6.6.1.6. 
Fluent English speakers. 
6.6.1.7. 
Tolerate laying 20 minutes on a flat table for the PET scan. 
6.6.1.8. 
Ability to understand and the willingness to sign a written informed 
consent. 
6.6.2. Exclusion Criteria 
6.6.2.1. 
MMSE score lower than 22; all DLBS participants at the time of initial 
Wave 1 enrollment between 2008 - 2014 had an MMSE score of 26 or above, 
indicating normal cognitive function. However, in the time interval between 

 
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Waves, it is possible that mental capacity may have deteriorated. We will 
exclude all participants in Wave 3 testing who have an MMSE lower than 22. 
6.6.2.2. 
Taking some types of sedatives, benzodiazepines, or anti-psychotics. 
6.6.2.3. 
Currently undergoing chemotherapy or radiation for cancer. 
6.6.2.4. 
New history of substance abuse. 
6.6.2.5. 
Has a history of drug or alcohol dependence within the last year, or prior 
prolonged history of dependence. 
6.6.2.6. 
Recreational drug use in past six months. 
6.6.2.7. 
Central nervous systems disease or brain injury that would preclude 
participation in the study. 
6.6.2.8. 
Psychiatric or neurological disorder that would preclude participation in 
this study. 
6.6.2.9. 
Has clinically significant hepatic, renal, pulmonary, metabolic or 
endocrine disturbances which pose safety risk. 
6.6.2.10. Has a current clinically significant cardiovascular disease that poses a 
safety risk.  
6.6.2.11. Has a current clinically significant infectious disease or a medical 
comorbidity which poses a safety risk. 
6.6.2.12. Has received or will receive investigational medication within the 30 days 
of PET/CT scan.  
6.6.2.13. Has received or will receive a radiopharmaceutical for imaging or therapy 
within 24 hours of PET/CT scan. 
6.6.2.14. Is a participant who, in the opinion of the investigator(s), is otherwise 
unsuitable for a study of this type. 
 
6.7. STUDY PROCEDURES 
6.7.1. Screening/Baseline Procedures 

 
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In the past, participants who participated in this component of the study received an 
ECG and a separate physician visit where their medical history was reviewed to 
determine eligibility. In 2019, flortaucepir was approved by the FDA for medical use and 
there was no requirement for a physician in-person visit or the ECG prior to the scan. 
Thus, we have incorporated this practice, and in Wave 3 participants will not receive the 
ECG. In addition, we have eliminated the physician visit to determine eligibility for this 
study, and instead it will be collected via a phone screening. We can reduce the 
participant burden for this research scan by eliminating these two events and instead 
obtaining a verbal waiver of written consent. This will eliminate one visit for every 
subject by having both the physician review medical information electronically and the 
subject provide a verbal waiver of consent over the phone to determine eligibility.  
Assessments performed for clinical indications (not exclusively to determine study 
eligibility) may be used for baseline values even if the studies were done before written 
informed consent was obtained. 
All screening procedures will be performed within 30 days prior to registration unless 
otherwise stated. For participants who will complete their scan over 30 days since their 
screening date—most often, this is due to having to reschedule their initial appointment—
we will confirm whether their medications, medical history (e.g., surgeries), and allergies 
have changed since their initial screening. Any such changes will be documented, and 
changes that may affect their eligibility to participate in this study will be submitted to the 
physician to confirm whether they are still eligible to participate. 
The screening procedures include: 
6.7.2. Screening Procedures 
 
The verbal consent obtained over the phone will be used to obtain relevant medical 
information for screening prior to full informed consent at the time of the visit. The 
specific components of the screen are below. All of this information will be reviewed 
by a study physician to ensure participant safety before enrollment in the PET study. 
6.7.2.1. 
Medical history 
Complete medical and surgical history, history of infections and concurrent disease, and 
neurological disease history 
6.7.2.2. 
Review subject eligibility criteria 
6.7.2.3. 
Review concomitant medications 
6.7.2.4. 
Mini-Mental State Examination (when considered necessary) 

