Clinical trial NCT03040713
Conditions: Frontotemporal Dementia
Sponsor: Avid Radiopharmaceuticals
Start date: 2017-04-11; Completion date: 2018-10-24
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to assess the usefulness of flortaucipir in Positron Emission Tomography (PET) imaging for subjects diagnosed with Frontotemporal Dementia (FTD).

Detailed description:

Arms: arm 1: Subjects diagnosed by dementia specialist with a clinical Frontotemporal Dementia (FTD) syndrome and expected tau or tar DNA binding protein (TDP)-43 pathology receiving a flortaucipir PET scan
Interventions: intervention 1: Flortaucipir F18 intervention 2: Brain PET scan
Intervention descriptions: intervention 1: 370 megabecquerel (MBq)(10 millicurie \[mCi\]) injection, single dose intervention 2: positron emission tomography (PET) scan of the brain

Protocol documents:
Prot_000.pdf: 
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Sponsor: 
Avid Radiopharmaceuticals 
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-A19 
 
“18F-AV-1451 PET Imaging in Subjects with Frontotemporal Dementia” 
Planned number of subjects (Enrolled): Approximately 25 
 
Subjects diagnosed by a dementia specialist with a clinical Frontotemporal Dementia 
(FTD) syndrome and expected tau or TDP-43 pathology. 
Name of compound: 18F-AV-1451([F-18]T807) 
Dose: 370 MBq (10 mCi) 
Route of Administration:  Intravenous (IV) bolus 
Study Phase:  I 
Study Centers:  Approximately 3 centers in the United States 
Trial Objectives:  
The primary objective of this study is: 
• To evaluate 18F-AV-1451 retention in PET scans of FTD subjects. 
 
A secondary objective of this study is: 
• 
To expand the 18F-AV-1451 safety database. 
Eligibility: 
See Section 5.3, Selection of Subjects. 
Study Design: 
This is a phase I study that will evaluate imaging characteristics of 18F-AV-1451 in 
subjects with Frontotemporal Dementia (FTD).  
 
Subjects followed in a referral center research cohort for FTD will be contacted to 
participate and must provide informed consent before starting any 18F-AV-1451-A19 study 
procedures. Screening assessments may take place over several days and will include 
demographic information, a medical assessment for eligibility, ECG, a brief cognitive 
assessment (e.g. MMSE), and florbetapir F 18 Positron Emission Tomography (PET) 
imaging.  The screening florbetapir F 18 PET scan is to be performed to assess for 
evidence of amyloid pathology and should be interpreted by a local reader prior to 
enrollment. Subjects will receive a single IV bolus injection of approximately 370 MBq 
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Sponsor: 
Avid Radiopharmaceuticals 
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 
(10 mCi) +10% of florbetapir F 18 followed by a saline flush. A 20-minute continuous, 
dynamic PET brain scan will begin approximately 50 minutes following the dose 
administration; 
 
Subjects who qualify for the study will come to the imaging center at a later date and will 
have a catheter(s) placed for IV administration of 18F-AV-1451. Vital signs will be taken 
in a supine position immediately prior to administration of 18F-AV-1451 (within 30 
minutes prior to injection) and at the completion of imaging prior to subject discharge.  
Subjects will receive a single IV bolus injection of approximately 370 MBq (10 mCi) 18F-
AV-1451 followed by a saline flush. A 30 minute dynamic image will begin 
approximately 75 minutes following the dose administration.  
 
Adverse events will be continuously monitored during the imaging sessions.  Subjects who 
experience any adverse event 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, but not less than 48 hours, after each imaging visit, to 
confirm subject well-being and to collect information about any new adverse events.   
 
 
Assessments and Endpoints 
Details of the assessments that will be performed at each visit are detailed in Section 7.1. 
Subjects will complete the following: 
• Screening Visit, including florbetapir F 18 PET imaging 
• 
18F-AV-1451 PET Imaging Visit 
• Follow-up Phone Calls 
Tracer uptake in subjects will be evaluated by both qualitative and quantitative techniques.  
Statistical Methods:  
Descriptive Statistics will be used to summarize the clinical characteristics and the 18F-
AV-1451 uptake. The pattern of 18F-AV-1451 tracer binding will be measured both by 
qualitative visual analysis and by SUVr.    
  
