Clinical trial NCT01812213
Conditions: Mild Cognitive Impairment
Keywords: Mild Cognitive Impairment
Sponsor: Navidea Biopharmaceuticals
Start date: 2013-03-01; Completion date: 2017-11-02
Enrollment: 76 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To investigate whether \[18F\]NAV4694 positron emission tomography (PET) scan findings have the ability to distinguish subjects with mild cognitive impairment (MCI) who progress to Alzheimer's disease (AD) from those who do not.

Detailed description:

Arms: arm 1: Intravenous \[18F\]NAV4694 (8.1 mCi) administered once every 18 months
Interventions: intervention 1: [18F]NAV4694
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
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Clinical Trial Protocol: NAV4-04 
Study Title: 
Beta-Amyloid Imaging With [18F]NAV4694 Positron Emission 
Tomography (PET) in Predicting Progression to Alzheimer’s 
Disease (AD) in Subjects with Mild Cognitive Impairment (MCI) 
Study Number: 
NAV4-04 
Study Phase: 
2 
Product Name: 
[18F]NAV4694 
IND Number: 
106,157 
EudraCT Number: 
2013-002514-12 
Indication: 
[18F]NAV4694 positron emission tomography (PET) can detect 
cerebral β-amyloid deposition.  The absence of [18F]NAV4694 
uptake (and thus β-amyloid deposition) is inconsistent with a 
diagnosis of Alzheimer’s disease at the time of imaging. 
Investigators: 
Multicenter 
Germany 
Coordinating 
Investigator: 
Osama Sabri, PhD 
Department of Nuclear Medicine 
University of Leipzig 
Sponsor: 
Navidea Biopharmaceuticals 
Sponsor Contact: 
Joanna Shuping 
+1 614-822-2388 
Chief Medical Officer: 
Cornelia Reininger, MD, PhD 
+1 978-655-2800 ext. 155 
 
 
Date 
Original Protocol: 
06 February 2013 
Amendment 1: 
07 June 2013 
Amendment 2: 
13 May 2014 
 
Confidentiality Statement 
This protocol and all of the information relating to it are confidential and proprietary property 
of Navidea Biopharmaceuticals 


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SYNOPSIS 
Study title 
Beta-Amyloid Imaging With [18F]NAV4694 Positron 
Emission Tomography (PET) in Predicting Progression to 
Alzheimer’s Disease (AD) in Subjects with Mild Cognitive 
Impairment (MCI) 
Short title 
Detection of β-amyloid in the brain of subjects with MCI 
Study phase 
Phase 2 
Study objective(s) 
To investigate whether [18F]NAV4694 positron emission 
tomography (PET) scan findings have the ability to 
distinguish subjects with mild cognitive impairment (MCI) 
who progress to Alzheimer’s disease (AD) from those who 
do not. 
Name of radioactive drug 
substance 
[18F]NAV4694 
Dose(s) 
The administered [18F]NAV4694 radioactive dose will be 
8.1 mCi (300 MBq) ± 20%.  The tracer mass dose 
specification will be ≤ 40 µg.  The total administered volume 
will be ≤ 10 mL. 
Route of administration 
Intravenous (IV) injection  
Duration of treatment 
One or two injections of a diagnostic agent over 18 months. 
Indication 
[18F]NAV4694 positron emission tomography (PET) can 
detect cerebral β-amyloid deposition.  The absence of 
[18F]NAV4694 uptake (and thus β-amyloid deposition) is 
inconsistent with a diagnosis of Alzheimer’s disease at the 
time of imaging 
Study objectives 
Primary Objective 
To investigate whether [18F]NAV4694 positron emission 
tomography (PET) scan findings have the ability to 
distinguish subjects with mild cognitive impairment (MCI) 
who progress to AD from those who do not. 
Assessment of the primary objective will be based on the 
sensitivity, specificity, PPV, and NPV of [18F]NAV4694 
PET scan findings (e.g., majority read findings of baseline 
scan) in predicting progression from MCI to AD type 
dementia at 18 months. 
Secondary Objectives 
• To evaluate the sensitivity, specificity, NPV, and PPV of 
quantitative findings (e.g., SUVRs) in predicting 
progression of MCI to AD type dementia in a subset of 
20 subjects at 18 months , using a data driven (and a pre-


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specified) threshold for positivity.   
• To determine the overall changes in amyloid burden over 
time in subjects with visually positive vs. negative scans 
(by comparison of baseline and 18-month scan composite 
SUVR in a subset of 20 subjects). 
• To determine in a subset of 20 subjects whether changes 
in quantitative [18F]NAV4694 uptake over time correlate 
with the rate of cognitive decline in subjects with MCI 
over 18 months. 
• To determine the increase in risk of progression to AD 
for a unit change between subjects in baseline subject 
level baseline SUVR value. 
• To evaluate safety and tolerability of [18F]NAV4694 in 
subjects with MCI. 
Main criteria for inclusion 
1. Subject has signed informed consent to participate in the 
study and continues to give willing consent for 
participation 
2. Age ≥ 55 years and diagnosed by the investigator with 
MCI 
3. Educational level of at least 6 years  
4. Female subjects will not be of child-bearing potential  
5. Availability of a “study partner” who can assist in 
completing rating scales, for the duration of the study   
6. Cognitive complaints reported by the subject and 
confirmed by the “study partner”  
7. Clinical Dementia Rating (CDR) global score = 0.5 
8. Mini-mental state examination (MMSE) score of 24-30 
9. Diagnostic and Statistical Manual of Mental Disorders, 
Version 4, Text Revised (DSM-IV-TR) criteria of 
dementia not fulfilled 
Ability to complete all procedures and assessments, 
including neuropsychological testing and have the ability to 
comply with all requirements of PET and MRI 
Study design 
Open label, non–randomized, multi-center study in subjects 
with MCI 
Methodology 
The proposed study includes: screening, baseline neuro-
cognitive testing and PET imaging, neuro-cognitive follow-
up examinations (at 6, 12, 18, 24, 30, and 36 months).  In 
addition, a subset of 20 subjects will undergo PET and MR 
imaging at 18 months. Each subject will be in the study for a 
fixed period of time (36 months) or until the subject 
withdraws from the study.   
Screening Visit: The screening visit will include review of 


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trial eligibility, consent, collection of subject-specific 
characteristics, vital signs, physical and neurological exams, 
neuro-cognitive testing, magnetic resonance imaging, and 
blood and urine laboratory testing 
Baseline testing: Neuro-cognitive exams and safety 
laboratory analyses will be performed. 
Baseline [18F]NAV4694 injection and PET imaging: All 
subjects will receive a single IV injection of the 
investigational product, and a PET scan will be performed 
from 50 to 70 minutes post injection. Vital signs will be 
completed within 10 minutes both before and after injection 
and again 30 minutes after injection.  ECGs will be 
completed within 10 minutes both before and after injection. 
Each subject will undergo a follow-up visit approximately 24 
hours post injection, and a telephone follow up will occur 7 
(+ 3) days after the imaging visit. 
Neuro-cognitive follow-up exams at 6, 12, 18, 24, 30 and 
36 months:  During these exams, cognitive and functional 
performance will be evaluated. The investigator will review 
all clinical and neuro-cognitive data gathered during the trial 
to determine the diagnostic status (progression to 
Alzheimer’s dementia). DSM-IV-TR criteria will be used to 
determine whether a subject has dementia and if so, which 
type. Probable AD will be confirmed using criteria from 
National Institute of Neurologic, Communicative Disorders, 
and Stroke – AD and Related Disorders Association 
(NINCDS-ADRDA) (McKhann et al., 1984). 
 
18--month activities (in a subset of 20 subjects):  
MR imaging: MR imaging will be completed within 
the 30 days before the 18-month PET imaging visits. 
18-month follow-up testing: Physical and neurological 
exams and safety laboratory analysis will be performed 
in the 7 days prior to PET imaging. PET imaging 
visits:  PET imaging procedures will be the same as 
employed at baseline.  A 24-hour and 7-day follow-up 
will be conducted as described for baseline.  
Planned trial dates 
Start of study  
 
End of Study 
 
March 2013 
December 
2018 
 
Planned number of trial 
centers / countries 
Approximately 15 sites in US and Germany 


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Number of subjects 
Total: Approximately 120 evaluable subjects.  An evaluable 
subject will be defined as a subject who has a 
clinician/investigator SoT diagnosis and who has had a 
baseline [18F]NAV4694 PET scan that can be assessed by the 
independent blinded readers. 
Evaluation of Imaging 
[18F]NAV4694 PET will be assessed using visual 
interpretation and standardized quantitative assessment, both 
performed at the image core lab. The former will consist of 
an independent visual assessment by 3 blinded independent 
readers. 
Target regions of interests (ROIs) include the frontal, lateral 
temporal, and parietal cortices and the posterior 
cingulate/precuneus. The cerebellar cortex will serve as the 
reference region.  The SUVR for each region, as well as for a 
composite of all regions, will be calculated.  The MRI 
obtained at screening (and before each PET scan, as 
applicable) will be used for anatomical co-registration with 
the brain PET scan. 
Primary variables 
The positivity/negativity of the baseline [18F]NAV4694 PET 
scan (as determined by the majority read finding of the 
3 readers) compared with the final clinical diagnosis at 18 or 
36 months 
Plan for statistical analysis 
This will be an exploratory trial with descriptive statistics 
only and no hypothesis testing. 
For the primary efficacy variables, the sensitivity, 
specificity, PPV, and NPV of [18F]NAV4694 PET scan 
findings in predicting progression of MCI to AD type 
dementia (or the lack thereof) after 18 months will be 
estimated based on the visual assessment of the baseline PET 
scan.  The estimates will be displayed with corresponding 
95% confidence intervals (CI). 
The sensitivity, specificity, PPV, and NPV of the 
quantitative assessment (SUVRs) will be determined, based 
both on the pre-determined and a data-driven threshold for 
positivity. 
Secondary analyses will consist of (a) assessment of the 
differences in distribution of baseline subject-level SUVRs 
for subjects who are diagnosed as negative and positive for 
transition to AD,  (b) correlation of changes in subject-level 
SUVRs from baseline to the final time point with change 
from baseline neurocognitive test results assessed at 6, 12, 
18, 24, 30, and 36 months, and (c) attempt to model the 
relationship of baseline subject-level SUVRs to SoT 


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diagnosis using logistic regression. 
Data collected up to and including the 18-month time point 
will be summarized after completion of the 18-month time 
point.  This summary will not include hypothesis testing and 
will be conducted only after all subjects remaining on study 
have completed the 18-month time point and will not involve 
unblinding of any subject’s 24-, 30-, or 36-month data.  This 
18-month summary will be used for regulatory submission 
and for decision making by the sponsor. 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................11 
LIST OF APPENDICES ..........................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................12 
TRIAL ADMINISTRATIVE STRUCTURE ..........................................................................15 
LABORATORIES AND OTHER INSTITUTIONS FOR TRIAL CONDUCT .....................15 
1 
INTRODUCTION ...........................................................................................................16 
1.1 
Background ............................................................................................................16 
1.2 
Benefit-Risk Assessment .......................................................................................18 
2 
STUDY OBJECTIVES ....................................................................................................20 
2.1 
Primary Objective ..................................................................................................20 
2.2 
Secondary Objectives.............................................................................................20 
3 
OVERVIEW OF METHODOLOGY AND DESIGN .....................................................21 
3.1 
Overall Study Design .............................................................................................21 
3.2 
Justification for Study Design and Population.......................................................22 
3.2.1 
Study Partner ................................................................................................23 
3.2.2 
Rational for Subject Selection .....................................................................23 
3.2.3 
Justification for Radiation Exposure With Proposed [18F]NAV4694 
PET Radioactive Dose .................................................................................24 
3.3 
Justification of Safety Plan ....................................................................................24 
3.4 
Protocol Adherence ................................................................................................25 
3.5 
Study Duration .......................................................................................................25 
4 
STUDY POPULATION ..................................................................................................26 
4.1 
Eligibility ...............................................................................................................26 
4.1.1 
Inclusion Criteria .........................................................................................26 
4.1.2 
Exclusion Criteria ........................................................................................26 
4.1.3 
Justification of Selection Criteria .................................................................27 
4.2 
Recruitment ............................................................................................................27 
4.3 
Withdrawal .............................................................................................................27 
4.4 
Replacement ...........................................................................................................28 
4.5 
Subject Identification .............................................................................................28 
5 
INVESTIGATIONAL PRODUCT ..................................................................................29 
5.1 
Identification of Investigational Product ...............................................................29 
5.2 
Identity and Production ..........................................................................................29 
5.3 
Dosage and Administration....................................................................................30 


