Clinical trial NCT01518374
Conditions: Alzheimer Disease Mild Cognitive Impairment Neurodegenerative Diseases
Keywords: Male or female subjects at least 18 years of age AD MCI
Sponsor: Avid Radiopharmaceuticals
Start date: 2009-12-01; Completion date: 2017-05-03
Enrollment: 1768 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This protocol is designed to standardize imaging studies using florbetapir F 18 PET to provide information on amyloid burden in subjects participating in other studies (companion protocol) such as longitudinal studies of aging and studies of biomarkers for neurodegenerative diseases.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Florbetapir F 18
Intervention descriptions: intervention 1: 370 MBq (10 mCi)

Protocol documents:
Prot_000.pdf: 

















































































SAP_001.pdf: 
Statistical Analysis Plan: 18F-AV-45-A14 
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STATISTICAL ANALYSIS PLAN 
DATE OF PLAN: 
01 May 2018 
BASED ON: 
18F-AV-45-A14 Protocol, 17-Feb-2013 (Amendment 3) 
STUDY DRUG: 
Florbetapir 18F (18F-AV-45) 
PROTOCOL NUMBER: 
18F-AV-45-A14 
STUDY TITLE: 
Clinical Evaluation of Florbetapir F 18 (18F-AV-45) 
SPONSOR: 
Avid Radiopharmaceuticals, Inc. 
3711 Market Street 
Philadelphia, PA 19104 
215-298-0700
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 
NCT01518374




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TABLE OF CONTENTS 
 
1. 
LIST OF ABBREVIATIONS.......................................................................................5 
2. 
INTRODUCTION ........................................................................................................6 
3. 
STUDY OBJECTIVES ................................................................................................7 
4. 
STUDY DURATION AND VISIT SCHEDULE ........................................................8 
5. 
CLINICAL ASSESSMENTS .......................................................................................9 
5.1. 
Screening and Baseline Assessments ...........................................................................9 
5.2. 
Image visit Assessments ...............................................................................................9 
5.3. 
Follow up ......................................................................................................................9 
6. 
GENERAL CONSIDERATIONS ..............................................................................10 
6.1. 
Analysis Populations ..................................................................................................10 
6.1.1. 
Enrolled Population ....................................................................................................10 
6.1.2. 
Efficacy Population ....................................................................................................10 
6.1.3. 
Safety Population ........................................................................................................10 
7. 
SUBJECT DISPOSITION AND ELIGIBLITY CRITERIA .....................................11 
8. 
BASELINE PATIENT DATA ...................................................................................12 
8.1. 
Baseline Demographic and Physical Characteristics ..................................................12 
8.2. 
Concomitant Medications ...........................................................................................12 
9. 
EFFICACY .................................................................................................................13 
10. 
SAFETY AND TOLERABILITY ..............................................................................14 
10.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............14 
10.1.1. 
Summaries of Adverse Event Incidence Rates for All Patients .................................14 
10.1.2. 
Missing and Partial AE Onset Dates ..........................................................................14 
10.1.3. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death ..........................................................................15 
10.2. 
Concomitant and Other Medications ..........................................................................15 
10.3. 
Routine Laboratory Data ............................................................................................15 
10.4. 
Vital Signs ..................................................................................................................15 
10.5. 
Study Termination Status ...........................................................................................15 
11. 
INTERIM ANALYSES ..............................................................................................17 
 


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LIST OF TABLES 
 
Table 1: 
List of Abbreviations ....................................................................................................5 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Aß 
Amyloid-ß 
Aß+ 
Amyloid positive, AD-like 
Aß- 
Amyloid negative, not AD 
AD 
Alzheimer’s disease 
CERAD 
Consortium to Establish a Registry for Alzheimer’s Disease 
CN 
Cognitively Normal 
CRF 
Case report form 
PET 
Positron emission tomography 
SD 
Standard deviation 
SE 
Standard error 
SUVR 
Ratio of standardized uptake values 
 


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2. 
INTRODUCTION 
 
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting more 
than 4 million people in the United States alone. However, diagnosis and treatment of the disease 
have been hampered by the absence of reliable non-invasive markers for the underlying 
pathology.   
 
Florbetapir F 18 is well-tolerated imaging tracer, that has an acceptable radiation dosimetry 
profile at the proposed injected dose level of 370Mq (10mCi) and can distinguish patients with 
AD from normal subjects, and may be useful for the detection of amyloid plaque pathology in 
the brains of living subjects. This protocol has been developed to allow non-Avid investigator 
initiated studies to incorporate florbetapir F 18 in their protocol. The purpose of this statistical 
analysis plan (SAP) is to describe the statistical methods used in safety evaluation of subjects 
who exposed to florbetapir injection under this protocol. This SAP should be read in conjunction 
with protocol. 