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL NUMBER:   18F-AV-1451-A19 ....................................................... 1 
DATE AND VERSION: ........................................................................................ 1 
05 MAY 2016, FINAL .......................................................................................... 1 
1. 
INTRODUCTION ............................................................................ 10 
2. 
TRIAL OBJECTIVES ...................................................................... 11 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER PARTICIPANTS 12 
4. 
TEST DRUG AND CONTROL AGENTS ...................................... 12 
4.1. 
Descriptive Name:  18F AV-1451 ..................................................... 12 
4.2. 
Descriptive Name:  Florbetapir F 18 ................................................ 13 
4.3. 
Radioactive Labeling ........................................................................ 13 
4.4. 
Decay Characteristics ....................................................................... 13 
4.5. 
Formulation and Dose 18F-AV-1451 Injection ................................. 13 
4.6. 
Formulation and Dose Florbetapir F 18 Injection ............................ 14 
4.7. 
Packaging 18F-AV-1451 Injection .................................................... 14 
4.8. 
Packaging Florbetapir F 18 Injection ............................................... 14 
4.9. 
Storage and Handling 18F-AV-1451 Injection .................................. 14 
4.10. 
Storage and Handling Florbetapir F 18 Injection ............................. 15 
5. 
INVESTIGATIONAL PLAN ........................................................... 15 
5.1. 
Overall Design and Plan of Trial ...................................................... 15 
5.2. 
Planned Dosage and Duration of Treatment ..................................... 15 
5.2.1. 
Dosage and Administration .............................................................. 15 
5.2.2. 
Rationale for Dosage ........................................................................ 16 
5.3. 
Selection of Subjects ......................................................................... 16 
5.3.1. 
Inclusion Criteria .............................................................................. 16 
5.3.2. 
Exclusion Criteria ............................................................................. 17 
5.4. 
Prior and Concomitant Therapy ........................................................ 18 
5.5. 
Removal of Subjects from Trial ....................................................... 18 
5.6. 
Premature Termination of Trial/Closure of Center .......................... 18 
6. 
PRODUCT RISK ASSESSMENT ................................................... 19 
7. 
PROCEDURES AND METHODS .................................................. 19 
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7.1. 
Assessment Periods .......................................................................... 19 
7.1.1. 
Screening Visit: Visit 1 ..................................................................... 19 
7.1.1.1. 
Screening Florbetapir F 18 PET scan ............................................... 20 
7.1.2. 
18F-AV-1451 PET Imaging Visit: Visit 2 ......................................... 21 
7.2. 
Observations and Measurements ...................................................... 22 
7.3. 
Protocol for Image Collection .......................................................... 23 
7.4. 
Good Clinical Practice and Monitoring ............................................ 24 
7.5. 
Informed Consent and Subject Information ..................................... 24 
7.6. 
Documentation .................................................................................. 25 
7.7. 
Adverse Events (AE) ........................................................................ 25 
7.7.1. 
Adverse Event Monitoring ................................................................ 26 
7.7.2. 
Adverse Event Definitions ................................................................ 26 
7.7.3. 
Adverse Event Documentation ......................................................... 28 
7.7.4. 
Reporting of Serious Adverse Events ................................................ 28 
8. 
STATISTICAL ANALYSIS ............................................................ 29 
8.1. 
General Statistical Considerations .................................................... 29 
8.1.1. 
Sample Size Estimation .................................................................... 29 
8.1.2. 
Populations for Analysis ................................................................... 30 
8.2. 
Analyses ............................................................................................ 30 
8.2.1. 
Efficacy Analyses ............................................................................. 30 
8.2.2. 
Safety Analyses ................................................................................ 30 
9. 
USE OF DATA AND PUBLICATION ........................................... 30 
10.
INVESTIGATOR’S REGULATORY OBLIGATIONS ................. 31
10.1. 
Institutional Review Board (IRB) ..................................................... 31 
10.2. 
Informed Consent ............................................................................. 31 
10.3. 
Protocol Adherence .......................................................................... 32 
10.4. 
Documents Necessary for Initiation of the Trial .............................. 32 
10.5. 
Study Drug Control........................................................................... 32 
10.6. 
Data Collection ................................................................................. 32 
10.7. 
Adverse Events ................................................................................. 33 
10.8. 
Records Retention ............................................................................. 33 
11.
APPENDICES .................................................................................. 35
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11.1. 
References ......................................................................................... 35 
11.2. 
Trial Flow Chart ............................................................................... 37 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ABBREVIATIONS AND DEFINITIONS  
 
Aβ 
Beta amyloid  
AD 
ADR 
Alzheimer’s disease 
Adverse Drug Reaction 
Adverse Event 
(AE) 
 
 
amu 
 
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. 
 
Atomic mass unit 
Audit 
 
 
 
 
 
 
β+ 
 
bvFTD 
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). 
 
Beta decay 
 
Behavioral variant Frontotemporal Dementia 
 
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. 
 
CI 
 
CNS 
 
Confidence Interval 
 
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.  
ECG 
 
Electrocardiogram 
 
Efficacy 
 
EOS 
Efficacy is the ability of a treatment to achieve a beneficial intended 
result. 
End of Synthesis 
FDA 
US Food and Drug Administration  
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FDG 
18F – Fluorodeoxyglucose 
FTD 
GCP 
hERG 
IB 
ICF 
Frontotemporal Dementia 
Good Clinical Practice 
human Ether-à-go-go-Related Gene 
Investigator’s Brochure 
Informed Consent Form 
ICH 
International Conference on Harmonization 
Institutional 
Review Board 
/Independent 
Ethics Committee 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
the safety, welfare and human rights of the subjects participating in a 
clinical study are protected. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
IV 
Intravenous 
Kd
keV 
Dissociation Constant 
Kiloelectronvolt 
LAR 
MBq 
Legally authorized representative 
Megabecquerel 
mCi 
MedDRA 
Millicurie 
Medical Dictionary for Regulatory Activities 
MHD 
MMSE 
Maximum Human Dose 
Mini-Mental State Examination 
MRI 
Magnetic Resonance Imaging 
mSv 
MW 
N 
Millisivert, a derived unit of ionizing radiation dose in the 
International System of Units 
Molecular weight 
Number, or total 
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NDA 
 
NLT 
 
NORM-JECT® 
New Drug Application 
 
Not Less Than 
 
syringes which are latex-free, contain no rubber, no silicone oil, styrene 
or DEHP and are DNA-free 
NOAEL 
No Observable Adverse Effect Level 
PET 
PHF tau 
PhRMA 
Positron Emission Tomography 
Paired Helical Filament tau 
Pharmaceutical Research and Manufacturers of America 
PSP 
 
v/v 
 
QT 
 
Progressive supranuclear palsy 
 
Percentage solution 
 
A measure of the time between the start of the Q wave and the end of 
the T wave 
 
SAP 
SAS 
SD 
Serious Adverse 
Event (SAE) 
 
 
 
SOC 
SOP 
SUVr 
TdP 
Statistical Analysis Plan 
Statistical Analysis System 
Standard Deviation 
A 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, 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. 
System organ class 
Standard Operating Procedure 
Standard Uptake Value Ratio 
Torsades de Pointes 
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1. 
INTRODUCTION  
The clinical diagnosis of patients with dementia is challenging and is frequently 
inaccurate compared to pathological diagnosis at autopsy.  Although Alzheimer’s disease 
(AD) is the most common cause of dementia, other etiologies including Fronto-Temporal 
Dementia (FTD), vascular dementia and Dementia with Lewy Bodies occur in a 
substantial number of cases, (Barker et al. 2002) and there may be substantial overlap in 
the clinical presentation of these disorders. In clinico-pathological studies, 10 - 20% of 
patients diagnosed with AD in life did not have pathology consistent with the disease at 
autopsy (Lim et al. 1999, Mayeux et al. 1998, Ranginwala et al. 2008).  Conversely, a 
recent study showed that 40% of dementia patients diagnosed with a disorder other than 
AD by an expert neurologist in life had AD pathology (i.e., AD or mixed dementia) on 
post mortem examination (Beach et al. 2012). 
 