 
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6.7.2.5. 
Physician Review of subject’s medical history, eligibility criteria and 
concomitant medications prior to enrollment 
6.7.3. Procedures On Day of Treatment 
Participants will complete the in-person visit at UTSW PET Imaging Center. 
Assessments will be conducted by a study RA, with the PET Injection and PET scan being 
conducted by a UTSW PET Technologist. An Attending physician will assess the 
participant’s post-scan vital signs and review any evidence for possible adverse events 
prior to discharge. 
6.7.3.1. 
Informed Consent 
Informed consent and HIPAA consent will be completed on the day of the scan before 
any other procedures are done.  
6.7.3.2. 
MMSE 
Participants who have not completed the MMSE questionnaire in the last 30 days will 
be asked to complete the questionnaire for purposes of this research study. 
6.7.3.3. 
Pregnancy Test  
The day of scanning, females that are of childbearing potential will have a urine pregnancy 
test performed once again. Results of these tests must be negative in order to proceed with the 
PET scan.  
6.7.3.4. 
Pre-dose Vital signs 
Subject’s weight, height, supine blood pressure, pulse rate, and respiratory rate will be 
collected.  
6.7.3.5. 
Adverse event assessment 
Participants will be assessed for possible adverse events that occur as a result of study 
procedures beginning at the time of written informed consent occurred up to the time of 
the follow-up phone call described in section 6.7.3. See sections 6.8.2 and 6.8.3 for Adverse 
Event monitoring and reporting. 
6.7.3.6. 
PET Injection 
The subject will receive up to a target dose of 370 MBq as a single IV bolus of [18F]AV-
1451. Participant will be assessed for any adverse events. 

 
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6.7.3.7. 
PET Scan  
Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT 
scanner for a 20-minute brain scan. In total, the imaging visit could take up to 180 minutes 
for the physician to clear the patient for safety. A member of UTSW staff will be nearby 
during the procedure. The PET/CT scanner at the PET/CT Center will be used to perform 
scans for this study. Participant will be assessed for any adverse events. 
6.7.3.8. 
Post-dose Vital signs  
Subject’s supine blood pressure, pulse rate, and respiratory rate will be taken after PET 
scan is complete. 
6.7.3.9. 
Post-dose Physician visit 
A physician will see and discharge the subject.  Physician will ascertain any adverse 
events that occurred during visit. 
6.7.3.10 
Participant Compensation 
Screen Procedure. If participants complete the screen procedures, $25 will be 
deposited to their study account which operates as a cash-based bank card.   
The Scanning Visit.  Participants who go on to be scheduled for the AV-1451 Wave 3 
PET Session will be compensated $200 additional dollars on this card, even if the session 
is terminated for some reason.  The bank card is study-specific card all enrolled participants 
can use it to withdraw cash or as a credit card. The card can be used as either debit or credit, 
and participants will be instructed by study personnel on how to use the card.  
Travel Costs.  If travel exceeds 50 miles, participants will be approved to receive 
$0.58.5 a mile for each additional mile. If a participant prefers not to drive, they can arrange 
transport with an outside source (eg Uber, Lyft, Cab service) and get reimbursed from their 
receipts, or we can arrange travel with a university approved carrier and charge it directly 
to our accounts. We will also make flight arrangements if they are necessary.  
Serving As A Stand-By Participant. The scanning agent we use is quite expensive and 
can only be used the day of the scan. For this reason, it is problematic for us if someone 
does not show up. Just in case this happens, we are paying an extra participant $100 to be 
ready to participate in a scan if someone does not show up. Each stand-by participant would 
sit in the waiting room for 2-3 hours. 
6.7.4. Follow-up Procedures 
Study personnel will make a follow-up phone call to the participant within 2 to 3 
business days after the scan, but no less than 48 hours post injection. The purpose of this 

 
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phone call will be to check if participants have experienced any new adverse events since 
injection on the imaging day.  
Furthermore, as the DLBS is a longitudinal study, participants may continue to be 
contacted every 4 years for study participation for as long as the study is funded. 
 
 
 
 

 
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6.7.5. Time and Events Table for [18F]AV-1451 Study 
1Height and weight will be measured prior to injection on imaging day. 
 
6.7.6. Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator(s) for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be documented 
and may include: 
Evaluations 
Pre-Visit 
Screen 
Visit  
Pre-dose 
Visit 
Dose 
Visit  
PET Imaging 
Visit  
Post-Imaging 
2 – 3 days  
Post-Injection 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
Medical / Disease 
History 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
 
 
 
 
 
Physician Review of 
eligibility via email 
X 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
MMSE 
X 
X 
 
 
 
 
Vital Signs1 
 
X 
 
 
X 
 
Pregnancy Test 
 
X 
 
 
 
 
[18F]AV-1451 
Administration 
 
 
X 
 
 
 
PET Imaging 
 
 
 
Continuous 20-
minute scan 
 
 
Physician Visit prior to 
discharge 
 
 
 
 
X 
 
Follow-up Phone Call  
 
 
 
 
X 
Adverse Event 
Assessment 
 
 
X 
X 
X 
X 

 
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6.7.6.1. 
Subject withdraws consent (termination of treatment and follow-up). 
6.7.6.2. 
Subject is unable to comply with protocol requirements. 
6.7.6.3. 
Treating physician determines continuation on the study would not be in 
the subject’s best interest. 
6.7.6.4. 
Subject (female) tests positive for pregnancy at any point in the study. 
 