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3. 
STUDY OBJECTIVES 
 
The specific objectives of this protocol were to expand the safety database of florbetapir F 18 
PET imaging safety, amyloid binding, and long-term outcome, and to provide standardized 
conditions for florbetapir F 18 use, data collection, and analysis in other studies (companion 
protocols). This SAP will only assess the safety of florbetapir.  Imaging assessments for the 
study population were scientifically interesting at the time the study was initiated, but are no 
longer relevant to the field, as the efficacy of the companion studies, as well as other efficacy 
studies, have been extensively published in the academic literature. 
 


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4. 
STUDY DURATION AND VISIT SCHEDULE 
 
The following flow chart describes the study duration and visit schedule: 
Evaluations 
Screen 
 
Pre-
dose 
 
Dose 
Injection Circulation 
(0 – 50 minutes)3 
Continuous PET 
Imaging 10 
minutes 
End of Imaging 
24-72 
hours post 
injection   
Signed Consent 
X 
 
 
 
 
 
 
 
Medical / Disease History 
X 
 
 
 
 
 
Concomitant Meds 
X 
X 
 
 
 
 
MMSE 
X 
 
 
 
 
 
Physician Visit 
X 
X1 
 
 
X1 
 
Vital Signs 
 
X 
 
 
 
 
Urine Pregnancy Test 
X 
X 
 
 
 
 
Florbetapir F 18 
Administration 
 
 
X 
 
 
 
PET Imaging2 
 
 
 
 
Continuous 10 
minute scan - 50 
minutes after 
dose injection 
 
 
Follow-up Phone Call 
 
 
 
 
 
 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 
X 
X3 
 
 


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5. 
CLINICAL ASSESSMENTS 
5.1. 
Screening and Baseline Assessments 
There are many clinical assessments data collected in companion protocols. For the safety 
evaluation purpose of this protocol, the following screening and baseline assessments will be 
included: 
1). Subjects’ birth year, sex, race, ethnicity, and education; 
5.2. 
Image visit Assessments 
AE, and/or SAE; vital signs: immediate prior to injection, and at the end of study visit, prior to 
discharge (approximately 50 minutes after florbetapir F 18 administration). 
5.3. 
Follow up  
A follow-up phone call to the subject (or the caregiver as appropriate) will be conducted 
approximately 24-48 hours after the imaging session to confirm their well-being and query them 
about any new adverse events. 


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6. 
GENERAL CONSIDERATIONS 
Study day is calculated as assessment date minus date of study drug (florbetapir) administration 
+ 1. Date of florbetapir administration is defined as study day 1. 
 
Individual data will be displayed in listings sorted by subject identification number.  The subject 
identification number is a combination of the site number and the subject number. 
 
Continuous data will be summarized using the following descriptive statistics: number of 
subjects (n), mean, standard deviation (SD), median, minimum (min), and maximum (max). 
Categorical data will be summarized using the number (n) and percentage (%) of subjects for 
each category. When count data are presented, the percent will be suppressed when the count is 
zero in order to draw attention to the non-zero counts. The denominator for all percentages will 
be the number of subjects in that treatment group within the population of interest unless 
otherwise specified. 
 
All analyses will be conducted using SAS® Version 8.2 or higher. 
6.1. 
Analysis Populations 
6.1.1. 
Enrolled Population 
Not all subjects enrolled in companion protocol would receive a florbetapir scan. The purpose of 
this protocol is to evaluate the safety of florbetapir, therefore the enrolled population will not be 
defined in this SAP.   The disposition table will summarize the study subjects based on safety 
population.    
6.1.2. 
Efficacy Population 
No efficacy analyses will be performed, hence no efficacy population is defined for this safety 
report. 
6.1.3. 
Safety Population 
The safety population will consist of all subjects who received at least one injection of 
florbetapir 18F.  All safety endpoints will be summarized using the safety population. 


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7. 
SUBJECT DISPOSITION AND ELIGIBLITY CRITERIA 
Disposition of subjects including the number and percentage of subjects will be displayed based 
on Safety population. Since there no efficacy analysis planned for this protocol, the efficacy 
population will not be included in the disposition table.  
 
A listing will present subject disposition data. 
 


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8. 
BASELINE PATIENT DATA 
8.1. 
Baseline Demographic and Physical Characteristics 
Frequency distributions and summary statistics for demographic and baseline characteristics will 
be presented all subjects in the Safety population. 
 
Demographics and baseline characteristics will be also presented in listings.  
 
8.2. 
Concomitant Medications 
Due to the consideration that this protocol is focus on safety evaluation of florbetapir F18, the 
concomitant medications are not be presented.  If concomitant medications are needed to explain 
safety findings, tables and listings will be generated post hoc. 