Accurate antemortem diagnosis can be particularly challenging in FTD given the clinical 
and pathologic heterogeneity of the disease (Rabinovici and Miller 2010). Most cases of 
FTD can be classified into two major pathologic categories: (1) diseases that involve tau 
deposition (FTD-Tau) and (2) conditions associated with tau-negative, ubiquitin and 
TDP43-positive inclusions (FTD-TDP) (Mackenzie et al. 2010). In a minority of cases, 
FTD-Tau can be predicted during life with high accuracy based on the presence of a 
known mutation in the MAPT gene, or based on a highly correlated clinical phenotype 
(e.g. progressive supranuclear palsy (PSP) - Richardson’s Syndrome) (Josephs et al. 
2006).  However, the relationships between other FTD clinical phenotypes and 
pathologic subtypes are far less predictable (Forman et al. 2006, Hodges et al. 2004, 
Josephs et al. 2011, Kertesz et al. 2005). For example, the underlying histopathology in 
patients with behavioral-variant FTD (bvFTD), the most common clinical FTD 
syndrome, is split equally between FTD-Tau and FTD-TDP (Josephs et al. 2011) and 
there are currently no known reliable methods to distinguish the two during life. 
Accurately determining the underlying neuropathology during life is a critical need to 
enhance the development and testing of biologically specific drugs targeting tau or TDP. 
 
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 Aβ negative tissue.  Scatchard analysis based on this heterogeneous autoradiography 
assay yielded an estimated Kd of 15nM. A saturation binding experiment using purified 
PHF 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. 
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 
(0.0955 ± 0.0134 mSv/MBq), followed by the small intestine and the liver.  The Effective 
Dose was 0.0235 ± 0.0016 mSv/MBq. This results in an estimated Effective Dose of 
8.70 mSv for an anticipated 370 MBq (10 mCi) injection and is comparable to the 
effective dose of approved 18F-labeled compounds such as fluorodeoxyglucose (FDG) 
and florbetapir F 18 injection. 
 
18F-AV-1451 may be useful as a marker of tau pathology in patients with AD and other 
neurodegenerative disorders.  Several preliminary studies using 18F-AV-1451 have been 
completed (e.g., Chien et al., 2013). The purpose of the current study is to extend these 
findings by evaluating the usefulness of AV-1451 in FTD and in particular, whether the 
regional pattern of tau deposition typical of AD is present in FTD cases. 
 
2. 
TRIAL OBJECTIVES 
 
Trial Objectives:  
The primary objective of this study is: 
• To evaluate 18F-AV-1451 retention in PET scans of Frontotemporal Dementia (FTD) 
subjects.  
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A secondary objective of this study is: 
• To expand the 18F-AV-1451 safety database. 
 
3. 
SPONSOR, INVESTIGATOR(S) AND OTHER 
PARTICIPANTS 
 
The trial is sponsored by: 
 
Avid Radiopharmaceuticals 
3711 Market Street, 7th Floor 
Philadelphia, PA 19104 
Phone: +1 215-298-0700 
 
The medical contact is: 
Approximately 3 centers in the United States will participate in this trial. 
 
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 
 
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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 
 
 
 
 
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 18F-AV-1451 Injection 
 
18F-AV-1451 Injection is a sterile, apyrogenic clear solution  for intravenous bolus 
administration. 18F-AV-1451 Injection contains 18F-AV-1451 (drug substance)  
formulated in 10% (v/v) ethanol, USP in 0.9% sodium chloride injection, USP. 
N
N 
H 
O 
O 
O 
1 8 F 
1 8 F-AV-45
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The shelf-life of 18F-AV-1451 Injection is dependent on the strength or specific activity 
calculated at End-of-Synthesis (EOS) but is not more than 10 hours post EOS. The 18F-
AV-1451 Injection expiration time and date will be provided on the label on the 
secondary packaging of each vial or syringe. 
 
4.6. 
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. 
 
4.7. 
Packaging 18F-AV-1451 Injection 
 
18F-AV-1451 Injection is contained in a sterile, non-pyrogenic septum sealed Type I glass 
vial or a sterile apyrogenic syringe. Vials and syringes containing 18F-AV-1451 Injection 
are stored in an opaque shield (secondary packaging) which protects personnel from 
radiation exposure. The shield may be packaged in a Type A shipping container for 
shipment to the imaging facility. 
4.8. 
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. 
4.9. 
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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4.10. 
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. 
5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Design and Plan of Trial 
This is a phase I study that will evaluate imaging characteristics of 18F-AV-1451 in 
subjects with Frontotemporal Dementia (FTD).  
Subjects followed in a referral center research cohort for FTD will be contacted to 
participate and must provide informed consent before starting any 18F-AV-1451-A19 
study procedures. Diagnosis be will determined by companion study with detailed 
characterization provided by enrolling physician. Screening assessments may take place 
over several days and will include demographic information, a medical assessment for 
eligibility, ECG a brief cognitive assessment (e.g. MMSE), and florbetapir F 18 Positron 
Emission Tomography (PET) imaging.  The screening florbetapir F 18 PET scan is to be 
performed to assess for evidence of amyloid pathology and should be interpreted by the 
local reader prior to enrollment. 
Subjects who qualify for the study will come to the imaging center at a later date and will 
have a catheter(s) placed for IV administration of 18F-AV-1451. Vital signs will be taken 
in a supine position immediately prior to administration of 18F-AV-1451 (within 30 
minutes prior to injection) and at the completion of imaging prior to subject discharge. 
Subjects will receive up to a target dose of 370 mBq as a single IV bolus of 18F-AV-1451.  
A 30 minute dynamic image starting approximately 75 minutes post injection will be 
obtained. 
Adverse events will be continuously monitored during the imaging sessions.  Subjects 
who experience any adverse event 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, but not less than 48 hours, after each imaging visit, to 
confirm subject well-being and to collect information about any new adverse events.   
5.2. 
Planned Dosage and Duration of Treatment 
5.2.1. 
 Dosage and Administration 
 
18F-AV-1451: 
 
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All subjects will receive a single IV bolus administration of approximately 370 MBq (10 
mCi) of 18F-AV-1451 Injection. 
 