6.8. ADVERSE EVENTS 
6.8.1. Experimental Drug 
6.8.1.1. 
Contraindications 
There are no known contraindications to the usage of flortaucipir F 18 ([18F]AV-1451). 
Pregnant or lactating females have been excluded from all [18F]AV-1451studies due to the 
potential risks of radiation to the fetus. Non-radioactive flortaucipir was positive in the in 
vitro hERG assay with an IC50 of 0.610 μM. If the flortaucipir hERG channel IC50 is 
converted to a ng/mL concentration (161 ng/mL), and compared to the maximum 
theoretical flortaucipir peak plasma concentration in a subject given a 20 μg dose (3.8 
ng/mL), the safety margin is at least 42-fold. The safety margin increases to over 900-fold 
when accounting for plasma protein binding in the calculation (plasma protein unbound 
fraction, fu-human = 0.047). Additionally, in vitro cardiovascular assessments in dogs 
showed no evidence of QT prolongation. Nonetheless, until sufficient human 
cardiovascular safety data are available, clinical studies will exclude subjects with a history 
of risk factors for torsade de pointes and subjects taking drugs known to prolong the QT 
interval. 
6.8.1.2. 
Special Warnings and Precautions for Use 
To ensure study integrity and to reduce any risk to participants, study personnel will 
closely monitor: (1) the participant’s study experience, (2) the actual vs. target study 
accrual rates, (3) participant attrition (e.g. withdrawals, dropouts), (4) patterns of adverse 
events (AEs) and unanticipated events, (5) patterns of protocol deviations/violations, (6) 
study stopping points and (7) changes in risk/benefit. Findings from the tau scan and all 
other research results will not be shared with the participants as explicitly noted in the 
consent form. Participants will be screened by a physician remotely before scheduling the 
scan and screened by a physician in person before leaving the scanning area. Researchers 

 
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call participants about 48 hours after the PET/CT imaging session to see if participants 
experienced any side-effects that may have occurred within 24 hours post-injection.  
Potential risks and discomforts will be prevented and/or minimized to the greatest extent 
possible by using procedures such as appropriate training of personnel, monitoring, 
withdrawal of the subject upon evidence of difficulty or adverse event; referral for 
treatment, counseling, or other necessary follow-up. The study records will be treated as 
private to the extent permitted by law. Reassurance will be provided as needed and 
participants will be reminded that their continued participation in the study is completely 
voluntary.  
6.8.1.3. 
Interaction with other medications 
Comprehensive drug-drug interaction studies have not been performed in subjects to 
delineate the effect that other medications may have on the distribution of [18F]AV-1451.   
Please refer to the investigator brochure, Appendix V, for detail on the preclinical in 
vitro results of non-radiolabeled AV-1451 to human liver microsomes and MDCK-MDR1 
cells. This testing did not yield evidence for inhibition of CYP enzymes or P-glycoprotein 
transport at concentrations greatly exceeding expected plasma concentrations at 
recommended human dosing for imaging (maximum 20 µg [18F]AV-1451).  
Because of the positive in-vitro hERG assay, albeit correlating to concentrations of 
[18F]AV-1451 expected to far exceed that encountered at imaging doses (~42-900 fold 
safety margin), subjects with prolonged QTc interval, risk factors for prolonged QTc, or 
taking drugs known to prolong QT interval will be excluded. 
6.8.1.4. 
Adverse Reactions 
 
All reported events were mild or moderate in severity, and all 
subjects recovered. 
 
Risks of adverse reactions associated with [18F]AV-1451 
administration: In completed studies with a total of 273 subjects the 
following adverse events were reported in at least 1% of subjects and 
were not thought by the investigator(s) to be related to study procedures, 
or otherwise thought by the investigator(s) to be related to [18F]AV-1451: 
diarrhea, headache, muscle spasm, dysgeusia, injection site pain 
6.8.1.4.2.1. 
Risks and discomforts associated with the PET/CT scan 
procedures: 