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9. 
EFFICACY  
This SAP will only assess the safety of florbetapir F18 by examining reported adverse events for 
the study.  Imaging assessments for the study population were scientifically interesting at the 
time the study was initiated, but are no longer relevant to the field, as the efficacy of the 
companion studies have been extensively published in the academic literature. 


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10. 
SAFETY AND TOLERABILITY 
All safety analyses will be conducted using the safety population.  
10.1. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
In this study, an Adverse Event (AE) is defined as any undesirable experience occurring to a 
subject after an injection of florbetapir F 18, whether or not it is considered as related to the 
investigational product. Laboratory test abnormalities considered by the Investigator to be 
clinically relevant should be reported as AEs.  For this protocol, treatment-emergent AEs 
(TEAE) are considered as any undesirable experiences, signs, or symptoms that begin or worsen 
in intensity or frequency at the time of or after the administration of study drug, and within 48 
hours since study drug injection. These will be recorded on the AE pages.   
 
The incidence of AEs will be presented overall by system organ class (SOC) and by preferred 
term.  Incidence of AEs by severity and relationship to study medication will also be presented.  
Adverse events resulting in discontinuation from the study and the incidence of serious adverse 
events (SAE) will be summarized. 
 
Pre-existing conditions (i.e., undesirable experiences, signs, or symptoms that begin prior to the 
Screening Visit) will be recorded on the medical history and/or physical exam pages and will not 
be summarized in this study. 
  
10.1.1. 
Summaries of Adverse Event Incidence Rates for All Patients 
All treatment-emergent AEs will be presented in a summary table, by SOC and preferred term. At 
each level of summarization, a subject will only be counted once per SOC or preferred term. For 
example, if a subject reports multiple TEAEs with the same SOC, then that SOC will only be 
incremented by one. As with the SOC, if a subject reports multiple AEs with the same preferred 
term, then that preferred term will only be incremented by one since subject counts will be 
presented.  AEs will be presented in descending order of frequency.  An additional table will 
present TEAEs is descending frequency by preferred term only. TEAEs will also be summarized 
by relationship to study drug, and by severity. 
All AEs will also be presented in a listing.  
 
10.1.2. 
Missing and Partial AE Onset Dates 
In the event that only a partial end date (month/year) is available, and month/year occurs before 
that of study drug injection date, the adverse event will be considered as non-treatment-
emergent.  However, if the onset date is a partial date (month/year) and month/year occurs on or 
after that of study drug injection date, the following cases will be considered:  
 
• If month/year of the onset date is greater than the month/year of study drug injection date, 
the adverse event will be considered treatment-emergent; 
• If month/year of the onset date is equal to the month/year of study drug injection date, 
and the end date is present, the end date will be used to determine when the adverse event 


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resolved.  If the end date is on or after study drug injection date, the adverse event will be 
considered treatment-emergent; otherwise, if the adverse event stopped before study drug 
injection date, then it will not be treatment-emergent; 
• If month/year of the onset date is equal to the month/year of study drug injection date, 
and the end date is a partial date, the adverse event will be considered treatment-
emergent. 
 
10.1.3. 
Summaries of Adverse Incidence Rates for Serious Adverse Events (SAE), 
Adverse Event Dropouts, and Death 
A serious adverse event (SAE) is an AE that is fatal or life-threatening, or results in 
hospitalization, prolongation of hospitalization, persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect. A life-threatening AE is an AE that, in the view of the 
investigator, places the subject at immediate risk of death from the reaction as it occurred.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject or subject and may requie medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
 
If there are any SAE, they will be presented by system organ class and preferred term in a table 
and a listing. All AEs collected with an outcome of “Fatal” will be presented in a listing. 
 
 
10.2. 
Concomitant and Other Medications 
Concomitant medication information will not be summarized in this study. 
 
10.3. 
Routine Laboratory Data 
Not done for this study. 
10.4. 
Vital Signs 
 
Vital signs (blood pressure, pulse, respiratory rate, and body temperature) will not be 
summarized in this study.  The safety profile of florbetapir F 18 is well-characterized and no 
safety issues related to vital signs are expected.  Should safety analyses from this study indicate 
that vital sign data should be examined more carefully, post hoc tables and listing will be 
generated.  
10.5. 
Study Termination Status 
 
For this protocol, the end of study is defined as the completion of 24-48 hours follow up phone 
call post 18F-florbetapir scan. The reason for study termination will also be summarized in 
disposition table.  The primary reasons for study termination include: completed study, lost to 


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follow-up, consent withdrawn, administrative decision, and others. 


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11. 
INTERIM ANALYSES 
Interim analysis is not planned for this study.