Florbetapir F 18: 
Subjects will receive a single IV bolus administration target dose of 370 MBq (10 mCi) 
of Florbetapir F 18 Injection. 
 
5.2.2. 
Rationale for Dosage  
 
18F-AV-1451 will be administered IV in a radioactive dose of 370 MBq with a maximum 
human dose (MHD) limited to 20 µg of compound by weight.   
 
 
The Effective Dose of 8.70 mSv for a 370 MBq (10 mCi) injection is comparable to the 
effective dose of approved 18F-labeled compounds such as FDG and florbetapir F 18 
injection. 
 
The proposed dose has been shown to have acceptable image quality in previous human 
studies. 
 
5.3. 
Selection of Subjects 
Approximately 25 subjects will be enrolled. 
5.3.1. 
Inclusion Criteria 
Subjects diagnosed by a dementia specialist with symptomatic clinical syndromes 
with expected Frontotemporal Dementia pathology will be enrolled. Clinical 
syndromes associated with FTD pathology include: behavioral-variant FTD, FTD 
with motor-neuron disease, non-fluent/agrammatic and semantic variants of 
primary progressive aphasia, progressive supranuclear palsy syndrome and 
corticobasal syndrome. Symptomatic carriers of a known autosomal dominant 
gene mutation associated with FTD, including: MAPT, GRN, C9ORF72, 
TARDP, CMP2B, VCP, FUS as well as non-gene carriers are eligible for 
enrollment. 
Diagnosis will be determined by companion study with detailed characterization 
provided by enrolling physician. 
 
Subjects who are identified with one of the above clinical syndromes of FTD 
pathology and meet all of the following criteria are eligible to enroll in this trial: 
1. Male or female subjects at least 18 years of age; 
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2. Subjects who give informed consent or have a legally authorized (LAR) to 
consent for study procedures.   
3. Subjects who have volumetric brain MRI images obtained as part of the site’s 
companion protocol within one year of enrollment available for submission to 
Avid. (If the subject does not have a prior MRI available for submission to 
Avid, an MRI may be conducted under this protocol if the subject is able to 
tolerate one.); and 
4. Subjects who in the opinion of the investigator can tolerate the PET scan 
procedures. 
 
5.3.2. 
Exclusion Criteria 
 
1. Have clinically significant cardiac, hepatic, renal, pulmonary, metabolic, or 
endocrine disturbances as indicated by history, which in the opinion of the 
investigator might pose a potential safety risk to the subject;  
2. Have a history of risk factors for Torsades de Pointes (TdP) (e.g.,  
hypokalemia, family history of Long QT syndrome), including clinically 
significant findings on ECG, or are taking drugs that are known to cause QT-
prolongation (a list of prohibited and discouraged medications is provided by 
the Sponsor);   
3. Have a history of drug or alcohol dependence within the last year, or prior 
prolonged history of dependence unless approved by the sponsor;  
4. 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 at the 
time of screening and negative serum or urine β-HCG on imaging day) or 
breastfeeding at screening. Females must agree to avoid becoming pregnant, 
and agree to refrain from sexual activity or to use reliable contraceptive 
methods for 24 hours following administration of 18F-AV-1451 Injection; 
Males with female partners who are pregnant or of childbearing potential must 
agree to refrain from sexual activity for 24 hours following administration 
of 18F-AV-1451 Injection.  Additionally, males must agree not to donate 
sperm for 24 hours following administration of 18F-AV-1451 Injection; 
5. Have a history of relevant severe drug allergy or hypersensitivity (Relevant 
severe drug allergies should be determined by the PI, and any questions about 
a subject’s eligibility can be directed to Avid. If a subject has a history of 
severe drug allergies, it may be dangerous for them to participate in a study); 
6. Are patients who have received an investigational medication under an FDA 
IND protocol within 30 days prior to the planned imaging session for this 
study, with the exception of medications allowed in the companion study and 
approval from sponsor. Additionally, the time between the last dose of the 
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previous experimental medication and imaging must be at least equal to 5 
times the terminal half-life of the previous experimental medication.  
7. Are patients who have received a radiopharmaceutical for imaging or therapy 
within the past 24 hours prior to either imaging session for this study.   
8.  Have evidence of amyloid deposition as demonstrated by a positive 
florbetapir F 18 PET scan.  
9. Are patients who, in the opinion of the investigator, are otherwise unsuitable 
for a study of this type. 
 
5.4. 
Prior and Concomitant Therapy 
 
Except as noted in the exclusion criteria, all medications (prescription or over-the-
counter) that have been started prior to screening may be continued during the 
course of the trial.  All medications, including investigational 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 on the Concomitant Medication Page 
of the electronic Case Report Form (eCRF).   
 
5.5. 
Removal of Subjects from Trial 
 
Subjects must be removed from the trial if: 
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 SAE occurs. The date and reason 
for discontinuation should be noted on the eCRF. 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/Contract Research Organization (CRO) monitors or to provide required 
access to data and source documents, staff turnover, inadequate staffing, and 
inadequate enrollment.  Except in cases affecting subject safety, the investigator 
may complete final study evaluations for ongoing subjects. In all cases of center, 
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or study termination, appropriate steps will be taken to ensure the safety of study 
subjects. 
6. 
PRODUCT RISK ASSESSMENT 
 
The most up-to-date and complete information regarding the use of 18F-AV-1451 
Injection can be found in the investigator's brochure.  
 
 
In brief, 18F-AV-1451 Injection is an experimental imaging agent that will be used at 
relatively low (tracer) doses.  However, 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 and vital 
signs. 
 