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5.4 
Treatment Assignment ...........................................................................................30 
5.5 
Blinding..................................................................................................................30 
5.6 
Packaging and Labeling .........................................................................................31 
5.7 
Drug Logistics, Storage, and Accountability .........................................................32 
5.8 
Supply, Dispensing, and Return.............................................................................32 
5.9 
Drug Accountability...............................................................................................33 
6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT .................................34 
6.1 
Prior and Concomitant Therapy .............................................................................34 
6.2 
Post-Study Therapy ................................................................................................34 
7 
SCHEDULE OF EVALUATIONS AND VISIT DESCRIPTION .................................35 
7.1 
Schedule of Evaluations .........................................................................................35 
7.2 
Visit Description ....................................................................................................35 
7.2.1 
Screening Visit .............................................................................................35 
7.2.2 
Baseline Testing Visit (within 7 days before [18F]NAV4694 injection) .....36 
7.2.3 
Baseline [18F]NAV4694 Injection and PET Imaging Visit .........................36 
7.2.3.1 
Before Injection .................................................................................36 
7.2.3.2 
Administration of [18F]NAV4694 (≤ 56 days after the screening 
visit) ...................................................................................................36 
7.2.3.3 
Post [18F]NAV4694 Injection ............................................................37 
7.2.4 
Safety Follow-Up Visit (24 ± 4 hours after PET imaging visit) ..................37 
7.2.5 
Telephone Follow-up 7 (+ 3) days post injection ........................................37 
7.2.6 
Neuro-Cognitive Follow-up Examinations at 6-, 12-, 18-, 24-, 30-, and 
36- Months (± 30) days post injection .........................................................37 
7.2.7 
Additional 18-Month Activities (in a subset of 20 subjects) .......................38 
7.2.7.1 
Within 30 Days Before 18-month PET Imaging ...............................38 
7.2.7.2 
Within 7 Days Before 18-month PET Imaging .................................38 
7.2.7.3 
PET Imaging and Follow Up .............................................................38 
7.2.8 
Neuro-Cognitive Testing Schedule (screening and 6-, 12-, 18-, 24-, 30-, 
and 36-month visits) ....................................................................................39 
7.2.9 
End of Study ................................................................................................39 
8 
PROCEDURES AND VARIABLES ..............................................................................40 
8.1 
Population Characteristics .....................................................................................40 
8.1.1 
Demographic and Other Baseline Characteristics .......................................40 
8.1.2 
Medical and Surgical History ......................................................................40 
8.1.3 
Prior and Concomitant Medication ..............................................................40 
8.1.4 
Inclusion Criteria Assessments at Screening to Confirm Mild Cognitive 
Impairment ...................................................................................................40 
8.1.4.1 
Clinical Dementia Rating Scale .........................................................41 
8.1.4.2 
Mini-Mental State Examination .........................................................42 


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8.1.4.3 
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition, Text Revision Criteria for Dementia ....................................42 
8.1.4.4 
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition, Text Revision Criteria for Major Depressive Disorder, 
Recurrent ............................................................................................43 
8.1.5 
Assessment of Cognitive Performance at Baseline .....................................45 
8.1.5.1 
Alzheimer’s Disease Cooperative Study Scale for Activities of 
Daily Living in Mild Cognitive Impairment ......................................45 
8.1.5.2 
Rey Auditory Verbal Learning Test ..................................................45 
8.1.5.3 
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog) ......46 
8.1.6 
Assessment of Cognitive Performance at the 6-, 12-, 18-, 24-, 30-, and 
36-Month Assessments ................................................................................47 
8.1.7 
MRI Examination of the Brain ....................................................................47 
8.1.8 
PET Image Acquisition ................................................................................50 
8.1.8.1 
Subject Level Visual Assessment (Primary Efficacy Endpoint) .......53 
8.1.8.2 
Subject Level Quantitative Assessment (Secondary Efficacy 
Endpoints) ..........................................................................................55 
8.2 
Pharmacokinetics ...................................................................................................56 
8.3 
Safety .....................................................................................................................56 
8.3.1 
Adverse Events ............................................................................................56 
8.3.1.1 
Definition of Adverse Event ..............................................................56 
8.3.1.2 
Categories for Adverse Event Assessment ........................................57 
8.3.1.3 
Assessments and Documentation of Adverse Events ........................58 
8.3.1.4 
Expected Adverse Events ..................................................................59 
8.3.1.5 
Serious Adverse Events .....................................................................60 
8.3.2 
Further Safety Assessments .........................................................................62 
8.3.2.1 
Physical Examination.........................................................................62 
8.3.2.2 
Vital Signs ..........................................................................................62 
8.3.2.3 
Electrocardiogram ..............................................................................62 
8.4 
Other Procedures and Variables.............................................................................63 
8.4.1 
Blood Sampling ...........................................................................................63 
8.4.2 
Laboratory Data Related to Screening and Safety .......................................63 
8.4.3 
Blood Sampling and Processing for Genetic Analyses ................................66 
9 
STATISTICAL METHODS ............................................................................................67 
9.1 
Introduction ............................................................................................................67 
9.2 
Randomization Methods ........................................................................................67 
9.3 
Pooling of Study Centers .......................................................................................67 
9.4 
Efficacy Variables ..................................................................................................67 
9.4.1 
Primary Efficacy Variables ..........................................................................67 
9.4.2 
Secondary Efficacy Variables ......................................................................68 
9.5 
Pharmacokinetic Variables ....................................................................................68 


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9.6 
Safety Variables .....................................................................................................68 
9.6.1 
Primary Safety Variables .............................................................................68 
9.7 
Sample Size Justification .......................................................................................68 
9.8 
Handling of Missing Data ......................................................................................69 
9.9 
Statistical Analysis .................................................................................................69 
9.9.1 
Analysis Populations ....................................................................................69 
9.9.2 
Analysis of Baseline and Demographic Characteristics ..............................69 
9.9.3 
Analysis of Primary Variables .....................................................................69 
9.9.4 
Analysis of Secondary Variables .................................................................70 
9.9.5 
Safety Analyses ............................................................................................71 
9.10 
Interim Analyses ....................................................................................................71 
10 DATA HANDLING AND QUALITY ASSURANCE ...................................................72 
10.1 
Data Recording ......................................................................................................72 
10.1.1 
Electronic CRF design .................................................................................72 
10.2 
Monitoring .............................................................................................................72 
10.3 
Data Processing ......................................................................................................72 
10.4 
Auditing .................................................................................................................73 
10.5 
Archiving ...............................................................................................................73 
10.6 
Premature Termination of the Study ......................................................................73 
10.6.1 
Study as a Whole .........................................................................................74 
10.6.2 
Center ...........................................................................................................74 
10.6.3 
Study Participant ..........................................................................................74 
11 ETHICAL AND LEGAL ASPECTS...............................................................................75 
11.1 
Ethical and Legal Conduct of the Study ................................................................75 
11.2 
Subject Information and Consent...........................................................................75 
11.3 
Financing/Financial Disclosure .............................................................................76 
11.4 
Publication Policy ..................................................................................................76 
11.5 
Subject Injury .........................................................................................................76 
12 REFERENCE LIST .........................................................................................................77 
 


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LIST OF IN-TEXT TABLES 
Table 1. 
Neuro-Cognitive Testing and Assessment of Progression to Dementia ......39 
Table 2. 
Manufacturer Specific Recommended Acquisition Parameters for 
Volumetric Required T1 3D MRI, T2, FLAIR and Optional DWI 
Images. ........................................................................................................49 
Table 3. 
Definitions of Regional Cortical Tracer Uptake Scores ..............................54 
Table 4. 
Documentation of Regional RTUS Score ....................................................55 
Table 5. 
The Regions of the Brain Used for ROI Sampling for Subject Level 
Quantitative Analysis ..................................................................................56 
Table 6. 
Clinical Laboratory Parameters ...................................................................64 
Table 7. 
Amount of Blood Withdrawn ......................................................................65 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Events .......................................................................................80 
Appendix 2 Sponsor Signatures.......................................................................................82 
Appendix 3 Investigator’s Signature ...............................................................................83 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AD 
Alzheimer’s disease 
ADAS Cog 
Alzheimer’s Disease Assessment Scale-Cognitive  
ADCS-MCI-ADL 
Alzheimer’s Disease Cooperative Study Scale for Activities of Daily 
Living in Mild Cognitive Impairment 
ADL 
activities of daily living 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
ADR 
adverse drug reaction 
ADRDA 
Alzheimer’s Disease and Related Disorders Association 
AE 
adverse event 
ALARA 
as low as reasonably achievable 
ALT 
alanine aminotransferase 
A-MCI 
amnestic MCI 
ApoE4 
apolipoprotein E4 
CDR  
Clinical Dementia Rating  
CRA 
clinical research assistant / associate 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, 
text revision 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
effective dose 
FCSRT 
Free and Cued Selective Reminding Test 
FDA 
Food and Drug Administration 
FDG 
[18F]fluorodeoxyglucose 


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FOV 
field of view 
FT3 
free triiodthyronine 
FT4 
free thyroxine 
FWHM 
full width half maximum  
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GT 
glutamyl transferase 
Hb 
hemoglobin 
HCT 
hematocrit 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRC 
Image Review Charter 
IRB 
institutional review board 
ISF 
investigator’s site file  
ITD 
intent-to-diagnose  
IV 
intravenous 
MBq 
megabequerel 
MCH 
mean corpuscular hemoglobin 
mCi 
millicurie 
MCI 
mild cognitive impairment 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute 
mL 
milliliter 
MMSE 
Mini Mental State Examination 
MNI 
Molecular NeuroImaging, New Haven, CT 


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MRI 
magnetic resonance imaging 
NINCDS-ADRDA 
National Institute of Neurological and Communicative Disorders 
and Stroke - AD and Related Disorders Association 
NPV 
negative predictive value 
NYU 
New York University 
OLINDA 
Organ Level INternal Dose Assessment 
PET 
positron emission tomography 
PIB 
[11C]Pittsburgh compound B 
PP 
per protocol  
PPV 
positive predictive value 
QA 
quality assurance 
RAVLT 
Rey Auditory Verbal Learning Test 
ROC 
receiver operating characteristics 
ROI 
region of interest 
RTUS 
regional tracer uptake score 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoT 
standard of truth 
SUSAR 
suspected unexpected serious adverse reaction 
SUV 
standard uptake value 
SUVR 
standard uptake value ratio 
TMF 
trial master file 
TSH 
thyroid stimulating hormone 
VOI 
volume of interest 
 


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TRIAL ADMINISTRATIVE STRUCTURE 
The principal investigator must sign the protocol signature sheet before trial participant 
recruitment may start.  Likewise, all protocol amendments must be signed and dated by the 
principal investigator before coming into effect. 
The name and address of the participating center, the investigators, and all required signature 
documents will be maintained in the trial master file (TMF). 
In addition to the principal investigator, there are additional on-site roles that may be 
performed by other sub-investigators:   
• Subject referral to the trial 
• Review of subject eligibility and medical records  
• Safety assessments 
• Cognitive assessments 
• Injection and PET imaging  
• On-site PET image analysis 
 
Blinded reading of positron emission tomography (PET) images will be done at the core 
image laboratory listed below. 
Trial personnel not listed in this section are identified in a separate personnel list.  This list 
will be updated as needed.  The list of personnel will be available in the center’s investigator 
site file (ISF). 
LABORATORIES AND OTHER INSTITUTIONS FOR TRIAL 
CONDUCT 
Responsibility 
Name 
Affiliation / Address 
Statistical analysis and 
programming 
STATKING 
STATKING Clinical Services 
759 Wessel Drive 
Fairfield, OH 45014 
Central laboratory  
(clinical laboratory tests) 
PPD GCL 
PPD Global Central Lab 
2 Tesseneer Drive 
Highland Heights, KY 41076 
Image core laboratory  
Molecular 
NeuroImaging 
 
MNI – Molecular NeuroImaging L.L.C. 
60 Temple Street, Suite 8A 
New Haven, CT 06510 
 


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1 
INTRODUCTION 
1.1 
Background 
“Mild cognitive impairment” (MCI) is a concept that describes the cognitive changes that are 
more severe than those associated with normal aging and greater than expected for an 
individual’s educational level, but less severe than those associated with dementia and which 
do not noticeably interfere with the activities of daily living (ADL).  The term MCI was first 
used by Flicker (1991) and described in more detail by Petersen et al. (1999).  Recently a 
working group convened by the Alzheimer’s Association and the National Institutes on 
Aging (Albert et al., 2011) has proposed and drafted updated criteria.  The criteria originally 
published in 1999 include: (1) memory complaint reported by the subject or an informant, (2) 
objectively measured memory impairment for age and education, (3) generally normal 
cognition outside of memory, (4) largely preserved ADL, and (5) not demented.  The 
proposed updated criteria for “MCI due to AD” broadened the memory complaint and 
impairment to include other aspects of cognition such as attention, executive function, 
language, and visuo-spatial skills. 
MCI criteria have been extensively evaluated over the years, and modifications have been 
suggested by Petersen et al. (Petersen et al., 2001; Petersen, 2004) and other groups with the 
aim to identify those cognitive deficits that may predict the risk to progress to dementia, 
particularly to dementia of the Alzheimer’s type.  Based on various patterns of deficits 
measured in neuropsychological tests, subtypes of MCI have been identified.  Petersen and 
Negash (2008) developed a classification of MCI subtypes based on the affected cognitive 
domain (amnestic versus non-amnestic) and the number of (one versus multiple) domains 
affected.  Gauthier et al. (2006) suggested adding an additional subtype for subjects who had 
only subjective memory or cognitive complaints and found that the risk to progress to 
dementia was highest in amnestic MCI, lower in non-amnestic MCI and lowest in subjects 
with “subjective memory complaints.”  Based on subtle differences in memory and cognitive 
complaints, Roundtree et al. (2007) subdivided amnestic MCI into 2 subgroups, amnestic 
MCI (A-MCI) and a more subtle type amnestic-subthreshold MCI (AS-MCI).  However, the 
authors found both types of AMCI to have similar progression rates to AD. 
In keeping with discordance across definition of MCI subtype, the results of longitudinal 
studies of rates of progression from MCI to AD have varied from as low as 5% per year 
(Feldmann et al, 2007) and 12% to 15% per year (Petersen et al., 1999); (Petersen, 2009); 
(ADNI)) to 20% to 30% per year (Ritchie et al., 2001); (Larrieu et al., 2002). 
Taken together, these data indicate that additional markers/criteria are needed to better 
identify persons at risk of developing AD.  If AD could be diagnosed at an earlier stage of 
disease progression before clinical dementia has fully developed, successful intervention 
with current and future treatments could potentially be improved considerably. 