 
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• Subjects will be required to lie still in the scanner during PET/CT 
scan acquisition; 
• Being in the PET/CT scanner may cause discomfort including 
musculoskeletal (neck or back) pain, or claustrophobia. 
6.8.1.4.2.2. 
Risks of radiation exposure (including [18F]AV-1451 and 
low dose CT scan): [18F]AV- 1451 administration and the 
accompanying CT scan for attenuation correction contribute to a 
subject’s long-term cumulative radiation exposure, which is 
associated with an increased risk of developing cancer. Additionally, 
higher levels of radiation can cause damage to the developing fetus. 
• The amount of radiation exposure is similar to other 18F 
radiopharmaceuticals. 
• Females of childbearing potential will usually be excluded from 
[18F]AV-1451 studies unless they are surgically sterile, agree to 
use reliable contraception, or refrain from sexual activity. 
• Females of childbearing potential who do participate must not be 
pregnant or breastfeeding at screening (negative serum β-HCG at 
screening and a negative urine β-HCG within 24 hours prior to 
injection), and must agree to avoid becoming pregnant. 
• Female and male study subjects must agree to refrain from sexual 
activity or to use reliable contraceptive methods for 90 days 
following administration of [18F]AV-1451 injection. 
6.8.1.4.2.3. 
The risk of harm to the subjects from radiation for this 
study can be compared to risks from everyday activities. For 
example, the risk of developing fatal cancer during one’s lifetime 
from this radiation exposure is comparative to the risk of suffering a 
fatal car crash while driving 918 miles in an automobile. 
PET/CT Scan - Placement of the IV catheter for isotope injection may result in pain, 
infection, or bruising at the site. Placement of an IV catheter may cause anxiety. 
Psychological Stress – Participants could experience uneasiness from questions being 
asked or knowing that personnel have their personal information.  
Loss of Confidentiality – There is a risk for loss of confidentiality. Every effort will be 
made to keep information confidential; however, this can never be guaranteed.  

 
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Other Risks - There is a very low risk of developing fatal cancer during the participant’s 
lifetime from this radiation. There may possibly be other side effects that are unknown at 
this time.  
6.8.2. Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies. Adverse events are reported in a routine manner at scheduled 
times during a trial. Additionally, certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring of subject safety and care.  
All subjects experiencing an adverse event, regardless of its relationship to study 
therapy, will be monitored until:  
• the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline or is stable in the opinion of the investigator(s);  
• there is a satisfactory explanation other than the study therapy for the changes 
observed;  
• or death. 
6.8.2.1. 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, 
clinical event, or disease, temporarily associated with the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the research. 
 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be expected 
or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed consent, 
through 2 days post treatment will be considered acute adverse events.   
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Adverse 

 
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events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log 
according to the general guidelines provided by the NCI CTCAE and as outlined below.   
Grade 1: Mild  
Grade 2: Moderate 
Grade 3: Severe or medically significant but not immediately life threatening 
Grade 4: Life threatening consequences 
Grade 5: Death related to the adverse event 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
• Results in death   
• Immediately life-threatening  
• Results in inpatient hospitalization1,2 or prolongation of existing hospitalization.  
• Results in persistent or significant disability/incapacity.  
• Results in a congenital anomaly/birth defect  
• Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A serious 
adverse event determination does not require the event to be related to the research. That 
is, both events completely unrelated to the condition under study and events that are 
expected in the context of the condition under study may be serious adverse events, 
independent of relatedness to the study itself. As examples, a car accident requiring > 24 
hour inpatient admission to the hospital would be a serious adverse event for any research 
participant; likewise, in a study investigating end-stage cancer care, any hospitalization or 
death which occurs during the protocol-specified period of monitoring for adverse and 
serious adverse events would be a serious adverse event, even if the event observed is a 
primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2NCI defines hospitalization for expedited AE reporting purposes as an inpatient 
hospital stay equal to or greater than 24 hours. Hospitalization is used as an indicator of 

 
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the seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor treatment 
(e.g. hydration) and released in less than 24 hours. Furthermore, hospitalization for 
pharmacokinetic sampling is not an AE and therefore is not to be reported either as a routine 
AE or in an expedited report. 
6.8.2.2. 
Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but 
not defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term unanticipated 
adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from the regulatory 
agencies considers unanticipated problems to include any incident, experience, or outcome 
that meets ALL three (3) of the following criteria: 
• Unexpected in terms of nature, severity or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied;  
 
 
 
 
 
 
AND 
• Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); 
 
 
 
 
 
 
AND  
• Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. Note: According to OHRP, if the adverse event 
is serious, it would always suggest a greater risk of harm. 
Follow-up  
All adverse events will be followed up according to good medical practices.  
6.8.3.  Steps to Determine If a Serious Adverse Event Requires Expedited 
Reporting to the HRPP 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
Step 2: Grade the adverse event using the NCI CTCAE v5. 