There are no data on the effects of 18F-AV-1451 Injection in human perinatal 
development.  . For this reason, females must avoid becoming pregnant. Females 
must use adequate contraceptive methods for 24 hours after administration of 18F-
AV-1451 Injection. 18F-AV-1451 Injection must not be administered to females who 
are pregnant, or lactating. Males with female partners who are pregnant or of 
childbearing potential must agree to refrain from sexual activity for 24 hours 
following administration of 18F-AV-1451 Injection. Additionally, males must agree 
not to donate sperm for 24 hours following administration of 18F-AV-1451 Injection. 
7. 
PROCEDURES AND METHODS 
 
7.1. 
Assessment Periods (See Section 11.2, Trial Flow Chart) 
       
 
The study will consist of the following sequence of activities:  
 
7.1.1. 
Screening Visit: Visit 1 
Screening may take place over several days. All screening assessments will 
preferably be performed within 60 days prior to the 18F-AV-1451 PET imaging 
session.   
Screening assessments will include: 
• Informed consent; 
• Demographics (age, gender, education, race, ethnicity); 
• Medical history, concomitant medications; 
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• Disease history (date/months since symptom onset, date/months since 
diagnosis, family history of relevant neurologic disease); 
• An ECG will be performed to assess the subject’s cardiac status. If an 
ECG was performed within the last 12 months and is available for 
review, the ECG does not need to be repeated;  
• Cognitive status interview, including MMSE; 
• MRI of the brain, only for those subjects who do not have a prior MRI 
(obtained within one year of enrollment) available for submission to 
Avid and are able to tolerate one; 
• Serum pregnancy test (women of childbearing potential);  
• A physician will see the patient during the screening visit. 
• Florbetapir F 18 PET scan (see section 7.1.1.1 for details) 
7.1.1.1. 
Screening Florbetapir F 18 PET scan 
The screening florbetapir F 18 PET scan is to be performed to assess for evidence 
of amyloid pathology and should be interpreted by the local reader prior to 
enrollment. Amyloid scans that have been obtained within 3 years of screening 
can be submitted for review by the local reader for enrollment criteria. If deemed 
interpretable, the subject would not need to complete the screening florbetapir F 
18 PET scan.  
• For women of childbearing potential, a negative pregnancy test must be 
obtained within 24 hours prior to injection; If screening serum pregnancy 
test obtained within 24 hours prior to injection, the pregnancy test need 
not be repeated. 
• Height and body weight will be measured prior to injection. 
• A physician or licensed/credentialed medical professional (that is, a PET 
technologist, imaging center nurse, or a regional equivalent) designated by 
the site principal investigator 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) 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 20-
minute continuous, dynamic PET brain scan will begin approximately 50 
minutes following the dose administration; 
• A physician or licensed/credentialed medical professional (that is, a PET 
technologist, imaging center nurse, or a regional equivalent) designated by 
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the site principal investigator 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. 
 
7.1.2. 
 18F-AV-1451 PET Imaging Visit: Visit 2 
 
The 18F-AV-1451 PET scan should be performed at least 16 hours apart from the 
Florbetapir F 18 PET scan due to the half-life of fluorine 18. The following 
assessments will be performed for all subjects: 
• Females of childbearing potential will have a urine or serum pregnancy 
test prior to injection (the result must be negative for the subject to be 
administered 18F-AV-1451);  
• A physician or licensed/credentialed medical professional (that is, a PET 
technologist, imaging center nurse, or a regional equivalent) designated by 
the site principal investigator must see the subject prior to administration 
of 18F-AV-1451 to determine if they are still suitable to undergo the scan; 
• Vital signs will be taken in a supine position immediately prior to 
administration of 18F-AV-1451 (within 30 minutes prior to injection) and 
at the completion of imaging at discharge.  
• Body weight will be measured prior to injection. 
•  Subjects will receive a single IV bolus injection of approximately 370 
MBq (10 mCi) 18F-AV-1451 followed by a saline flush. A 30 minute 
dynamic image will begin approximately 75 minutes following the dose 
administration; 
• Subjects will be observed continuously for signs of adverse events, or 
serious adverse events;  
• A physician or licensed/credentialed medical professional (that is, a PET 
technologist, imaging center nurse, or a regional equivalent) designated by 
the site principal investigator 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 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 
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business days, the follow-up phone call can occur the following business 
day.  
7.2. 
Observations and Measurements 
   
Informed Consent 
 
Potential subjects will be allowed to read a written informed consent form.  The 
principal investigator, or designee, will explain all study procedures, risks, and 
alternative therapies to the subject.  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.  
 
All informed consent forms must be approved by Avid or designee, and by the 
appropriate Institutional Review Board (IRB) prior to use. 
 
Medical History  
The investigator or designee will obtain an updated history at the screening visit. 
• Relevant demographic information  
• Review of body systems 
• Social history 
• Medical and surgical history 
• Concurrent medications 
Whenever possible, the medical history will be confirmed by medical records. 
Vital Signs  
Vital signs (pulse rate, respiratory rate, supine blood pressure) will be taken at the 
following time points: 
• Screening Florbetapir F 18 Imaging  
o Immediately prior to injection of florbetapir F 18 
 
• 
18F-AV-1451 Imaging Visit 
o Prior to the administration of 18F-AV-1451 Injection 
o After the completion of imaging, prior to discharge.   
 
Height and Weight 
At both imaging visits body weight will be measured, lightly clothed.  Height will 
only be measured as part of the 18F-AV-1451 imaging visit. 
Electrocardiogram 
A resting ECG will be recorded at screening if a previous ECG performed within 
the last 12 months is not available for review.  
 
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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 the 18F-AV-1451 imaging visit and 
florbetapir F 18 imaging visit (except as specified in section 7.1.1.1) prior to 
injection for females of childbearing potential (defined as pre-menopausal, less 
than 2 years post-menopausal or not surgically sterile).  
 
MRI 
Electronic copies of volumetric brain MRI scans obtained as part of the site’s 
companion protocol will be submitted to Avid, or designated imaging core lab. If 
one is not available for submission to Avid or designated imaging core lab, an 
MRI may be performed under this protocol if the subject is able to tolerate one. 
The MRI sequences and acquisition parameters will be described in a separate 
document. 
 
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.   
Physician Visit 
A physician must see the subject at screening to confirm that the subject is 
appropriate for participation in the trial. A physician or licensed/credentialed 
medical professional (that is, a PET technologist, imaging center nurse, or a 
regional equivalent) designated by the site principal investigator must see the 
subject at baseline, prior to drug administration and at study end, prior to 
discharge from the imaging sessions. At discharge, the physician or designee 
should review all safety data and briefly examine/query the subject regarding 
potential adverse events or other treatment issues.   
 