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Among biomarkers potentially capable of predicting which individuals with MCI will go on 
to develop AD dementia, targeted PET tracers that permit noninvasive detection of 
β-amyloid deposition in the brain during life appear to be the most suitable, since: 
• Deposition of β-amyloid in the cerebral gray matter is known to be central to the 
pathogenesis of AD such that, for a definitive diagnosis thereof, β-amyloid plaques (and 
tau neurofibrillary tangles) must be present in the brain at autopsy (McKhann et al., 
1984). 
• This pathology is known to occur early in the AD disease process long before (i.e., up to 
20 years) development of detectable clinical symptoms (Braak and Braak, 1991). 
• Genetic data support the concept that dysregulation of β-amyloid metabolism with 
formation of insoluble aggregates may be a central causative factor in the neurobiology 
of both early and late onset AD (Reitz and Mayeux, 2010).  
• Finally, β-amyloid is the target for the numerous novel and potentially disease-modifying 
therapies of AD. 
 
The first PET tracer used clinically for visual and quantitative assessment of β-amyloid 
deposition in the brain was the radioactive carbon ([11C])-labeled “thioflavin T” derivative, 
N-methyl-[11C]2-(4-methylaminophenyl)-6-hydroxybenzothiazole, also known as the [11C] 
Pittsburg B compound or [11C] PIB (Klunk et al., 2004).  Several groups have assessed the 
rate of progression to AD in [11C]-PIB-positive MCI subjects compared with subjects with a 
[11C]-PIB-negative PET scan.  In all published studies, a higher progression rate to AD was 
observed in subjects with signs of [11C]-PIB-uptake in their brain, although the yearly 
progression rates varied considerably in these studies from 30% (Forsberg et al., 2008) to 
47% (Forsberg et al., 2008) to over 60% per year (Villemagne et al., 2008). 
However, the 20 minute radioactive half-life of [11C] restricts the use of [11C]PIB to PET 
centers with an on-site cyclotron and extensive radiochemistry infrastructure.  Thus, an 
[18F]-labeled molecule with a radioactive half-life of 110 minutes would be preferable since 
it allows widespread distribution of the tracer to more than one PET center with a single 
production run, as is currently the case with [18F]-fluorodeoxyglucose (FDG). 
2-(2-fluoro-6-methylaminopyridin-3-yl)-1-benzofuran-5-ol 
([18F]NAV4694; 
previously 
referred to as [18F]AZD4694) is an [18F]-labeled radiotracer that has demonstrated high 
affinity and specificity for β-amyloid in nonclinical and clinical studies.  In a recent Phase 2 
study (D2750N00006) involving 24 subjects (10 AD, 10 older healthy volunteers, and 
4 young healthy volunteers), subjects with AD could be differentiated from healthy 
volunteers (young and older) on the basis of both visual and quantitative analysis (e.g., using 
standard value uptake ratio [SUVR] calculation of various pre-specified ROIs) of the scans.  
For visual assessment, the test-retest reliability was excellent (3% to 5%), and for the SUVRs 
the intraclass correlation coefficient was 0.96 to 1.00 for most regions.  The tracer was well 
tolerated, and no adverse events (AEs) were considered to be related to [18F]NAV4694.  It 
should also be noted that, in contrast to other [18F] β-amyloid-targeted neuro-PET ligands 
[18F]NAV4694 exhibits very little white matter uptake.  Non-specific white matter uptake 


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can make differentiation between a positive and negative PET scan difficult and can 
potentially hinder detection of low levels of β-amyloid present, for example, in the early 
stages of AD such as MCI.  
The present study will be a prospective open-label, 5-center study administering 
[18F]NAV4694 as a diagnostic agent to detect the presence or absence or β-amyloid in the 
cerebral gray matter.  The primary statistical approach will entail a comparison of outcome 
(e.g., progression to dementia of the Alzheimer’s type, cognitive decline) between subjects 
with a positive or negative β-amyloid PET scan who have MCI.  It is expected that the 
assessment of the [18F]NAV4694 PET image will enable accurate classification of MCI 
subjects into those at risk and those not at risk of developing dementia of the Alzheimer’s 
type before the appearance of any clinical symptoms of dementia. 
1.2 
Benefit-Risk Assessment 
There is an unmet clinical need for a biomarker indicating the presence of AD pathology 
before symptoms become clinically apparent.  If preventive measures are to be efficacious in 
AD, they have to be initiated in patients early in the preclinical phase of the disease or early 
in life for those at high risk to develop the disease.  The present study aims to identify 
persons with MCI progressing to AD by means of in vivo imaging of β-amyloid deposition in 
the brain using [18F]NAV4694 PET performed at baseline and at 18 and 36 months. All 
subjects participating will be ≥ 55 years of age. Therefore, pregnant or potentially pregnant 
women will not be included.  
Safety and Tolerability of the Active Substance Administered 
The mass dose of the active substance will be up to 40 µg per subject.  It is expected that a 
single intravenous (IV) injection of [18F]NAV4694 with this microdose of ligand will not 
produce any pharmacological effects. 
Excellent safety of [18F]NAV4694  has been indicated by clinical results from three 
completed trials.  In study (D2750C0001), 22 subjects (10 AD and 12 HVs) were 
administered [18F]NAV4694.  Seven AEs were reported for 5 subjects, including 1 serious 
adverse event (SAE); none of the AEs were considered related to the investigational product.  
In study (D2750N00006), 27 subjects (11 AD and 16 HVs) were administered 
[18F]NAV4694.  Fifteen AEs were reported for 9 subjects; none of the AEs were considered 
related to the investigational product.  In study (D2750C00002), 16 subjects (8 ADs and 8 
HVs) were administered [18F]NAV4694. Five AEs were reported by 4 subjects; one adverse 
reaction (cough) was considered by the investigator to be related to [18F]NAV4694.  In these 
3 trials, the clinical results obtained for routine safety parameters demonstrated no trends and 
were not indicative of a safety concern, thus confirming nonclinical findings. 
Total Effective Dose of the Required PET Imaging Procedure 
Initial dosimetry data were determined in study D2750C0001, in which 5 HVs were 
administered ~210 MBq of [18F]NAV4694 and underwent serial, whole body PET scanning 


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over approximately 6 hours post injection. For all subjects taken together, the mean urinary 
bladder wall radiation absorbed dose was the largest; 0.11 ± 0.017 mSv/MBq (mean ± SD), 
with a range of 0.097 to 0.14 mSv/MBq (bladder void interval 4.8 hours). There were no 
other mean organ radiation doses exceeding 0.10 mSv/MBq. The effective dose (ED) of 
[18F]NAV4694 was 0.023 mSv/MBq (4.8 hour bladder void interval), which is comparable to 
that of 18F-FDG (effective dose equivalent [EDE] = 0.027 mSv/MBq). 
High quality PET imaging relies on attenuation correction (AC), which is usually achieved 
with a transmission scan acquired immediately before or after emission scanning.  In the 
present study, AC should be performed before emission scanning and before any required 
repositioning of the subject.  In addition to dedicated PET scanners, in the present study, state 
of the art PET/computed tomography (CT) machines will also be permitted.  For dedicated 
PET scanners AC is performed using an external radionuclide source such as germanium-68 
with the resulting ED of the transmission scan < 0.05 mSv.  The low dose CT for a PET/CT 
scanner should not exceed 0.25 mSv.   
Risk and Benefit 
Clinical results derived with other tracers to present have indicated the clinical value of PET 
scanning for detection of the presence or absence of β-amyloid during life (Rowe et al., 2008; 
Vandenberghe et al., 2010; Barthel et al., 2011).  In particular the absence of this protein in 
the brain has been considered particularly useful in that it makes the presence of AD highly 
unlikely.  Although the diagnostic value of PET imaging with [18F]NAV4694 has not yet 
been confirmed and the tracer is not yet approved for detection of β-amyloid deposition in 
the brain, clinical studies with this “second generation” PET tracer will generate valuable 
prospective clinical safety and efficacy data contributing to the current knowledge base.  In 
addition, knowledge of the [18F]NAV4694 scan results can provide increased diagnostic 
certainty and resulting increased quality of life, for both subjects and their families.  
Aside from the radiation exposure from tracer administration and transmission scanning 
(described above), the risks to subjects are mainly related to the intravenous (IV) injection.  
IV injection is known to carry a small risk of infection, injection site pain, and hematoma. 
This information on risk and benefit will be conveyed to all participating subjects verbally 
and in writing as part of the informed consent process prior to inclusion in the trial.  In view 
of an excellent safety profile of the drug substance and the clear medical need for a tracer of 
this type, the discomfort of the subjects and the low risk resulting from the radiation dose 
appear justified. 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To investigate whether [18F]NAV4694 positron emission tomography (PET) scan findings 
have the ability to distinguish subjects with mild cognitive impairment (MCI) who progress 
to AD from those who do not. 
Assessment of the primary objective will be based on the sensitivity, specificity, positive 
predictive value (PPV), and negative predictive value (NPV) of [18F]NAV4694 PET scan 
findings (e.g., majority read findings of baseline scan) in predicting progression from MCI to 
AD type dementia at 18 months.  
2.2 
Secondary Objectives 
• To evaluate the sensitivity, specificity, NPV, and PPV of quantitative findings 
(e.g., SUVRs) in predicting progression of MCI to AD type dementia at 18 months, using 
a data driven (and a pre-specified) threshold for positivity.   
• To determine the overall changes in amyloid burden over time in subjects with visually 
positive vs. negative scans (by comparison of baseline and 18-month scan in a subset of 
20 subjects). 
• To determine in a subset of 20 subjects whether changes in quantitative [18F]NAV4694 
uptake over time correlate with the rate of cognitive decline in subjects with MCI over 
18 months. 
• To determine the increase in risk of progression to AD for a unit change between subjects 
in subject level SUVR value. 
• To evaluate safety and tolerability of [18F]NAV4694 in subjects with MCI. 
 


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3 
OVERVIEW OF METHODOLOGY AND DESIGN 
3.1 
Overall Study Design 
This is an open label, non–randomized, multi-center study in subjects with MCI.  This will be 
an exploratory study with descriptive statistics only and no hypothesis testing.  The standard 
of truth (SoT) will be the final clinical classification at 18 months, established by the 
investigator who will also be responsible for the neuro-cognitive testing and who will be kept 
blinded to the results of the PET scan.  
The proposed study includes: screening, baseline neuro-cognitive testing and PET imaging, 
neuro-cognitive follow-up examinations (at 6, 12, 18, 24, 30, and 36 months). In addition, a 
subset of 20 subjects will undergo PET and MR imaging at 18 months. Each subject will be 
in the study for a fixed period of time (36 months) or until the subject withdraws from the 
study.   
Screening: At screening, medical history will be recorded from the subject and verified 
and/or supplemented by the “study partner” (see Section 3.2.1).  Physical, neurological, and 
neuro-cogntive assessments will be performed; only subjects who are not demented will be 
enrolled in the study.  All subjects will have a magnetic resonance imaging (MRI) scan of the 
brain and laboratory tests, unless these have been performed within 6 months of screening.  
In addition to providing a 3D T1-weighted volumetric image to be used for co-registration 
with the PET scan and subsequent SUVR generation, the brain MRI scanning (both 3D T1- 
and T2-weighted images) is required for visualization of structural abnormalities that assist in 
ruling out other causes of impaired cognition and/or constitute pre-specified exclusion 
criteria.  The images will also be evaluated by the core image laboratory for the presence and 
degree of general cerebral and/or medial temporal lobe (MTL) atrophy and the presence or 
absence of peri-ventricular white matter.  
Baseline PET Imaging: All subjects will receive a single IV injection of the investigational 
product, and a PET scan will be performed from 50 to 70 minutes post injection to assess the 
uptake pattern of [18F]NAV4694 in the brain.  For assessment of the primary efficacy 
endpoint, the PET images will be visually evaluated by 3 independent blinded readers at the 
core image laboratory and will be categorized as β-amyloid positive (yes or no) according to 
a pre-specified scoring system.  
An additional unblinded read will be performed by the on-site radiologist or nuclear 
medicine physician using a provided Visual Image Training Manual. 
PET image acquisition, processing, display and visual/quantitative analysis methods are 
discussed briefly in Section 8.1.8 and in detail in the Image Review Charter (IRC). 
Each subject will be asked to return to the site for a follow-up visit (20 to 28 hours after 
investigational product administration), and a telephone follow-up will occur 7 (+ 3) days 
thereafter.  Safety will be assessed during both follow-up visits.  