 
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Step 3: Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE may NOT be related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur to the end of the acute adverse events reporting 
period as defined in section 6.8.2 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the treatment. An 
adverse event is considered unexpected, for expedited reporting purposes only, when either 
the type of event or the severity of the event is not listed in: 
• the current known adverse events listed in the Agent Information Section of this 
protocol (if applicable) 
• the drug package insert (if applicable) 
• the current Investigator’s Brochure (if applicable) 
• the Study Agent(s)/Therapy(ies) Background and Associated Known Toxicities 
section of this protocol 
6.8.3.1. 
Reporting Unanticipated Problems Involving Risks to Subjects or 
Others (UPIRSOs) and SAEs to the UTSW and UTD HRPP/IRB, AVID 
Radiopharmaceutical, and FDA 
UTSW reportable event guidance applies to all research conducted by or on behalf of 
UT Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, 
etc. that meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a 
subject’s underlying condition or not expected as a risk of the study; therefore, 
not included in the investigator’s brochure, protocol, or informed consent 
document), AND 

 
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2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized.  Note: According to OHRP, if the adverse 
event is serious, it would always suggest a greater risk of harm. 
UPIRSO and SAEs must be promptly reported to: 
• Avid Radiopharmaceuticals within 24 hours of principal investigator (PI) 
awareness; For reporting, please contact 
MAILINDATA_GSMTINDY@LILLY. COM; 
• UTSW and UTD Human Research Protection Program/Institutional Review 
Board within 5 working days of PI awareness. 
• FDA no later than 15 calendar days after the sponsor determines that the 
suspected adverse reaction or other information qualifies for reporting (21 CFR 
312.32(c)(1)).  
Events NOT meeting UPIRSO or SAE criteria: 
 
Events that do NOT meet UPIRSO or SAE criteria should be tracked, evaluated, 
summarized, and submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combined.pdf. 
 
6.9. DRUG INFORMATION 
6.9.1. [18F]AV-1451 for Injection 
7-(6-[F-18]fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole 
 
 
MW = 262.27 amu 

 
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6.9.1.1. 
Descriptive name: Flortaucipir F 18; [18F]AV-1451 
6.9.1.2. 
Classification: Positron Emitting Radiopharmaceutical 
6.9.1.3. 
Mode of Action: Flortaucipir F 18 is under investigation as a diagnostic 
PET radiopharmaceutical for in vitro imaging of tau pathology in patients with 
AD and related neurodegenerative diseases characterized by the presence of 
tau pathology. The primary pharmacodynamic data obtained on flortaucipir F 
18 show a high selectivity for binding to tau protein aggregates vs. β-amyloid 
in human brain tissue and rapid uptake in the brain with clearance from normal 
tissue in mice, rats and non-human primates. These data indicate that 
flortaucipir F 18 is potentially an important new tool for the in vitro assessment 
of tau protein aggregates (e.g. neurofibrillary tangles (NFTs)), thus providing a 
possible biomarker of the progressive pathology underlying neurodegeneration 
in AD. Such an agent may prove useful in the diagnosis, follow-up and 
therapeutic monitoring of AD and other dementias. 
6.9.1.4. 
Storage and Stability: [18F]AV-1451 for Injection is stored at room 
temperature. [18F]AV-1451 for Injection should be stored within the original 
container or equivalent radiation shielding.   
6.9.1.5. 
Protocol Dose: [18F]AV-1451 for Injection will be administered IV up to 
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 [18F]FDG and florbetapir F 18 injection. 
The proposed dose has been shown to be well tolerated and to have 
acceptable image quality in preliminary human studies. 
6.9.1.6. 
Preparation: [18F]AV-1451 for Injection is a clear solution containing 
[18F]AV-1451 (drug substance) formulated for intravenous bolus 
administration. [18F]AV-1451 for Injection will be formulated in a solution 
containing 10% (v/v) ethanol, USP in 0.9% sodium chloride injection, USP. 

 
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Drug product is manufactured to meet Avid Radiopharmaceutical’s set of 
specifications. 
The expiration time and date of [18F]AV-1451 for Injection are provided on 
the outer label of each dose based on specific activity or strength. Expiration 
time is 10 hours post End of Synthesis or when the strength self-life 
specification is reached (≥ 37 MBq/mL), whichever is soonest. [18F]AV-1451 
for Injection is be stored at room temperature. 
6.9.1.7. 
Route of administration for this study: The route of administration will 
be a single, intravenous bolus.  
6.9.1.8. 
Incompatibilities: There are no known absolute contraindications to 
[18F]AV-1451. The effects of [18F]AV-1451 have not been studied in pregnant 
or lactating females and subjects that are either pregnant or lactating will be 
excluded from the study. 
Severe drug allergies may pose a potential safety risk. Subjects will be 
screened by a physician for relevant drug allergy history and will excluded at 
the discretion of the screening physician.   
Preclinical in vitro testing of non-radiolabeled AV-1451 showed a positive 
potassium ion channel assay as detailed in the investigator brochure. The 
theoretical peak plasma concentration of [18F]AV-1451 following the maximum 
recommended dose of 20 µg [18F]AV-1451 suggest a 42 fold safety margin when 
compared to the IC50 resulting in the positive test. This safety margin is likely 
vastly underestimated when plasma protein binding is also accounted for ~900 
fold safety margin. However, given the relatively limited safety data available 
to date in humans, subjects with documented prolonged QTc interval on 
screening EKG, those with historical risk factors for QT prolongation, and 
subjects taking medications known to cause QT prolongation (determined at 
physician screening) will be excluded.   
6.9.1.9. 
Availability: Provided by UTSW Department of Radiology Cyclotron and 
Radiochemistry 
Xiankai Sun, PhD, Director 
Associate Professor, Radiology 
Director, Cyclotron and Radiochemistry Program 
UT Southwestern Medical Center 
2201 Inwood Rd, NE3.240 
Dallas, Texas 75390 