7.3. 
Protocol for Image Collection 
 
The sponsor will prepare and distribute imaging manuals for 18F-AV-1451 and 
florbetapir F 18 image acquisition parameters and transmission procedures prior 
to site initiation.   
 
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7.4. 
Good Clinical Practice and Monitoring 
All clinical studies performed under the direction of Avid/CRO will be conducted 
in accordance with applicable regulatory requirements and International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) and 
Avid/CRO Standard Operating Procedures (SOP).  
This includes: 
1. IRB approval:  An investigation will be initiated at a study site only after the 
IRB for that study site has given their written approval of the protocol and 
informed consent;    
2. Informed Consent:  Study procedures will not be initiated until the informed 
consent form is signed;   
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 FTD 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 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, consistent with the requirements of the State where the 
subject resides and local IRB guidance.  Subjects with the capacity to understand 
that they are engaging in a research study should affirm that they do not object to 
participating by signing on the Subject Assent line of the consent form.  Subjects 
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lacking the capacity to assent and/or dissent will not be precluded from 
participation, but would not be required to sign the consent form. 
 
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 for their records. 
 
7.6. 
Documentation 
 
18F-AV-1451 and florbetapir F 18 PET scans will be saved in an appropriate 
electronic format as specified in the imaging manuals.  A copy of all scans, 
including the MRI 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 eCRFs.  All data in the eCRFs 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 its 
designees.  Completed source documents and eCRFs may need to be made 
available and complete for an audit by the FDA, other international regulatory 
authorities, or Avid at any time.  eCRFs and all other records must be filed in 
accordance with applicable laws and regulations (see Section 10.6). 
 
7.7. 
Adverse Events (AE) 
 
Avid’s standards for recording and reporting adverse events (AEs) are to be 
followed regardless of applicable regulatory requirements that may be less 
stringent.  All AEs must be fully recorded on the adverse event eCRFs. 
Investigators will be instructed to report to Avid, or its designee, their assessment 
of the potential relatedness of each AE to study drug 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 eCRFs.  Signs and symptoms of 
each AE should be described in detail (e.g., start and stop dates/time, 
severity/intensity, relationship to study drug, action taken, and outcome).  
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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 study drug. 
 
7.7.2. 
 Adverse Event Definitions 
Adverse Events 
 
An adverse event is any undesirable experience occurring to a subject during a 
clinical trial, whether or not considered related to the study drug. 
 
For reporting purposes, Avid will distinguish among pre-existing conditions, 
trial-emergent adverse events and treatment-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 
eCRF pages. During the study, site personnel will record any change in the 
condition(s) and occurrence and nature of any AEs.  Signs and symptoms that 
are believed to be due to the pre-existing condition(s) (started prior to dose of 
study medication) do not have to be recorded in the AEs section of the eCRF, 
unless there is an increasing in frequency and severity. Additionally, signs or 
symptoms or changes in pre-existing conditions that occur outside the trial 
defined adverse event reporting period (e.g., between each imaging visit 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 administration of 18F-AV-1451. 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. 
Trial-emergent adverse events are undesirable experiences, signs or symptoms 
that begin, or worsen in intensity or frequency, after the informed consent, and 
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prior to administration of study drug at the imaging visit.  In order to capture 
possible adverse effects of trial participation, trial-emergent AEs will also be 
reported during the baseline imaging period but not during the 48 hour 
windows following the administration of 18F-AV-1451 or Florbetapir. These 
will be recorded on the adverse event pages. 
The end of study, for the purpose of adverse event reporting, is defined as 48 
hours after the last study drug administration. 
 
 
Serious Adverse Event (SAE) 
 
A 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 a 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 IB. 
 
Relationship to Study Drug 
 
Investigators will be instructed to report their assessment of the potential 
relatedness of each adverse event to protocol procedure or study drug.  The 
assessment of the relationship of an adverse event to the administration of the 
study drug is a clinical decision based on all available information at the time 
of the completion of the eCRF. 
 
Intensity/Severity of an Adverse Event 
 
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In addition to assessing the relationship of the administration of the study drug 
to adverse events, an assessment is required, in order to determine the 
intensity (severity) of the event.  
 
The following classifications should be used: 
 
Mild:   
A mild adverse event is an adverse event, usually transient in nature and 
generally not interfering with normal activities. 
 
Moderate:   
A moderate adverse event is an adverse event that is sufficiently 
discomforting to interfere with normal activities. 
 
Severe:   
A severe adverse event is an adverse event that incapacitates the subject and 
prevents normal activities.   Note that a severe event is not necessarily a 
serious event; nor must a serious event necessarily be severe. 
 
7.7.3. 
Adverse Event Documentation 
 
All adverse events must be fully recorded on the adverse event eCRFs.  
Documentation must be supported by an entry in the subject file.  Laboratory 
tests, vital signs and ECG abnormalities considered by the Investigator to be 
clinically relevant should be reported on the adverse event eCRFs.  Signs and 
symptoms of each AE should be described in detail (e.g., start and stop dates, 
severity/intensity, relationship to study drug, 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 receives a dose of study drug 
will be collected in the eCRF as Adverse Events until 48 hours after the  
dosing of the study drug, regardless of the investigator’s opinion of causation.   
Thereafter, SAEs are not required to be reported in the eCRF as Adverse 
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Events unless the investigator feels the events were related to either 
investigational product or drug delivery system, or a protocol procedure If the 
investigator does not feel the event was related to the investigational product 
or drug delivery system or protocol procedure, then the event should be 
recorded in the eCRF as Medical History for the subject. Regardless of the 
investigator’s assessment of relatedness or timing, all SAEs that occur after 
the subject receives the investigational product should be submitted to Lilly 
GPS for processing to determine applicability of any expedited reporting 
requirements.. 
 