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Neuro-cognitive follow-up exams and diagnostic status (6, 12, 18, 24, 30, and 36 months) 
and 18-month MR:  During these exams, cognitive and functional performance will be 
evaluated every 6 months ± 30 days at scheduled visits.  The Clinical Dementia Rating 
(CDR), Alzheimer’s Disease Cooperative Study Scale for Activities of Daily Living in Mild 
Cognitive Impairment (ADCS-MCI-ADL), and Mini-Mental Status Examination (MMSE), 
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog), the Rey Auditory Verbal 
Learning Test (RAVLT) and Diagnostic and Statistical Manual of Mental Disorders, fourth 
edition, text revision (DSM-IV-TR) criteria for major depressive disorder, recurrent will be 
used. Diagnostic status is the documentation of the subject’s current diagnosis of MCI or 
dementia.  Unscheduled (interim) visits and evaluations are allowed if a study subject, a 
“study partner,” or the subject’s personal physician believes this is necessary, e.g., if there is 
a marked cognitive decline.  The 18-month MR image will be completed within the 30 days 
before the 18-month PET imaging visits and will be performed only for the subset of 
20 subjects that is imaged at 18 months.  
18-month PET:  PET imaging will follow the 18-month clinical and neuro-cognitive visits 
for a subset of 20 subjects.  Subjects will receive a single IV injection of the investigational 
product, and a PET scan will be performed from 50 to 70 minutes post injection to assess 
[18F]NAV4694 uptake pattern in the brain. Diagnostic status is the documentation of the 
subject’s current diagnosis of MCI or dementia.    
Note: The end of study may also be due to subject’s discontinuation or termination from the 
study. 
The Schedule of Study Events (see Appendix 1) contains a detailed description of all study 
procedures and time points.   
Assessment of Alzheimer’s disease 
DSM-IV-TR criteria will be used to determine whether a subject has dementia and if so, 
which type.  Probable AD will be confirmed using criteria from National Institute of 
Neurologic, Communicative Disorders, and Stroke – AD and Related Disorders Association 
(NINCDS-ADRDA) (McKhann et al., 1984). 
Here, the MRI will be performed to rule out non-AD type brain pathology, e.g., cortical or 
subcortical stroke, brain tumor, normal pressure hydrocephalus. 
3.2 
Justification for Study Design and Population 
This study is designed to establish imaging with the PET tracer [18F]NAV4694 as a 
diagnostic method to assist in identifying subjects at increased risk of progression to AD 
dementia.  If a positive β-amyloid PET scan is indeed predictive of increased risk of 
progression from MCI to AD, this prognostic test could be used in conjunction with clinical 
data to select subjects for preventive treatment prior to the emergence of clinical signs of 
dementia.  It could also be used for subject selection and/or enrichment in clinical studies 
evaluating new disease modifying therapies.  Information regarding the change in amyloid 


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load over time (between the baseline and 18-month PET scan) may be used to determine the 
relationship between cognitive decline and β-amyloid concentration and will be examined as 
a secondary outcome. 
3.2.1 
Study Partner 
Each subject in the study must have a “study partner.”  A “study partner” for this study is 
defined as a friend or family member who is in close contact with the study subject (at least 
10 hours per week), who can assist in completing rating scales, participate in interviews, and 
answer questions during phone calls, etc., for the duration of the study.  The study partner 
should accompany the study subject to the clinical appointments throughout the study and 
supply information as needed.  If the study partner is unable to accompany the subject, he/she 
should be available via telephone to complete the scales, interviews, and questions. 
The study partner will be asked to judge changes in behavior or cognitive and memory 
performance of the subject. 
3.2.2 
Rational for Subject Selection 
The selection criteria as described in the inclusion criteria (see Section 4.1.1) are based on 
the following considerations: 
Although it is generally accepted that subjects with MCI have a higher risk of developing AD 
than subjects without MCI (average annual progression rate of up to 15%), for a considerable 
percentage of subjects, MCI may be a stable or reversible condition that does not progress to 
dementia. 
There is a lack of agreement on the criteria that should be used to determine whether an 
individual does or does not have MCI (Dubois, 2000). 
However, the risk to progress to AD seems to be highest in A-MCI with a lower risk in non-
A-MCI, and the lowest risk in subjects with “subjective memory complaints” (Gauthier et al., 
2006). 
When A-MCI was further sub-divided into 2 subgroups, A-MCI (as defined by Petersen’s 
operational criteria, 2001) and a more subtle type AS-MCI, both types had similar 
progression rates to AD (Rountree et al., 2007). 
To meet the objectives of this study, study subjects should meet criteria for MCI as originally 
described by Petersen et al. (1999), i.e., the memory domain must be affected, but should 
also include those subjects with subtle memory impairment, as described by Rountree (2007) 
and Albert, et al. (2010) 


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3.2.3 
Justification for Radiation Exposure With Proposed [18F]NAV4694 PET 
Radioactive Dose 
In nuclear medicine imaging, the diagnostic quality of an image is dependent upon the 
number of radioactive events (or counts) detected by the camera in the regions of interest 
(ROIs).  The number of recorded events (counts) increases with the duration of the 
acquisition period and, for a given acquisition period, with the radioactivity administered.  
Although the injected radioactivity should then be high, the higher the applied radioactivity 
dose, the higher the radiation exposure to the subject.  Thus, in nuclear medicine, the optimal 
radioactive dose for a given radiopharmaceutical is usually defined as the lowest radioactive 
dose that renders an image of sufficient quality to provide high diagnostic confidence, 
commonly referred to as ALARA (as low as reasonably achievable) practices for radiation 
exposure. 
Human radiation dosimetry of [18F]NAV4694 PET was investigated in 6 healthy male 
volunteers who received approximately 210 MBq in study (D2750C0001).  The OLINDA 
(for Organ Level INternal Dose Assessment) software (Stabin et al., 2005) was used to 
calculate radiation exposure. The ED per applied radioactivity was 0.023 mSv/MBq 
(4.8 hour urinary void interval).  With the injected activity of 210 MBq, this results in an ED 
of 4.83 mSv, extrapolating to a proposed injected activity of 300 MBq, this results in an ED 
of 6.9 mSv.   
For a listing of the respective radiation absorbed doses to body organs, see the Investigator’s 
Brochure.  
The ED upon administration of [18F]NAV4694 PET can be compared with that resulting 
from a routine thoracic or abdominal computed tomography (CT) scan or from 
administration of [18F]-FDG, the only PET radiopharmaceutical currently in widespread 
clinical use.  With [18F]-FDG, the ED per administered radioactivity is 0.019 mSv/MBq.  The 
radioactive dose typically injected for cancer imaging is 370 MBq of [18F]-FDG which 
corresponds to an ED of 7 mSv.  In brain imaging with [18F]-FDG, the dose recommended by 
the European Association of Nuclear Medicine is 125 to 250 MBq.  However, the [18F]-FDG 
package insert recommends a dose of 185 to 370 MBq for adults, resulting in an administered 
ED of approximately 3.5 to 7 mSv. The ED value resulting from the recommended 
[18F]NAV4694 dose (approximately 6.9 mSv/300 MBq) is within this range. 
3.3 
Justification of Safety Plan 
Safety pharmacology testing in animals up to present have demonstrated a favorable safety 
profile with no relevant neuroreceptor binding of [18F]NAV4694 and no effect on central 
nervous or cardiovascular system.  In an extended single-dose toxicity study in rats and 
1-month repeated-dose toxicity studies in rats and dogs, [18F]NAV4694 was well tolerated at 
doses greater than 25 times the maximum intended human dose.  Details of the nonclinical 
safety studies can be found in the Investigator’s Brochure. 


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A favorable safety profile has also been demonstrated in humans in a Phase 1 trial 
(D2750C0001) that evaluated safety, pharmacokinetics, and dosimetry in 20 subjects (10 AD 
and 10 healthy volunteers), a Phase 1 trial (D2750C00002) that evaluated safety and efficacy 
at a low and high mass dose in 16 subjects (8 AD and 8 HVs), and a Phase 2 trial 
(D2750N00006) that evaluated safety, test-retest reliability, and efficacy of different 
scanning parameters in 24 subjects (10 AD, 10 older healthy volunteers, and 4 young healthy 
volunteers). There were no safety or tolerability concerns identified in these trials.  Only one 
AE (cough) occurred that was judged by the investigator to be related to the investigational 
product (trial D2750C00002).  In the present trial, the design of the safety plan permits an 
appropriate and adequate evaluation of the safety response to [18F]NAV4694 under baseline 
and post- investigational product administration conditions and allows a comparison of this 
study’s safety data set with that of the previous studies.  The measures used to assess safety 
are well defined and reliable within the context of the PET imaging environment, and the 
proposed safety analyses are adequate to assess the effects of study drug injection.  The 
safety plan aims to restrict the collection of data up to and including 20 to 28 hours post 
injection based on the pharmacokinetic characteristics of [18F]NAV4694 and the absence of 
any study procedures beyond this time point aside from a 7 day telephone follow-up. 
3.4 
Protocol Adherence 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
the study conduct; the investigator may not modify or alter the procedures described in this 
protocol. If protocol modifications are necessary, all alterations that are not solely of an 
administrative nature require a formal protocol amendment (see Section 11.1 for the 
involvement of International Ethics Committee(s) IEC(s)/ International Review Board(s) 
IRB(s)). 
If an investigator has deviated from the protocol in order to eliminate an immediate hazard to 
subjects or for other inevitable medical reasons, the investigator shall document all such 
deviations, including the reasons thereof, and submit the document to the sponsor and the 
head of the medical institution as applicable. 
3.5 
Study Duration 
Subjects will be enrolled for approximately 36 to 38 months depending on the duration of the 
screening window (potentially 8 weeks). 
 


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4 
STUDY POPULATION 
4.1 
Eligibility 
Subjects with MCI, as established by a comprehensive neuro-cognitive evaluation (for details 
see Section 8.1.4) and diagnostic criteria, will be eligible to participate. 
Subjects who fulfill all respective inclusion and none of the exclusion criteria will be eligible 
for enrollment into the study.  All inclusion/exclusion criteria must be verified before a 
subject may be considered eligible for enrollment into the study.  A subject will be 
considered enrolled in the study on the morning of study day 1 when they arrive at the study 
site.  Written, dated (with time noted) informed consent will be obtained from all subjects. 
4.1.1 
Inclusion Criteria 
1. Subject has signed informed consent to participate in the study and continues to give 
willing consent for participation 
2. Age ≥ 55 years with a diagnosis of MCI 
3. Educational level of at least 6 years  
4. Female subjects will not be of child-bearing potential (> 1 year post-menopausal or 
surgically sterile)  
5. Availability of a “study partner” who can assist in completing rating scales for the 
duration of the study 
6. Cognitive complaints reported by the subject and confirmed by the “study partner” 
7. Clinical Dementia Rating (CDR) global score = 0.5 
8. Mini-mental state examination (MMSE) score of 24-30 
9. Diagnostic and Statistical Manual of Mental Disorders, Version 4, Text Revised (DSM-
IV-TR) criteria of dementia not fulfilled 
4.1.2 
Exclusion Criteria 
1. Has been previously enrolled in this study and received the investigational product 
2. Has received an investigational product within 30 days prior to screening  
3. Has received disease-modifying therapy that could have changed amyloid brain 
deposition 
4. Has exceeded yearly radioactive dose of 30 mSv 
5. Has a known allergy to the study drug or any of its constituents 
6. Has a history of alcohol abuse or alcohol dependency in the 3 years prior to study entry, 
or is an alcoholic or drug addict, as determined by the investigator 
7. Has ongoing clinically significant (as judged by the investigator), metabolic or any other 
disease that could currently cause impaired memory (e.g., untreated thyroid disease, 
vitamin or other nutritional deficiencies, chronic kidney, or liver disease) 
8. Memory impairment that can be attributed to a disease or condition other than an early 
phase neurodegenerative syndrome 
9. Has a parkinsonian movement disorder 


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10. Use of psychoactive medications that would affect the subject’s ability to reliably 
perform neurocognitive testing or create uncertainty in distinguishing between the effects 
of the psychoactive medication and the subject’s underlying cognitive impairment 
(e.g., benzodiazepines, sedatives, antipsychotics) 
11. Has received any contrast material (X-ray, MRI) or radiopharmaceutical within 48 hours 
prior to, or a therapeutic radiopharmaceutical (e.g., 131I) within 10 days prior to, or any 
radiopharmaceutical administration within 10 radioactive half-lives prior to the 
administration of the investigational product or for whom administration of such 
substances is planned within 7 days after investigational product administration 
12. History of major recurrent depressive disorder (per DSM-IV-TR) within the last 5 years 
prior to screening  
13. Has a brain tumor or other intracranial lesion, a disturbance of cerebral spinal fluid 
circulation (e.g., normal pressure hydrocephalus), and/or a significant history of head 
trauma or brain surgery  
14. Has signs of major cerebrovascular disease, as verified by medical history and/or brain 
MRI 
15. Is scheduled for surgery and/or another invasive procedure within the 7 days following 
investigational product administration   
16. Has any contraindication to MRI examination, e.g., metal implants, phobia, or cannot 
undergo an MRI for other reasons such as the inability to lie flat 
4.1.3 
Justification of Selection Criteria 
The selection of participants reflects a balance between including subjects with a higher 
likelihood of progressing to dementia of the Alzheimer’s type and those with a lower 
likelihood of progressing in a way that ensures that the study is feasible but includes a broad 
range of different types of MCI subjects with impaired memory.  In addition, the exclusion 
criteria were defined to exclude subjects with impaired memory caused by other diseases, 
such as metabolic diseases. 
4.2 
Recruitment 
Subjects will be recruited in accordance with the inclusion and exclusion criteria listed above 
from neurology or geriatric practices. Potentially suitable subjects will be asked by their 
treating specialist about their willingness to participate in this study.  
4.3 
Withdrawal 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the 
study at any time and without providing a reason.   
Should a subject withdraw after administration of the investigational product all efforts will 
be made to complete and report the observations up to the time of withdrawal as thoroughly 
as possible.  All 36 month visit procedures should be completed at the time of the subject’s 
withdrawal for those subjects withdrawing at or after 6 months post baseline injection as 
determined by the willingness of the subject. Priority for 36 month visit procedures should be 