 
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(Phone): 214-645-5978 
Email: Xiankai.Sun@utsouthwestern.edu  
6.9.1.10. Side effects:  
 
A review of the safety information for [18F]AV-1451 showed that 
the product is generally well tolerated with a low incidence of mild and 
transient adverse events. Investigator(s) should be aware of the following 
risk information related to [18F]AV-1451 and the PET/CT procedures: 
 
Risks of adverse reactions associated with [18F]AV-1451 
administration: In completed studies with a total of 59 subjects the 
following adverse events were reported in at least 1% of subjects and 
were not thought by the investigator(s) to be related to study procedures: 
diarrhea, headache, dysgeusia. 
6.9.1.11. Return and Retention of Study Drug 
[18F]AV-1451 (drug substance) is formulated in a clear solution 
containing 10% (v/v) ethanol, USP in 0.9% sodium chloride injection, USP. 
This solution will be kept one-year post-injection as required by FDA 
regulations. 
Contact for drug destruction policy: 
Marianna Dakanali, PhD 
Assistant Professor, Radiology 
Regulatory Affairs Officer, Cyclotron and Radiochemistry Program 
UT Southwestern Medical Center 
5323 Harry Hines Blvd, Dallas, TX, 75390-8542 
(Phone): 214-645-7611  
(Fax): 214-645-0857 
Email: Marianna.Dakanali@utsouthwestern.edu 
 
6.10. 
STATISTICAL CONSIDERATIONS 
6.10.1. Study Design/Study Endpoints 
This is a single-center study that uses two types of designs. First, the Wave 3 data will 
be analyzed separately and utilizes a cross-sectional design with age as a primary 
continuous variable, as well as multiple aspects of brain structure, brain function, cognitive 
performance, and amyloid deposition used as additional predictors of different types of 

 
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cognitive function (memory, speed of processing, executive function). Then, in a second 
series of analyses that integrate data from Wave 1, Wave 2, and Wave 3, a retrospective-
longitudinal design will be used to assess the relationship of present tau deposition to 
change in multiple aspects of brain structure, brain function, cognitive performance, and 
amyloid across time. Tau imaging agent administration is open-label, and imaging of 
participants will end when all eligible participants are scanned, all remaining participants 
have been contacted but are unable to be reached or unwilling to participate, or in the event 
that new safety data becomes available that indicates the study should be terminated. Study 
endpoints described in sections 6.5.4 and 6.5.5 are repeated below. 
6.10.1.1. Primary Endpoints 
The primary objective will involve completion of up to 125 [18F]AV-1451 PET scans 
on Wave 1 and 2 DLBS participants. Measures of cognition, MRI, and amyloid PET will 
have been collected in previous visits. Once the tau scan data are collected, data collection 
will stop. 
6.10.1.2. Secondary Endpoints 
Tau deposition will be estimated from Wave 3 data by the SUVr of [18F]AV-1451 in 
temporal regions (both left and right) of interest: (1) inferior temporal gyrus, (2) middle 
temporal gyrus, (3) superior temporal gyrus, (4) entorhinal cortex, (5) parahippocampal 
gyrus, and (6) fusiform gyrus. Amyloid accumulation will be measured as the SUVr value 
averaged across eight cortical regions: dorsal lateral prefrontal cortex, orbitofrontal cortex, 
lateral parietal cortex, posterior cingulate cortex, anterior cingulate cortex, precuneus, 
lateral temporal cortex, and occipital lobe. Both measures of tau and amyloid will be used 
as continuous measures rather than positive and negative dichotomy. In addition, there 
were 60 participants in Wave 2 who received tau imaging four years earlier. Change in tau 
deposition will be estimated for all returning participants who were among those that 
received tau imaging in both Waves 2 and 3. We also note that for all endpoints described 
below, we will analyze the data exclusively from Wave 3 in cross-sectional analyses, and 
then will also calculate change in all of these endpoints from Wave 1 to 3, and then 
retrospectively relate tau levels to changes in these endpoints.  
 