 
If a patient experiences a SAE after signing informed consent, but prior to 
receiving study drug, 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. 
The study data collected under companion protocol such as but not limited to 
subjects’ demographic and baseline characteristics, history taking, neurological and 
behavioral evaluations, and MRI will be transferred to Avid for analysis purposes. 
Amyloid scans used for review of enrollment criteria will also be transferred to Avid 
if applicable. 
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 for all subjects in 
the safety population according to clinical group.  Safety data will be summarized for 
all patients. 
Subject listings of all data from the eCRFs as well as any derived variables will be 
presented.  
8.1.1. 
Sample Size Estimation 
This study will enroll up to 25 subjects.  This sample size was chosen in order to 
allow for qualitative and descriptive review of 18F-AV-1451 PET binding in subjects 
with clinically defined FTD.  Based on prior studies, 10-15 cases are typically 
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sufficient for preliminary exploratory analysis.   The sample size for this study is 
slightly larger to accommodate the heterogeneous pathology that underlies 
FTD.   Results of the exploratory analysis from this study will permit planning of 
subsequent, hypothesis-driven studies. 
8.1.2. 
Populations for Analysis 
The efficacy population will include all patients for whom image data are available.   
All analyses involving tau imaging outcomes will be based on the efficacy 
population. Safety population will include all patients that received at least one dose 
of 18F-AV-1451 compound or Florbetapir F 18. Safety evaluation will be based on 
safety population.  
8.2. 
Analyses 
8.2.1. 
Efficacy Analyses 
18F-AV-1451 images will be evaluated  both by qualitative visual analysis and by 
regional SUVr.   Descriptive statistics will be applied to describe the distribution of 
tau deposition as measured by 18F-AV-1451 across clinical diagnosis groups and by 
florbetapir PET quantitation. Mean, standard deviation, median, minimum, and 
maximum values will be provided for continuous variables and counts and 
percentages will be provided for categorical variables.  
Details of analyses will be provided in statistical analysis plan (SAP). 
8.2.2. 
Safety Analyses 
Adverse events including injection site reactions will be summarized in terms of 
number and percentage of patients experiencing an AE. The AEs will be summarized 
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 patients who experience 
SAEs, or who discontinue due to AEs, will be summarized.  
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).  Avid’s policy is 
briefly summarized below: 
•
We commit to timely communication of meaningful results of controlled clinical
trials, regardless of outcome.
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• As a sponsor, we may recommend that the Investigator(s) delay or decline 
publication in cases where the study design, conduct, or data are insufficient to 
allow meaningful interpretation.  Avid and the Investigator(s) will discuss the 
study design and data in advance of the study, and again after completion, and 
will strive, through appropriate scientific debate, to reach a consensus regarding 
the potential merits of publication. 
• Avid retains the right to review any manuscripts, presentations, or abstracts before 
they are submitted for publication. Where differences of opinion or interpretation 
exist regarding data planned for publication, the parties (Avid and the 
Investigator) should try to resolve them through appropriate scientific debate.  
Avid retains the right to delay publication for up to 60 days to protect intellectual 
property.  
• Anyone who provides substantial contributions should receive appropriate 
recognition as an author or contributor when the manuscript is published.  
This is a multi-center study. The primary 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 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 and its approval 
must be obtained prior to its use.  A copy of the approval must be forwarded to 
Avid.  When necessary, an extension or renewal of IRB approval must be 
obtained and also forwarded to Avid. 
 
10.2. 
 Informed Consent 
 
A signed, written informed consent 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’s approved version of the informed consent form must be 
forwarded to Avid, or its designee, for review prior to being used to obtain patient 
consent. 
 
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10.3. 
 Protocol Adherence 
 
 
The protocol must be read thoroughly and the instructions must be followed 
exactly.  Where a deviation occurs, it must be documented, the sponsor/monitor 
informed, and a course of action agreed upon. 
 
10.4. 
 Documents Necessary for Initiation of the Trial 
Avid must be provided with the following documents prior to the enrollment of 
any subjects: 
• 
Original signed and dated Statement of Agreement page; 
• 
Copy of the IRB and radiation safety committee approval (if applicable); 
• 
Copy of the IRB stamped approved consent form; 
• 
Name and location of the laboratory utilized for laboratory assays, and 
other facilities conducting tests, including laboratory certification number 
and date of certification if available;  
• 
List of reference range laboratory values; and 
• 
Any additional licenses required in order to order to use 18F-AV-1451 or 
Florbetapir F 18. 
 
10.5. 
Study Drug Control 
The receipt of clinical supplies (e.g. 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 Injections and Florbetapir F 18 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 and all drug supplies must be 
justified.  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.   
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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 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 and Company 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 and Company 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 eCRF.  See section 7.7.4 for 
reporting serious adverse events 
 
If a SAE is determined to be unexpected (not previously reported or described by 
Avid), and study drug-related, Eli Lilly and Co. will notify the investigator in 
writing.  The investigator should forward this notification to the IRB within 24 
hours of receipt. 
 
10.8. 
Records Retention 
 
All correspondence (e.g., with Avid, IRB, etc.) relating to this clinical trial should 
be kept in appropriate file folders.  Records of subjects, source documents, and 
drug inventory sheets pertaining to the trial must be kept on file.  Records must be 
retained until the date a marketing application (NDA) is approved for the drug for 
the indication for which it is being investigated, or until 2 years following the date 
of clinical trial termination or completion, whichever is later.   If no application is 
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to be filed, or if the application is not approved for such indication, records should 
be kept until 2 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 
 
 
 
Barker WW, Cheryl AL, Kashuba A, Luis M.  Relative Frequencies of Alzheimer 
disease, Lewy body, Vascular and Frontotemporal dementia and Hippocampal 
Sclerosis in the State of Florida Brain Bank.  ADAD, 16:203-212, 2002. 
 
Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of 
Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-
2010. J Neuropathol Exp Neurol,71:266-73, 2012. 
 
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,Jan 1l34(2):467-68, 2013.  
 
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.  
 
Forman, M. S., J. Farmer, J. K. Johnson, C. M. Clark, S. E. Arnold, H. B. Coslett, et 
al. "Frontotemporal dementia: clinicopathological correlations." Ann Neurol,59(6): 
952-962, 2006. 
 