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safety and then neuro-cognitive assessments. An explanation should be given of why the 
subject is withdrawing or being withdrawn from the study. 
Subjects that begin regular use of concomitant medication that impairs cognition i.e., large 
doses of hypnotics, anxiolytics, tricyclic antidepressants and/or antipsychotics should be 
discussed with the medical monitor. Subjects taking cognition impairing medication may 
need to be withdrawn from the trial if the concomitant medication interferes with the 
investigator’s ability to detect change in the subject’s underlying cognitive impairment.  
The investigator may withdraw a subject from the study at any time at the discretion of the 
investigator for any of the following reasons:  
• A protocol violation occurs  
• A serious or intolerable AE occurs  
• A clinically significant change in a laboratory parameter occurs  
• At the investigator’s/sponsor’s discretion as long as it is in the best interest of the subject  
• The sponsor or investigator terminates the study  
• The subject requests to be discontinued from the study 
4.4 
Replacement 
Subjects will be replaced under the following conditions: 
• Subjects who prematurely discontinue participation before completion of the 6-month 
visit will be replaced. 
• Subjects who receive the study medication, but for whom the acquisition of PET imaging 
data is not adequately possible, e.g., due to inability to support the head immobilization 
regimen, an intercurrent adverse event, requiring priority treatment, or withdrawal of 
consent during imaging will be replaced by an additional subject. 
• Subjects who did not receive the study medication due to withdrawal of consent, any 
intercurrent medical reason that is not merely transient in manner, or the presence of an 
exclusion criterion will be replaced by an additional subject. 
4.5 
Subject Identification 
After the subject provides written informed consent, the site will assign the subject a 7-digit 
subject number. Subject numbers are to be assigned in a sequential manner using the 
following format:  
Digits 1 to 2: Trial number “04”  
Digits 3 to 4: Site number (e.g., “03”)  
Digits 5 to 7: Sequential subject number (e.g., “001”, “002”, “003”, etc.)  
For example, the first subject consented at Site 03 is subject number “04-03-001”.  
Subjects will maintain the same number given at screening for the entire study. If a subject is 
a screen failure, the number will not be used for any other subject. 


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5 
INVESTIGATIONAL PRODUCT 
5.1 
Identification of Investigational Product 
The investigational product is 2-(2-[18F]-fluoro-6-(methylamino)pyridin-3-yl)benzofuran-5-
ol ([18F]-NAV4694).  [18F]-NAV4694 will be prepared by a qualified PET Manufacturing 
Facility (PMF) from precursor supplied by Navidea Biopharmaceuticals. 
The nuclear medicine physician or designee is responsible for ensuring that deliveries of 
investigational product and other materials from the sponsor and/or the PMF are correctly 
received, recorded, handled, and stored safely and properly in accordance with all applicable 
regulatory guidelines, and used in accordance with this protocol. 
Unless otherwise agreed, investigational product transport containers (e.g., “lead pigs”) must 
be returned to the PET production center and investigational product and other materials 
disposed of (via decay or otherwise) on-site after use.  A list of investigational product(s) or 
other materials that were returned or disposed of must be prepared and signed by the 
principal investigator or designee.  If there are any discrepancies, an explanation for these 
should also be provided. 
The current Investigator’s Brochure will be supplied to the investigative center. 
5.2 
Identity and Production 
Investigational product will be manufactured and handled according to the applicable Good 
Manufacturing Practice (GMP) at a qualified PMF using an automated process that includes 
radio-labeling of the non-radioactive precursor (NAV4614) with fluorine-18 (the radioactive 
source of fluoride produced by an on-site cyclotron) followed by purification. Before release, 
each batch of investigational product will be assessed by a number of quality control tests 
according to methods approved by the sponsor.  The investigational product must meet pre-
specified criteria for appearance (clarity, color, particulate content), identity, purity, specific 
activity, pH, and bacterial endotoxin level; although tested for sterility, the results will not be 
available until after administration.  The investigational product will be formulated as a 
sterile solution for intravenous injection at the pre-specified radioactivity dose of 300 MBq 
(8.1 mCi) ± 20%.  All manufacturing, quality control testing, and documentation will be 
controlled and documented by the responsible person at the production site. 
The subject dose is prepared from a production batch in a manner such that at the timepoint 
of administration, the volume is between 1 and 10 mL and  the activity is 300 MBq (8.1 mCi) 
of [18F]NAV4694. 
A complete record of batch numbers and expiry dates of all study medication will be 
maintained in the Trial Master File (TMF). 
The PMF will assign individual batch numbers to all investigational product production runs.  
A complete batch documentation in which manufacturing, quality control, analytical results, 
and the batch release for human use are detailed will be generated.  These documents will be 
archived at the respective production site, with copies provided to the sponsor.  Copies of the 


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master batch documentation and of the individual manufacturing batch documentations will 
also be made available to the sponsor for the Trial Master File (TMF). 
5.3 
Dosage and Administration 
Study participants will be administered [18F]NAV4694 under the direct supervision of a 
nuclear medicine physician or designee.  For administration of [18F]NAV4694, access into a 
large vein (e.g., antecubital vein) should be established using a suitable indwelling catheter 
(e.g., Venflow).  To avoid extravasation of [18F]NAV4694, correct localization of the 
catheter must be ensured by a test injection of normal saline prior to the injection of 
[18F]NAV4694.  
Each study participant will receive a single IV injection of [18F]NAV4694 at baseline, and a 
subset of 20 subjects will receive a second single IV injection of [18F]NAV4694 at 18 months 
with a total radioactivity dose amounting to 300 MBq (8.1 mCi) ± 20% on each occasion. 
This single IV injection will contain a maximum mass dose of NAV4694 (total: 18F 
containing material plus 19F containing material) of no more than 40 µg and a total volume of 
up to 10 mL.  [18F]NAV4694 must be administered manually via slow IV injection followed 
by a 10 mL saline flush.  Note:  The use of a motorized power injection system is not 
permitted. 
The exact radioactive dose administered must be determined by calculating the difference 
between the radioactivity in the syringe immediately before injection and in the syringe and 
injection system immediately after injection using a suitable counter.  Measured radioactivity 
values and times of measurement will be recorded in the source documentation, along with 
the total injected volume.  Injected radioactivity values outside the above stated range, i.e., 
values lower than 240 MBq/6.48 mCi or higher than 360 MBq/9.72 mCi will be considered 
as protocol deviations. 
5.4 
Treatment Assignment 
In this open-label non-randomized pivotal study, all subjects will receive the same treatment. 
5.5 
Blinding 
This is an open-label study as the [18F]NAV4694 will be injected in an open-label manner. 
The overall assessment as to cognitive state (e.g., cognitive decline and/or progression to 
dementia) will be performed by the investigator who will be blinded to the results of 
[18F]NAV4694 PET findings (the baseline and 18-month scans) until the clinical diagnostic 
status for the subject has been determined at 36 months.  PET scan results can be shared with 
the subject at the end of their participation at the discretion of the investigator and preference 
of the subject.  Results of the subject’s genetic testing can be shared with the subject at the 
discretion of the investigator and the preference of the subject. 
The onsite PET image analysis will be performed by an onsite nuclear medicine physician or 
radiologist who is not otherwise participating in the diagnostic workup or diagnostic 


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categorization of the subject. This physician will not be blinded to the subject’s clinical 
information or diagnosis. 
The PET images of all subjects (baseline and 18-month visits) will be forwarded in DICOM 
3.0 format to the image core lab (Molecular NeuroImaging [MNI], New Haven, CT). Here, 
the PET images will be freed of all subject identifiers and independently assessed by 3 
blinded readers. 
For the 6-, 12-, 24-, 30-, and 36- month follow-up visits the investigator will conduct the 
neuro-cognitive examination on all subjects who have returned and will compare results to 
those of the previous visits for the purpose of assessing and documenting the subject’s 
current diagnosis and progression status. 
For the 18- month follow-up visit the investigator will again conduct the neuro-cognitive 
examination, in addition to a comprehensive clinical and neurological assessment of all 
returning subjects and compare the results to those of the previous visits for the purpose of 
assessing and documenting the subject’s current diagnosis and progression status. 
All Sponsor personnel and all service providers involved in the data analysis for the trial will 
remain blinded to all trial efficacy results until such time that the clinical database for the 
study has been locked. 
5.6 
Packaging and Labeling 
The investigational product will be provided in a vial. The vial (or syringe) will be shielded 
by a secondary container for radiation protection and product integrity purposes, and with the 
intent that the vial and secondary container remain together. 
The vial (or syringe) along with the secondary container will be labeled according to the 
local standards and the specifications of the local drug law in the local language.  As both are 
intended to remain together, reduced information is given on the vial (or syringe) label. 
 
All labels will be in accordance with the requirements of Good Clinical Practice (GCP) and 
FDA.  The label will include the following: 
• Name and address of sponsor 
• Name/identifier and strength of the preparation (including formulation) 
• Batch number, Lot Number, or Rx Number 
• Pharmaceutical dosage form 
• Route of administration 
• Date and time the total activity in the vial was measured 
 
Guidance to the investigator regarding dosage is provided in a separate document provided 
by the respective PMF site upon delivery of the investigational product (“Dosing Guide”). 


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This guidance is intended for the person administering the investigational product and 
provides a list of recommended volumes for multiple 5-minute increments (related to end of 
synthesis time) corresponding to approximately 300 MBq/8.1 mCi ± 20%. The volumes 
listed in this dosing guide are only recommendations, and different volumes for a particular 
timepoint may be interpolated on-site to achieve the target radioactivity dependent upon 
infusion systems and/or other factors. 
A sample copy of the label will be provided to the sponsor for use in the TMF. 
5.7 
Drug Logistics, Storage, and Accountability 
[18F]NAV4694 should be kept in a secure place under appropriate storage conditions for 
radioactive agents.  For all drug products, a system of medication numbering in accordance 
with all requirements of GMP will be used.  This will ensure that for each subject, any dose 
of [18F]NAV4694 can be identified and traced back to the production run. If imaging is not 
performed at the PET production center, the investigational product will be delivered to the 
PET imaging site by an approved courier.    The final quality control processes for the 
investigational product will occur and be documented before the substance is administered to 
the subject at the PET imaging center.    The investigational product will not be administered 
to the subject without release for human use. 
The investigator (or designated personnel) at the PET imaging site will ensure that the correct 
volume (containing 300 MBq/8.1 mCi ± 20%) will be filled from the vial into the syringe 
and that the administration of the investigational product does not exceed the expiry date and 
time as given on the appropriate documentation.  The investigator (or designated personnel) 
will manage the transfer of the syringe containing the investigational product to the person at 
the PET imaging site responsible for administering to the subject. 
If the location of syringe filling and study administration to the subject differs, then the 
investigator (or designated personnel) must ensure that the syringe is labeled appropriately to 
avoid any ambiguity. 
5.8 
Supply, Dispensing, and Return 
The study drug will be manufactured by a qualified PET production center and will be 
delivered to the study site on request of the investigator. 
The investigator must not order any investigational product before approvals from the 
IRB/IEC and competent authorities are available in written form. 
The shelf life of the investigational product is up to 8 hours from the time of calibration.  It 
should be noted that the investigator orders the investigational product for a certain time 
point of administration.  The PET production center will then provide an investigational 
product containing sufficient activity for the treatment at time of administration.  The 
investigational product should be prepared in a way that there will be enough activity for an 
administration at least up to 60 minutes later than the planned time of injection.  The 


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information on required volume at time of administration is provided to the nuclear medicine 
physician (or designee) by the PMF. 
All non-radioactive transport containers (opened, unopened, or empty) must be returned to 
the PET production center.  Containers (vials) that are radioactive or contained radioactive 
materials must be disposed of (after decay) at the PET imaging site after the study according 
to the local standard operating procedures/policies.  The disposal needs to be documented 
and filed in the investigator site file. 
5.9 
Drug Accountability 
The investigator (or designated personnel) will confirm receipt of the investigational product 
in writing and will use the investigational product only within the framework of this clinical 
study and in accordance with this study protocol.  For each subject he/she will keep a record 
of the investigational product dispensed including a printout providing relevant parameters of 
synthesis and formulation of the investigational product, and all other accompanying forms 
to the investigational product.  These documents are to be filed in the investigator site file. 
Overall drug accountability and reconciliation will be completed by the sponsor or its 
representative.  A list of investigational product vials and other materials that were returned, 
or disposed of, must be prepared and signed by the principal investigator or an appropriately 
qualified designee as documented in the study site responsibility sheet.  An overall 
accountability and reconciliation form of the investigational product will also be prepared 
and completed.  If there are any discrepancies, an explanation for these must be provided. 
Receipt, distribution, and return of the investigational product must be properly documented 
on the forms provided by the sponsor giving the following information:  study protocol 
number, sender, receiver, date, quantity, batch number, expiration date, and retest date, if 
applicable. 