Hippocampal volume and regional cortical thickness will be 
estimated using FreeSurfer (ver. 5.3), with surface parcellation manually 
edited, when necessary, by our team of experts.  
 
Estimates of white matter integrity will be collected using 
diffusion tensor measures. For functional measures, BOLD signal from 
contrasts of interest using selected ROI’s will be created using our 

 
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subsequent memory task and semantic judgment task and their 
relationship to tau deposition will be assessed. In addition, we will also 
use resting state data to look at how tau effects functional brain 
connectivity.  
 
Joint effects of tau and amyloid will be examined by including 
them as an interaction term in a linear mixed-model analysis. 
 
Cognitive decline will be assessed using the following constructs: 
processing speed, episodic memory, working memory, and executive 
function. Scores on these constructs will be averaged across relevant 
DLBS tasks and standardized based on performance at the beginning of 
this longitudinal study (Wave 1).  
6.10.2. Sample Size and Accrual 
To fulfill the primary objective of this research project, we intend to conduct tau PET 
imaging with up to 125 adults that were typically-aging at the start of this study. Scanning 
will take place over the span of the next 2 years with an anticipated accrual rate of 
approximately 7 subjects per month. This accrual rate was based on our experience imaging 
participants in the previous wave of data collection.  
Statistical power was computed using G*Power (ver 3.1) assuming successful collection 
of tau data for the full 125 subjects and using default G*Power parameters unless otherwise 
specified. The secondary objectives of this study (Sections 6.5.2.1 - 6.5.2.4) are assumed 
to involve linear relationships between variables for the purpose of this power analysis. 
With this sample size, we have an estimated power of 0.93 to detect linear relationships 
that are medium-sized (effect size: r = 0.30). This robust power level will allow for strong 
confidence in our findings, computation of more precise 95% confidence intervals on effect 
sizes, and more fine-grained post hoc analysis.     
6.10.3. Data Analyses 
For all analyses, testing the primary and secondary objectives of this study, our 
measures of interest will be measured continuously and entered into linear regression or 
linear mixed-models analyses as appropriate. For each objective, as we have noted earlier, 
we will first analyze the data cross-sectionally within Wave 3 to determine whether tau 
SUVr is related with our dependent variables. A test-wise alpha of 0.05 will determine 
finding significance regarding research hypotheses, and post hoc analyses will be corrected 
for family-wise error using the multi-stage Holm-Bonferroni method (Holm, 1979). Then 
we will model changes from Waves 1 - 3 in endpoints and their relationship to tau at Wave 
3. 

 
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6.10.3.1. Our primary objective, to determine the time course of tau deposition with 
age, will be first assessed by computing a linear regression between the AV-
1451 SUVr in each of our temporal regions of interest with participant age. 
Next, we will determine whether this relationship is better fit by a quadratic, 
exponential, or growth model. We predict that tau accumulation will accelerate 
in old age, thus supporting a non-linear rate of deposition. 
6.10.3.2. A linear mixed-model analysis will be used to relate our continuous SUVr 
measure of amyloid deposition with the SUVr for tau deposition in each of our 
temporal ROIs. An amyloid SUVr x time of testing interaction term will be 
used to predict changes in tau SUVr. We predict that increased amyloid burden 
will be associated with accelerated tau deposition.    
6.10.3.3. To determine differences in cognitive, structural, and functional decline 
between those with and without tau and amyloid pathology, we will perform 
multiple linear mixed-model analyses. All variables of interest will be included 
as continuous measures. Tau SUVr x time and amyloid SUVr x time 
interaction terms will be entered in these models to predict how amyloid and 
tau pathology predicts longitudinal changes in our cognitive, structural, and 
functional measure of interest. In line with recent research, we predict tau 
burden in particular to be strongly associated with more rapid structural and 
cognitive decline.   
6.10.3.4. Similar to section 6.10.3.3, relationships between estimated tau deposition 
(SUVr) with hippocampal volume and cortical thickness will be estimated by 
entering these variables as continuous measures in linear mixed-model 
analyses with interaction terms including time of scanning/testing. We 
hypothesize that elevated tau SUVr will be associated with more steep declines 
in hippocampal volume and cortical thickness. 
6.10.3.5. To examine the joint effect of tau and amyloid, these variables will be 
multiplied to form an interaction term (tau SUVr x amyloid SUVr x time) that 
will be entered in a linear mixed-model analysis to predict longitudinal 
changes in cognitive, structural, and functional measures. 
 