 
Hodges, J. R., R. R. Davies, J. H. Xuereb, B. Casey, M. Broe, T. H. Bak, et al. . 
"Clinicopathological correlates in frontotemporal dementia." Ann Neurol, 56(3): 399-
406, 2004. 
 
Josephs, K. A., R. C. Petersen, D. S. Knopman, B. F. Boeve, J. L. Whitwell, J. R. 
Duffy, et al. . "Clinicopathologic analysis of frontotemporal and corticobasal 
degenerations and PSP." Neurology, 66(1): 41-48, 2006. 
 
Josephs, K. A., J. R. Hodges, J. S. Snowden, I. R. Mackenzie, M. Neumann, D. M. 
Mann, et al.. "Neuropathological background of phenotypical variability in 
frontotemporal dementia." Acta Neuropathol, 122(2): 137-153, 2011. 
 
Kertesz, A., P. McMonagle, M. Blair, W. Davidson and D. G. Munoz.  "The 
evolution and pathology of frontotemporal dementia." Brain, 128(Pt 9): 1996-2005, 
2005. 
 
Lim A, Tsuang D, Kukull W, et al. Clinico-neuropathological correlation of 
Alzheimer's disease in a community-based case series. J Am Geriatr Soc, 47: 564–69, 
1999. 
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Mackenzie, I. R., M. Neumann, E. H. Bigio, N. J. Cairns, I. Alafuzoff, J. Kril, et al. . 
"Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar 
degeneration: an update." Acta Neuropathol, 119(1): 1-4, 2010. 
 
Mayeux R, Saunders AM, Shea S, et al. Utility of the apolipoprotein E genotype in 
the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on 
Apolipoprotein E and Alzheimer's Disease. N Engl J Med , 338: 506–11, 1998. 
 
 
Rabinovici, G. D. and B. L. Miller. "Frontotemporal lobar degeneration: 
epidemiology, pathophysiology, diagnosis and management." CNS Drugs 24(5): 375-
398, 2010. 
 
Ranginwala NA, Hynan LS, Weiner MF, White CL. Clinical criteria for the diagnosis 
of Alzheimer disease: still good after all these years. Am J Geriatr Psych,16:384-88, 
2008. 
 
 
Xia, C.F., et al. “[18F]T807, a novel tau positron emission tomography imaging agent 
for Alzheimer’s disease,” Alzheimers Dement, 1-11, 2013. 
 
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11.2. 
Trial Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Screening may take place over several days.  All assessments must be performed prior to the 18F-AV-1451 imaging session. 
b. 
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). 
c. 
For women of childbearing potential, a negative urine or serum (if required by local site) pregnancy test must be obtained within 24 hours prior to florbetapir F 18 injection and within 24 hours 
prior to 18F-AV-1451 injection. 
d. 
Vital signs (pulse, respiratory rate, supine blood pressure) and weight will be taken prior to dose administration.  
e. 
Height will be taken prior to dose administration  
f. 
Vital signs (pulse, respiratory rate, supine blood pressure) will be taken after completion of the PET scan prior to discharge.  
g. 
The screening florbetapir F 18 PET scan is to be performed to assess for evidence of amyloid pathology and should be interpreted by a local reader prior to enrollment 
Evaluations 
 
Screening 
Assessments
a 
Screening 
Florbetapir F 18 
PET Scanh 
 
18F-AV- 1451 
Imaging Visit 
Signed Informed Consent 
X 
 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Concomitant Medications 
X 
 
 
ECG 
X 
 
 
MMSE 
X 
 
 
MRI 
Xn 
 
 
Serum beta-hCG Pregnancy 
Test 
Xb 
 
 
Urine Pregnancy Test 
 
Xc 
Xc 
Vital Signs    
 
Xd,  
Xd, ,f,  
PET Brain Scan 
 
X, g, h, i 
Xj,k, 
Evaluation by a physician   
X 
Xl 
Xl 
Adverse Events  
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
Follow-up Phone Callm  
 
X 
X 
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h. 
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.  
i. 
At approximately 50 minutes following florbetapir  F18 injection, a continuous 20-minutes brain scan will begin 
j. 
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.  
k. 
At approximately 75 minutes following 18F-AV-1451 injection, a continuous 30-minute brain scan will begin. 
l. 
A physician (or licensed/credentialed medical professional) must see the subject prior to drug administration and at study end, prior to discharge from the imaging session. 
m. 
A follow-up phone call to the subject, or designated decision maker, will be conducted within 2 or 3 business days of each 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. 
n. 
If a prior MRI is not available for submission to Avid or designated imaging core lab, an MRI may be performed under this protocol if the subject is able to tolerate one. 
 
 
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INVESTIGATOR’S AGREEMENT TO PROTOCOL 
 
 
Protocol 18F-AV-1451-A19: 18F-AV-1451 PET Imaging in Subjects with Frontotemporal  
                                                Dementia 
 
 
 
Date and Version:  05 MAY 2016, FINAL 
 
 
I agree to conduct the study according to this protocol and to comply with its obligations, 
subject to ethical and safety considerations and all applicable regulations (ICH, CFR). 
 
I shall not disclose the confidential information contained in this protocol or any results 
obtained from the study, except for publication in accordance with Section 9 of this 
protocol, without written authorization from Avid. 
 
 
 
______________________________________              ___________________________ 
Printed Name                                                                    Date 
 
 
 
______________________________________ 
Signature 
 
 
 
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Avid Radiopharmaceuticals 
Protocol 18F-AV-1451-AI9 Final
9 
COMPUTER SOFTWARE 
Statistical Analysis Plan 
All analyses will be performed by Chiltern using SAS® Version 9.3 or later. All summary tables 
and data listings will be prepared utilizing SAS® software. 
The standard operating procedures (SOPs) of Chiltern will be followed in the creation and 
quality control of all data displays and analyses. 
10 REFERENCES 
I.
Clinical Study Protocol: 18F-A V-1451 PET Imaging in Subjects with Frontotemporal
Dementia. Date and Version: 05May2016, Final
Final Version LO 
Date· 14 Mar 2019 
Chillern lnlernatiomil Inc. 
CONnDENTIAL 
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