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6 
THERAPIES OTHER THAN INVESTIGATIONAL PRODUCT 
6.1 
Prior and Concomitant Therapy 
Subjects will be excluded from the study if they are taking regular medication that impairs 
cognition (as determined by the investigator), e.g., subjects who have received large doses of 
hypnotics, anxiolytics, tricyclic antidepressants, and/or antipsychotics.  
Subjects must not have any (even) short-term medication of large doses of hypnotics, 
anxiolytics, tricyclic antidepressants, and/or antipsychotics within 2 days before neuro-
cognitive testing.  In these cases, neuro-cognitive testing should be postponed.  
Subjects will be withdrawn from the study if they subsequently commence regular 
medication that impairs cognition (as determined by the investigator) during the study, 
i.e., large doses of hypnotics, anxiolytics, tricyclic antidepressants and/or antipsychotics. 
Subjects already being treated with acetylcholinesterase inhibitors and/or memantine should 
be on stable doses of these medications for 30 days prior to screening.   
If treatment with an acetylcholine esterase inhibitor and/ or memantine is initiated during the 
trial, the doses of these medications should be stable for 30 days before the next 
neurocognitive assessment. 
After a subject has progressed to dementia, exposure to disease-modifying therapy would not 
require withdrawal from participation. Subjects initiating disease-modifying therapy before 
progression to dementia would need to be withdrawn from participation.   
6.2 
Post-Study Therapy  
Not applicable. 


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7 
SCHEDULE OF EVALUATIONS AND VISIT DESCRIPTION 
7.1 
Schedule of Evaluations 
Evaluations will be performed during a period of 36 months, in addition to a screening period 
of maximum 8 weeks.  A schedule of evaluations is provided in the Schedule of Study 
Events (see Appendix 1). 
7.2 
Visit Description 
7.2.1 
Screening Visit 
• Preliminary review of inclusion and exclusion criteria 
• Obtain signed informed consent for study participation 
• Allocation of unique subject number; this number will be used to document the 
subject data in the eCRF and enrollment log 
• Interview including the following subject-specific characteristics 
- 
Demographic data 
- 
Postmenopausal status 
- 
Medical/surgical history (including concomitant diseases) 
- 
History of MCI 
- 
Family history of dementia 
- 
Documentation of diagnostic tests outside this study related to MCI diagnosis 
- 
Concomitant medications (medication history, see Section 6.1). 
• A battery of cognitive and functional performance evaluations will be conducted at 
the screening visit as described in Section 8.1.4 
• Vital signs (heart rate and blood pressure after at least 3 minutes in resting position) 
• Physical examination including height and weight and a review of major body 
systems. Any clinically relevant finding is to be documented as baseline finding. 
• Neurological examination  
• Urine collection for routine urinalysis 
• Blood draw, see Section 8.4.3 
- 
for routine blood hematology and chemistry parameters 
- 
for genetic analysis  
- 
for special laboratory tests related to cognitive impairment 
• Brain MRI (unless scan with adequate acquisition sequences is available from 
previous 6 months) 
• Final check of inclusion/exclusion criteria 


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7.2.2 
Baseline Testing Visit (within 7 days before [18F]NAV4694 injection) 
• A battery of cognitive and functional performance evaluations will be conducted at 
the baseline visit as described in Section 8.1.5 
• Physical examination 
• Safety laboratory samples will be collected, including samples for routine 
hematology, chemistry and urinalysis as described in Section 8.4.1 
• Concomitant medication review, see Section 6.1 
• Assessment of adverse events, see Section 8.3.1 
7.2.3 
Baseline [18F]NAV4694 Injection and PET Imaging Visit 
7.2.3.1 
Before Injection 
The baseline visit will take place on the PET imaging day prior to investigational product 
injection and will comprise the following procedures/assessments: 
• Body weight measurement 
• Insert intravenous catheter and check localization of indwelling catheter by test 
injection of normal saline 
• Vital signs (within 10 minutes prior to investigational product injection, subject in 
resting position for at least 3 minutes), see Section 8.3.2.2 
• Electrocardiogram (within 10 minutes prior to investigational product  injection, 
subject in resting position), see Section 8.3.2.2) 
• Assessment of adverse events, see Section 8.3.1 
7.2.3.2 
Administration of [18F]NAV4694 (≤ 56 days after the screening visit) 
Investigational product injection will comprise activities described in see Section 5.3. 
• Measurement of the [18F] radioactivity in the syringe immediately prior to injection 
• [18F]NAV4694 injection via slow IV injection followed by 10 mL saline flush (Note:  
The use of a motorized power injection system is not permitted) 
• Remove injection system  
• Measure residual [18F] radioactivity in the syringe and injection system immediately 
after injection 
• Assessment of adverse events, see Section 8.3.1 


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7.2.3.3 
Post [18F]NAV4694 Injection 
• Vital signs (within 10 minutes and 30 ± 5  minutes post injection), see Section 8.3.2.2 
• Electrocardiogram (within 10 minutes post injection), see Section 8.3.2.3 
• PET Imaging Session (scanning from 50 to 70 minutes post injection) 
• Assessment of adverse events, see Section 8.3.1 
7.2.4 
Safety Follow-Up Visit (24 ± 4 hours after PET imaging visit) 
This visit will comprise the following procedures/assessments: 
• Vital signs 
• Physical examination 
• Electrocardiogram 
• Blood draw for routine blood hematology and chemistry parameters, see Section 8.4.3 
• Urine collection for routine urinalysis 
• AE assessment 
• Concomitant medication assessment 
7.2.5 
Telephone Follow-up 7 (+ 3) days post injection 
A telephone follow-up will be performed with the subject 7 days post injection after study 
administration.  Focus of the interview is to determine any AEs that may have occurred 
subsequent to the previous post-imaging safety assessment by questioning the subject or 
study partner about any changes in the subject’s health or concomitant medications. 
7.2.6 
Neuro-Cognitive Follow-up Examinations at 6-, 12-, 18-, 24-, 30-, and 36- 
Months (± 30) days post injection 
• A battery of cognitive and functional performance evaluations will be conducted at 
the 6-, 12-, 18, 24-, 30-, and 36-month follow-up visits as described in Section 8.1.6. 
Neuro-cogntive examinations at 18-months should be completed in the 30 days 
before PET imaging. 
• DSM-IV-TR criteria will be used to determine whether a subject has dementia and if 
so, which type.  Probable AD will be confirmed using criteria from NINCDS-
ADRDA (McKhann et al., 1984). 


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7.2.7 
Additional 18-Month Activities (in a subset of 20 subjects) 
7.2.7.1 
Within 30 Days Before 18-month PET Imaging 
• MRI of the brain  
• A battery of cognitive and functional performance evaluations will be conducted as 
described in Section 8.1.5. 
 
7.2.7.2 
Within 7 Days Before 18-month PET Imaging  
• Neurological exam 
• Physical examination 
• The investigator will review all of the clinical and neuro-cognitive data gathered for each 
subject over the course of the trial to determine the diagnostic status (progression to 
Alzheimer’s dementia).   
• DSM-IV-TR criteria will be used to determine whether a subject has dementia and if so, 
which type.  Probable AD will be confirmed using criteria from NINCDS-ADRDA 
(McKhann et al., 1984). 
• Safety laboratory samples will be collected include samples for routine hematology, 
chemistry and urinalysis as described in Section 8.4.1 
• AE assessment 
• Concomitant medication assessment 
7.2.7.3 
PET Imaging and Follow Up 
• PET imaging - the same procedures will be performed as in the Baseline [18F]NAV4694 
Injection and PET Imaging Visit described in Section 7.2.3 
• Follow-up safety visit (24 ± 4 hours after PET imaging visit) - the same procedures will 
be performed as described in Section 7.2.4. 
• Follow-up telephone contact (7 days [+3 days] after PET imaging visit) - the same 
procedures will be performed as described in Section 7.2.5.  
 


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7.2.8 
Neuro-Cognitive Testing Schedule (screening and 6-, 12-, 18-, 24-, 30-, 
and 36-month visits) 
Neuro-cognitive assessments will be conducted according to the schedule shown in Table 1. 
Table 1. 
Neuro-Cognitive Testing and Assessment of Progression to 
Dementia 
 
Visit 
Assessmentsa 
Screening 
Baseline 
6-, 12-,18-, 24-, 
30-, and 36-
month visits 
CDR 
X 
 
X 
ADCS-MCI-ADL 
 
X 
X 
MMSE 
X 
 
X 
DSM-IV-TR criteria for dementia 
X 
 
X 
DSM-IV-TR criteria for major depressive disorder, 
recurrent  
X 
 
X 
RAVLT 
  
X 
X 
ADAS-cog 
 
X 
X 
ADAS-cog = Alzheimer’s Disease Assessment Scale-Cognitive; ADCS-MCI-ADL = Alzheimer’s Disease 
Cooperative Study Scale for Activities of Daily Living in Mild Cognitive Impairment CDR = Clinical 
Dementia Rating; DSM-IV-TR =  Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text 
revision; RAVLT = Rey Auditory Verbal Learning Test 
a 
See Sections 8.1.4, 8.1.5, and 8.1.6 for descriptions 
 
The investigators or nominated designee(s) responsible for conducting the neuro-cognitive 
tests will be blind to the results of the [18F]NAV4694  PET scans.  
7.2.9 
End of Study  
For the entire study, end of study is defined as last subject last visit. 


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8 
PROCEDURES AND VARIABLES 
8.1 
Population Characteristics 
8.1.1 
Demographic and Other Baseline Characteristics 
Approximately 120 evaluable male or female subjects with MCI aged ≥ 55 years will be 
included. Subjects must have ≥ 6 years of education. Additional prerequisites for 
participation are adequate visual and auditory acuity to complete neuro-cognitive testing, 
availability of reliable caregiver who is capable to provide correct information about the 
subject’s clinical symptoms and completion of the clinical and neuro-cognitive evaluation as 
well as assignment of a diagnosis of MCI. Subjects must have an MMSE score of 24-30 and 
a CDR score of 0.5. 
8.1.2 
Medical and Surgical History 
Medical and surgical histories are to be recorded for the following body systems: head, ear, 
eye, nose, throat, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, 
endocrine, neurological, and psychiatric and skin/dermatological.   
As part of the medical history, the date of the last spontaneous menstruation will be recorded, 
if childbearing potential is not excluded by surgical sterilization and/or hysterectomy. 
8.1.3 
Prior and Concomitant Medication 
All prior medication used within the last 30 days before the first screening examination and 
concomitant medications will be documented.  
For instructions regarding prior and concomitant medications, please refer to Section 6. 
8.1.4 
Inclusion Criteria Assessments at Screening to Confirm Mild Cognitive 
Impairment 
To determine whether a subject has MCI and no dementia, the following assessments will be 
performed by the on-site clinician during screening. 
Clinical Dementia Rating scale (see Section 8.1.4.1) 
Mini-Mental State Examination (see Section 8.1.4.2) 
In addition, the on-site clinician will determine that the subject does not meet the following 
criteria at screening. 
• Diagnostic and Statistical Manual of Mental Disorders, Version 4, Text Revised criteria 
for dementia (see Section 8.1.4.3) 


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If the result of any of these assessments does not meet the requirements specified in inclusion 
criteria (see Section 4.1.1), the subject will not be included in the study. 
If the subject meets all of the requirements specified in inclusion criteria, the following 
assessment will be made to determine whether depression may be responsible for or 
contributing to the clinical diagnosis of MCI. 
• Diagnostic and Statistical Manual of Mental Disorders, Version 4, Text Revised criteria 
for a major depressive disorder, recurrent (see Section 8.1.4.4) 
If the subject is suffering from major depressive disorder, recurrent, he/she will not be 
included in the study (see exclusion criterion 9, Section 4.1.2). 
8.1.4.1 
Clinical Dementia Rating Scale 
The CDR scale (Hughes et al., 1982; Morris, 1993) has become the gold standard for global 
rating of primary degenerative dementia and has been extensively validated (Morris et al., 
1988; Berg et al., 1992; Galasko et al., 1995).  Its advantage is that it incorporates the 
clinician’s assessment of subjects’ varying educational, cultural, socio-economic, and other 
types of bias in its staging. 
The CDR is a dementia rating instrument that uses a 5-point scale to characterize 6 domains 
of cognitive and functional performance applicable to AD and related dementias:  Memory, 
Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and 
Personal Care.  The necessary information to make each rating is obtained through a 
semi-structured interview of the subject and the subject’s “study partner.” 
In addition to ratings for each domain, a global CDR score may be calculated through the use 
of the following algorithm.  Memory is considered the primary category and all others are 
secondary.  The global CDR score is equal to the memory score if at least three secondary 
categories are given the same score as memory.  When the memory score is 0.5, the global 
CDR score equals 1 if at least three of the other categories are scored 1 or greater.  If the 
memory score is 0.5, the global CDR score cannot be 0; it can only be 0.5 or 1.  If the 
memory score is 0, the global CDR score equals 0 unless there is impairment (0.5 or greater) 
in two or more secondary categories, in which case the global CDR score equals 0.5.  
Whenever three or more secondary categories are given a score greater or less than the 
memory score, the global CDR score equals the score of the majority of the secondary 
categories from the side of the memory score that has the greater number of secondary 
categories.  If three secondary categories are scored on one side of the memory score and two 
secondary categories are scored on the other side of the memory score, the global CDR score 
equals the memory score. 
The above rules do not cover all possible scoring combinations. Unusual circumstances are 
scored as follows. 