6.11. 
STUDY MANAGEMENT 
6.11.1. Conflict of Interest 

 
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Any investigator(s) who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by the UTSW COI Committee and IRB according to 
UTSW Policy on Conflicts of Interest.  All investigators will follow the University conflict 
of interest policy. 
6.11.2. Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB must approve the consent form 
and protocol. 
In obtaining and documenting informed consent, the investigator(s) should comply with 
the applicable regulatory requirement(s), and should adhere to Good Clinical Practice 
(GCP) and to ethical principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. Each 
consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator(s) is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should 
be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion. 
6.11.3. Registration/Randomization Procedures 
Each newly consented subject will be numbered based on their assigned Dallas Lifespan 
Brain Study Number.  This number is unique to each subject and independent of all 
personal identifying information. 
This study does not require randomization; all participants will receive [18F]AV-1451. 
6.11.4. Data Management and Monitoring/Auditing 
6.11.4.1. Regulatory Documentation  
The following regulatory documents will be retained. 
• A copy of the official IRB approval letter for the protocol and informed consent. 
• IRB Federal-wide Assurance letter. 

 
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• CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study. 
• Form FDA 1572 appropriately filled out and signed with appropriate 
documentation  
• A copy of the IRB-approved consent form. 
6.11.4.2. CRFs and Source data 
Case report forms (CRFs) 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 CRFs must be backed up by source data. Original electronic 
versions of imaging studies are also considered source data and will be kept on file by the 
site/imaging center. 
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. 
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 CRF. 
The CRFs 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 CRFs must be completed for 
each patient enrolled in the trial. 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 CRF. 
6.11.5. Monitoring 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by monitor. This review 
includes but is not limited to accuracy of case report forms, protocol compliance, and 
AE/SAE management and reporting. Documentation of trial monitoring will be maintained 
along with other protocol related documents and will be reviewed during internal audit.   
6.11.6. Adherence to the Protocol 

 
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Except for an emergency situation, in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
6.11.6.1. Exceptions (also called single-subject exceptions or single-subject 
waivers): include any departure from IRB-approved research that is not due to 
an emergency and is: 
• intentional on part of the investigator(s); or 
• in the investigator(s)’s control; or 
• not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
o Reporting requirement: Exceptions are non-emergency deviations 
that require prospective IRB approval before being implemented. Call 
the IRB if your request is urgent. If IRB approval is not obtained 
beforehand, this constitutes a major deviation. 
6.11.6.2. Emergency Deviations: include any departure from IRB-approved 
research that is necessary to:  
• avoid immediate apparent harm, or 
• protect the life or physical well-being of subjects or others 
o Reporting requirement: Emergency deviations must be promptly 
reported to the IRB within 5 working days of occurrence. 
6.11.6.3. Major Deviations (also called violations): include any departure from 
IRB-approved research that: 
• Harmed or placed subject(s) or others at risk of harm (i.e., did or has the potential 
to negatively affect the safety, rights, or welfare of subjects or others), or 
• Affect data quality (e.g., the completeness, accuracy, reliability, or validity of 
the data) or the science of the research (e.g., the primary outcome/endpoint of 
the study) 
o Reporting requirement: Major deviations must be promptly reported 
to the IRB within 5 working days of PI awareness. 
6.11.6.4. Minor Deviations: include any departure from IRB-approved research 
that: 

 
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• Did not harm or place subject(s) or others at risk of harm (i.e., did not or did not 
have the potential to negatively affect the safety, rights, or welfare of subjects 
or others), or 
• Did not affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
o Reporting requirement: Minor deviations should be tracked and 
summarized in the progress report at the next IRB continuing review. 
6.11.7. Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended. When an amendment to the protocol substantially alters the study design or 
the potential risk to the patient, a revised consent form might be required.  
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
6.11.8. Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of the 
clinical research study. 
Government agency regulations and directives require that the study investigator(s) 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
6.11.9. Obligations of Investigators 

 
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The Principal Investigator and Co-Investigators are responsible for the conduct of the 
clinical trial at the site in accordance with Title 21 of the Code of Federal Regulations 
and/or the Declaration of Helsinki. The Principal Investigator and Co-Investigators are 
responsible for personally overseeing the treatment of all study patients. The Principal 
Investigator and Co-Investigators must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
The Principal Investigator and Co-Investigators will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator and Co-Investigators 
will provide access to his/her original records to permit verification of proper entry of data. 
At the completion of the study, all case report forms will be reviewed and accuracy of the 
data verified. 
 
6.12. 
REFERENCES 
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