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• With ties in the secondary categories on one side of the memory score, choose the tied 
scores closest to the memory score for the global CDR score.  For example, if the 
memory score and another secondary category equal 3, two secondary categories equal 2, 
and two secondary categories equal 1, then the global CDR score equals 2. 
• When only one or two secondary categories are given the same score as the memory 
score, the global CDR score equals the memory score as long as no more than two 
secondary categories are on either side of the memory score. 
• When the memory score is 1 or greater, the global CDR score cannot be 0; in this 
circumstance, the global CDR score equals 0.5 if the majority of secondary categories 
are 0. 
This global CDR score is useful for characterizing and tracking a subject's level of 
impairment/dementia (Morris, 1993). 
0 = Normal (no dementia) 
0.5 = Uncertain or deferred diagnosis  
1 = Mild dementia 
2 = Moderate dementia 
3 = Severe dementia 
The subjects to be included in this study must have a global rating score of 0.5 on the CDR 
and a diagnosis of MCI.  In addition scores in each of the six CDR domains will be included 
in the source documentation. 
8.1.4.2 
Mini-Mental State Examination 
The MMSE (Folstein et al., 1983) is the most widely used and studied screening measure of 
cognitive impairment.  It has the advantage of brevity, ease of administration (approximately 
10 minutes), and high test/retest and inter-rater reliability.  The MMSE is rated on a scale 
ranging from 0 (worst possible outcome) to 30 (best possible outcome, no measureable 
cognitive deficits).  Scores below 24 are traditionally taken as indicative of dementia, 
although the MMSE score alone will not be decisive in making a dementia diagnosis. 
The most sensitive items on the MMSE for dementia of the Alzheimer’s type are delayed 
recall of 3 items and orientation. 
8.1.4.3 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision Criteria for Dementia 
The DSM-IV-TR defines the diagnostic criteria for dementia as follows. 
A. The development of multiple cognitive deficits manifested by both 
1.  
memory impairment (impaired ability to learn new information or to recall 
previously learned information) and 


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2.  
one (or more) of the following cognitive disturbances: 
a. aphasia (language disturbance), or 
b. apraxia (impaired ability to carry out motor activities despite intact motor 
function), or 
c. agnosia (failure to recognize or identify objects despite intact sensory 
function), or 
d. disturbance of executive functioning (i.e., planning, organizing, sequencing, 
abstracting) 
B. The cognitive deficits in criteria A1 and A2 each cause significant impairment in social 
or occupational functioning and represent a significant decline from previous level of 
functioning. 
C. The course is characterized by gradual onset and continuing decline. 
D. The cognitive deficits in criteria A1 and A2 are not due to any of the following. 
1.  
other central nervous system conditions that cause progressive deficits in memory 
and cognition (e.g., cerebrovascular disease, Parkinson’s disease, Huntington’s 
disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor) 
2.  
systemic conditions that are known to cause dementia (e.g., hypothyroidism, 
vitamin B12 or folic acid deficiency, niacin deficiency, hypocalcemia, 
neurosyphilis, human immunodeficiency virus infection) 
3.  
substance-induced conditions 
E. The deficits do not occur exclusively during the course of a delirium. 
F. The disturbance is not better accounted for by another Axis I disorder (e.g., major 
depressive disorder, schizophrenia). 
8.1.4.4 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text 
Revision Criteria for Major Depressive Disorder, Recurrent 
Depression is a frequent accompanying symptom of dementia of the Alzheimer’s type (and 
other dementias), and severe, late-onset depression can lead to a similar degree of cognitive 
impairment.  In the present study, the DSM-IV-TR will be used to assist the on-site clinician 
in objectifying depressive symptoms in detecting/ruling out major depressive disorder, 
recurrent diagnosed more than 5 years prior to participation in this study as a cause for 
symptoms of cognitive impairment.  Results of the assessment will be recorded in the source 
documentation. 


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The DSM-IV-TR defines the criteria for Major Depressive Disorder, Recurrent as follows: 
A. Presence of two or more Major Depressive Episodes (Note:  To be considered separate 
episodes, there must be an interval of at least 2 consecutive months in which criteria are 
not met for a Major Depressive Episode.) 
B. The Major Depressive Episodes are not better accounted for by Schizoaffective Disorder 
and are not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional 
Disorder, or Psychotic Disorder Not Otherwise Specified. 
C. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode.  
(Note:  This exclusion does not apply if all of the manic-like, mixed-like, or hypomanic-
like episodes are substance or treatment-induced, or are due to the direct physiological 
effects of a general medical condition.) 
 
Criteria for Major Depressive Episode: 
A. Five or more of the following symptoms have been present during the same 2-week 
period and represent a change from previous functioning; at least one of the symptoms is 
either (1) depressed mood or (2) loss of interest or pleasure.  (Note:  Do not include 
symptoms that are clearly due to a general medical condition, or mood-incongruent 
delusions or hallucinations.) 
1. Depressed mood most of the day, nearly every day, as indicated by either subjective 
report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).  
(Note:  In children and adolescents, can be irritable mood.) 
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the 
day, nearly every day (as indicated by either subjective account or observation made 
by others) 
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 
5% of body weight in a month), or decrease or increase in appetite nearly every day.  
(Note:  In children, consider failure to make expected weight gains.) 
4. Insomnia or hypersomnia nearly every day 
5. Psychomotor agitation or retardation nearly every day (observable by others, not 
merely subjective feelings of restlessness or being slowed down) 
6. Fatigue or loss of energy nearly every day 
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being sick) 
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either 
by subjective account or as observed by others) 
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, or a suicide attempt or a specific plan for committing suicide 
 
B. The symptoms do not meet criteria for a Mixed Episode. 
C. The symptoms cause clinically significant distress or impairment in social, occupational, 
or other important areas of functioning. 


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D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug 
of abuse, a medication) or a general medical condition (e.g., hypothyroidism). 
E. The symptoms are not better accounted for by Bereavement, i.e., after the loss of a loved 
one, the symptoms persist for longer than 2 months or are characterized by marked 
functional impairment, morbid preoccupation with worthlessness, suicidal ideation, 
psychotic symptoms, or psychomotor retardation. 
8.1.5 
Assessment of Cognitive Performance at Baseline 
The following three tests will be performed: 
• Alzheimer’s Disease Cooperative Study Scale for Activities of Daily Living in Mild 
Cognitive Impairment (see 8.1.5.3) 
• Rey Auditory Verbal Learning Test (see Section 8.1.5.1) 
• Alzheimer’s Disease Assessment Scale-Cognitive (see 8.1.5.3) 
8.1.5.1 
Alzheimer’s Disease Cooperative Study Scale for Activities of Daily Living in 
Mild Cognitive Impairment 
This interview was developed to assess impairment of everyday tasks in non-demented 
subjects.  It is highly sensitive and covers 18 areas. The overall score varies between 0 (worst 
performance) and 78 (best performance). 
Subjects with minor limitations on complex ADL should not be excluded from the study.  
However, to ensure that subjects with significant functional impairment, including the loss of 
basic ADL and who might already have dementia, are not included, the ADCS-MCI-ADL 
will be used to assess deficits in more complex everyday tasks. 
This cut-off is based on results from the German group in an MCI study in which the study 
population was defined as having “No impairment on basic activities of daily living.  More 
complex activities of daily living may be slightly impaired” (Perneczky et al., 2006).  Using 
this definition, a significant difference between healthy normal volunteers and non-demented 
subjects with MCI was found in more complex ADL. 
8.1.5.2 
Rey Auditory Verbal Learning Test  
The Rey Auditory Verbal Learning Test (RAVLT) was developed in the 1940s as a measure 
of verbal learning and memory, including proactive inhibition, retroactive inhibition, 
retention, encoding versus retrieval, and subjective organization (Andersson et al., 2006).   
Testing procedures can be administered in approximately 15 minutes and begin with a list of 
15 words, which are read aloud by an examiner at the rate of one per second.  The subject is 
asked to repeat all remembered words, in any order.  This sequence is repeated five times.  A 
second list of 15 words is presented with only one recall attempt allowed.  Finally, the 
subject is asked to recall all words possible from the original list (Schmidt, 2010).  


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The RAVLT is scored by using the RAVLT Record Sheet and Score Summary which 
accompanies the RAVLT Handbook (Schmidt, 2010). 
8.1.5.3 
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-cog)  
The Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog; (Rosen et al., 1984)) 
will be used to assess cognitive performance. 
The 13 items in the ADAS-Cog (Mohs et al., 1997) will be used to assess the general 
cognitive performance of subjects in the study.  This is a well-accepted assessment 
instrument that has been used in large number of investigational studies and clinical trials.  
The ADAS-Cog is a brief cognitive test battery that assesses learning and memory, language 
production, language comprehension, constructional praxis, ideational praxis, and 
orientation. 
The 13 test items should be given in the order indicated. The Word Recall task is given first; 
the Delayed Word Recall task should be done approximately 5 minutes later.   
The 13 items are scored in the ranges given below.  The total ADAS-Cog 13-item score can 
range from 0 to 85; higher scores reflect more severe cognitive performance. 
- 
Word Recall  
 
 
 
 
0 to 10 
- 
Commands  
 
 
 
 
 
0 to 5 
- 
Constructional Praxis   
 
 
0 to 5 
- 
Executive Function   
 
 
0 to 10 
- 
Naming   
 
 
 
 
 
0 to 5 
- 
Ideational praxis  
 
 
 
0 to 5 
- 
Orientation  
 
 
 
 
 
0 to 8 
- 
Word Recognition  
 
 
 
0 to 12 
- 
Remembering Test Instructions  0 to 5 
- 
Comprehension   
 
 
 
0 to 5 
- 
Word Finding   
 
 
 
 
0 to 5 
- 
Spoken Language Ability  
 
0 to 5 
 
 
 
Number Cancellation   
 
 
0 to 5 
For the 6-, 12-, 18-, 24-, 30-, and 36-month visits the principal investigator will conduct the 
clinical and neurological assessment on all subjects who have returned and will compare 
results with those of the previous neuro-cognitive examination. 
Finally, the assessment of progression from MCI to dementia will be conducted by the 
principal investigator or investigator under the close consultation with the principle 


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investigator. These physicians will be blind to the results of the investigational PET scan. 
The final decision will be based on the neuro-cognitive test results over time as well as on an 
interview of the subject together with the study partner or spouse. 
8.1.6 
Assessment of Cognitive Performance at the 6-, 12-, 18-, 24-, 30-, and 36-
Month Assessments  
The following assessments will be performed by the on-site clinician at the 6-, 12-, 18-, 24-, 
30-, and 36-month visits 
• The CDR scale (see Section 8.1.4.1) 
• The ADCS-MCI-ADL (see Section 8.1.5.1) 
• The MMSE (see Section 8.1.4.2) 
• RAVLT (see Section 8.1.5.1) 
• ADAS-Cog (see Section 8.1.5.3) 
• DSM-IV-TR criteria of dementia not fulfilled (see Section 8.1.4.3) 
• DSM-IV-TR criteria for a major depressive disorder, recurrent (see Section 8.1.4.4) 
8.1.7 
MRI Examination of the Brain  
Brain MRI scanning (both 3D volumetric T1- and T2-weighted images) enables detailed 
visualization of structural abnormalities that assist, either in substantiating the diagnosis of 
probable AD (i.e., mesial temporal lobe [MTL] atrophy), or in identifying cerebral lesions 
that constitute pre-specified exclusion criteria.  In the present study, a non-contrast enhanced, 
T2 weighted brain MRI using a 1.5 or a 3 Tesla scanner and a non-contrast enhanced 3D 
volumetric T1-weighted brain MRI, along with the FLAIR sequence, must be performed 
during screening.  In addition to facilitating the above diagnostic tasks, the digital 3D 
T1-weighted images are required by the sponsor for co-alignment with the PET image data to 
create the anatomy-based regions of interest (ROIs) required for subsequent subject level 
visual and quantitative analysis of [18F]NAV4694 tracer uptake. 
T1-weighted acquisition procedure 
A T1-weighted, 3D sequence (e.g., MPRAGE or SPGR) is required, and adherence to the 
manufacturer specific recommendations stated in this protocol (below) are mandatory.  The 
total scan time is expected to be in the range of 20 to 30 minutes.  The field of view (FOV) 
must include the cerebellum and pons.  The recommended acquisition parameters for the T1 
3D sequence are displayed in Table 2.  In addition, approximately 6 oblique slices (slice 
thickness 5 mm, interslice gap 1 mm, in plane resolution 0.8 x 1.0 mm) parallel to the 
brainstem axis should be performed from a midsagittal scout image. 


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T2 acquisition procedure 
For detailed assessment of cerebral vasculature, a T2-weighted double echo sequence should 
also be performed.  The manufacturer specific recommended acquisition parameters for the 
T2 sequence are displayed in Table 2. 
Both the T1 and T2 weighted MRI scans are to be evaluated by a qualified on-site radiologist 
for structural pathology, including changes indicative of major vascular disease/ischemia, 
normal pressure hydrocephalus, and/or, MTL atrophy.  Medial temporal atrophy and 
ventricular volume assessment will be performed at MNI (New Haven, CT).  
FLAIR procedure 
The FLAIR procedure is also displayed within Table 2. Navidea has provided general 
guidance in acquiring the FLAIR sequence which should be performed along with the T1, 
and T2 sequences, and assessed to determine eligibility of the subject.  
Optional DWI procedure 
An optional DWI sequence can be used at the discretion of the investigator.  General 
guidance on this sequence is also displayed in Table 2. 
 


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Table 2. 
Manufacturer Specific Recommended Acquisition Parameters for 
Volumetric Required T1 3D MRI, T2, FLAIR and Optional DWI 
Images. 
 
FLAIR = Fluid Attenuated Inversion Recovery;  DWI = DiffusionWeighted Imaging; ETL = Echo Train 
Length; SPGR = Spoiled Gradient Recalled; TFE = Turbo Field Echo; MP-RAGE = Magnetization-
Prepared Rapid Acquisition with Gradient Echo; T = Tesla; GRE = Gradient Echo = AP = Anterior-
Posterior, RL-Right-Left,  
 


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At a minimum, the T1-weighted, 3D volumetric MRI images must be forwarded in Digital 
Imaging and Communications in Medicine (DICOM) 3.0 format to the imaging core 
laboratory, which is responsible for quality control, image data preparation, archiving, and 
subsequent performance of the independent blinded read (at MNI).  The details of performing 
the image transfer will be discussed with the study team on-site radiologist during the 
technical site set-up visit meeting with MNI.  . 
Assessment as to whether the brain MR images are normal (age-appropriate) or abnormal 
will be determined by an investigator or designee. 
8.1.8 
PET Image Acquisition  
Preparation of study participants 
Preparation of study participants consists of inserting an IV catheter (e.g., Venflow) into a 
vein, preferably in the study subject’s non-dominant arm.  Correct localization of the 
indwelling cannula must be ensured by test injection of normal saline prior to injection of the 
investigational product. 
Injection of the investigational product 
[18F] radioactivity in the syringe will be measured immediately prior to injection using a 
suitable counter.   
A tracer dose of 300 MBq (8.1 mCi) ± 20% [18F]NAV4694 with a substance dose not 
exceeding a mass of 40 µg should be administered as a slow IV injection.  The injection 
volume will be ≤ 10 mL. 
After injection of the investigational product, the cannula must be flushed with 10 mL saline.  
Measurement and documentation of the injected radioactivity 
[18F] radioactivity must be measured in the syringe and injection system immediately after 
injection using a suitable counter. 
The following data will be documented by the investigator in the source documentation: 
• Batch number  
• Date and time of end of calibration of the system used to measure radioactivity before 
and after injection 
• Date and time of expiration  
• Tracer mass per volume (µg per mL) 
• Radioactivity in syringe prior to injection (MBq, measured) and time of measurement  
• Time of injection 
• Volume of injection (mL) 


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• Radioactivity in syringe and injection system after injection (MBq, measured) and time 
of measurement 
For a fraction of the above data, the tear-off part of the label is the source document.  It will 
be stored in the ISF.  
Note: The data documented by the investigator will be used by the sponsor to calculate the 
following parameters:  Tracer mass injected (µg, calculated as the product of tracer mass per 
volume and volume of injection) and the injected radioactivity (MBq, calculated from the 
radioactivity measured prior to and after injection, the time point of injection, and the time 
points of radioactivity measurement).  If the counter used for measurement of radioactivity is 
calibrated for the time of injection, the injected radioactivity will be obtained by simple 
subtraction of the radioactivity measured in the syringe and injection system after injection 
from the radioactivity measured in the syringe prior to injection.  Furthermore, the time 
difference between the end of synthesis and the time of injection will be recorded. 
Placement of subject and head immobilization 
Images will be acquired using dedicated PET or PET-CT scanner capable of 3D PET image 
acquisition.  Study participants will be placed on the table of the PET or PET-CT scanner.  
To minimize head motion, the subject’s head will be immobilized using the institution’s head 
holder/fixation equipment (e.g., thermoplastic mask, paper tape).  The head of the subject 
will be positioned in the scanner with the total brain within the FOV.  Special attention must 
be paid to include the entire cerebellum in the image as this region serves as a reference 
region for subsequent quantification. 
Measurement of attenuation correction and emission scan acquisition 
After the subject is lying comfortably with the head immobilized, attenuation correction will 
be measured.  Measurement of attenuation correction must be started early enough to allow 
the first emission scan to proceed at the predefined time point (50 + 5 minutes after 
injection).  Attenuation correction must be performed via low dose CT or isotope 
transmission brain scan per camera protocol before start of the emission scan.  A scout scan 
to determine proper patient positioning is suggested to occur prior to the transmission scan. 
The 3D PET brain emission scanning should be performed in four 5 minute frames from 
50 to 70 minutes post injection using the following general guidelines: 
• Resolution of at least 4 to 5 mm full width half maximum (FWHM) value of the scanner. 
• 3D mode, zoom = 2.0 
• Use of a Neuroshield or similar scatter protector (optional) 
• Matrix size 128 x 128 x 64 
• Voxel size 2.5 x 2.6 x 2.4 mm (matched to the FWHM of the scanner) 
• Standardized correction for radioactive decay and scatter 


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• Data acquisition in 4 successive 5 minutes frames (4 x 5) 
• Iterative OSEM reconstruction algorithm (e.g., 4 iterations, 16 subsets), axial 
post filtering (Gaussian, FWHM 5.0 mm) 
 
Note: Individualized, site-specific acquisition parameters will be determined during the 
technical site visit. 
PET image optimization, quality control, image data transfer 
The sponsor and/or image core laboratory (MNI) will provide the on-site radiologist 
physician with any technical support necessary to ensure optimal PET image acquisition and 
rapid transfer to the image core laboratory.  To optimize parameters for PET acquisition for 
multi-center and multi-camera pooling of image data, a technical site set up visit will be 
performed by the image core laboratory (MNI) at each PET center before the study begins.  
The visit will include an overall evaluation of the center’s camera and related quality 
assurance (QA) procedures, processes, and controls over imaging data and the camera-
specific acquisition protocol developed, tested using a 3D Hoffman brain phantom, and 
saved.  Finally, image reconstruction and filtering, anonymization and DICOM conversion, 
as well as the logistics of image data transfer will be discussed.  All centers must agree to 
comply with the image acquisition methods, processing, and raw image data storage and 
transfer discussed during this meeting.  Each center will be provided with a technical site 
binder containing core laboratory contact details, a technical operations manual, and image 
data transfer documents, as well as a technical/correspondence log.  Recruitment of subjects 
into the study cannot proceed at a center until this visit has been performed. 
The investigator will document the manufacturer and type of the PET or PET/CT scanner 
used in both the subject’s file and eCRF.  At each center, the same PET or PET/CT scanner 
should be used during the entire course of the study, and any updates to hardware or software 
should be avoided.  If any changes are anticipated to occur, they must be reported to the 
image core laboratory and sponsor prior to being made, if at all possible. 
To facilitate rapid image QA and preparation of the images for the independent blinded read, 
each PET center must provide the [18F]NAV4694 PET image data set for each participant to 
the image core laboratory in DICOM 3.0 format – as close to within 24 hours of image 
acquisition as possible.  Transfer to the image core laboratory will be performed via secure 
file transfer protocol (sFTP) connection (preferred) or CD-ROM.   
PET Image QA, preparation, and storage; independent blinded read 
Upon receipt of the image data set by the image core laboratory, the anonymized 
[18F]NAV4694 PET images will be technically and scientifically quality assured 
(i.e., evaluated for proper conversion, interpretability, and diagnostic quality) and prepared 
for an independent blinded read.  All study participants who have a complete set of 
[18F]NAV4694 PET image data (including all time frames for the imaging period) acquired 
according to the study and camera specific protocol, irrespective of whether they are 


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regarded as interpretable by the on-site investigator, will be included in the blinded read.  
Feedback will be given to the respective center in case of technical and/or image quality 
issues arising.  In case of poor image quality, a pre-specified escalation plan between the 
image core laboratory and the sponsor will be implemented and recruitment stopped at that 
particular center until the quality issue is resolved.  All images will be stored in DICOM 
format, and a complete audit trail documenting any changes to the DICOM file headers or 
other manipulation of the data will be maintained. 
The efficacy evaluation of the [18F]NAV4694 PET images will be based on an independent 
blinded read, hosted by MNI (in New Haven, CT) and performed by 3 independent 
radiologists/nuclear medicine physicians experienced in the field of PET neuroimaging.  The 
readers will be blinded to all clinical data.  The readers will not be affiliated with the on-site 
evaluation of subjects at any of the study centers.  The blinded read will be conducted in 
accordance with GCP/ICH guidelines and the sponsor’s global and imaging core laboratory’s 
clinical standard operating procedures.  An electronic CRF (eCRF) will be used to ensure 
that the images and the diagnostic findings are properly aligned and to ensure that all 
questions are answered completely by the blinded readers.  The details of the independent 
blinded read will be presented in the IRC. 
8.1.8.1 
Subject Level Visual Assessment (Primary Efficacy Endpoint) 
The subject level visual assessment will be performed both by the independent blinded 
readers and by the on-site radiologist/nuclear medicine physician.  The visual assessment 
procedure of the PET scans specified below (based on the method originally described by 
Rowe et al. (2008) and modified by Barthel et al. (2011) for the PET tracer florbetaben and 
adapted for [18F]NAV4694) must be followed and the results recorded in the source 
documentation.   
Briefly, for each subject with a complete image data set, the independent blinded readers and 
the on-site investigators are to visually assess the regional tracer uptake score (RTUS) for the 
4 pre-specified brain regions (frontal cortex, posterior cingulate/precuneus, lateral temporal 
cortex, and the parietal cortex; see Table 3 and Table 4).   
As mentioned above, the on-site radiologist/nuclear medicine physician as well as the 
independent blinded readers (both) will assess the subject level score based on whether an 
RTUS score of 1 is obtained in all of the 4 pre-specified brain regions (subject level score of 
1) or if an RTUS score of 2 is obtained for any or all of the 4 pre-specified brain regions 
(subject level score of 2).  No deviations from this rule will be allowed. 
The above is to be performed for the imaging window 50 to 70 minutes post injection, both 
the onsite radiologist/nuclear medicine physician and the independent blinded reader will 
perform the visual assessments on the basis of the PET images alone, i.e., without 
co-registration of the MRI brain scans. 
Gray scale only is permitted as the display mode for the subject level assessment by the 
independent blinded readers.   The readers should select the mid-sagittal and transverse slices 


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at the level of the cerebellar white matter in which this region is best visualized.  This region 
will be chosen as the reference region for visual interpretation.   
The typical appearance of images is then as follows: 
Negative images (no cortical tracer uptake):  Gray matter in the respective pre-specified 
region appears of lower intensity when compared with the maximum white matter intensity 
in that region. The best way of determining this so called “target” white matter intensity is to 
compare with that of the white matter intensity in the cerebellum. 
Positive images (cortical tracer uptake): Gray matter region in the respective pre-specified 
region is of similar or higher intensity as that of the respective “target” white matter region.  
Per gray matter region, an RTUS score of 1 or 2 will be assigned, as described in Table 3: 
Table 3. 
Definitions of Regional Cortical Tracer Uptake Scores 
Regional Tracer Uptake Score (RTUS) 
Image Features 
1 
No cortical tracer uptake 
Tracer uptake in gray matter in the region is lower 
than in cerebellar or cortical white matter 
2 
Cortical tracer uptake observed Area of tracer uptake in some part of the region is 
equal to or higher than that present in white matter 
and higher than the cerebellar gray matter uptake 
− the area extends beyond the white matter rim to 
the outer cortical margin and 
− is seen in the majority of the axial slices in the 
respective region 
 


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The on-site radiologist/nuclear medicine physician and the independent blinded readers will 
document the RTUS score as follows: 
Table 4. 
Documentation of Regional RTUS Score 
Gray matter structures 
(cortical areas) 
Enter 1 or 2 
In case of side differences, a score 
of 2 will be documented 
Frontal cortex 
 
Posterior cingulate/precuneus 
 
Lateral temporal cortex 
 
Parietal cortex 
 
 
An overall subject level score will be assigned by “collapsing” scores of the pre-specified 
regions of putative relevance in the pathophysiology of AD into a single score of 1 or 2, as a 
means to assess β-amyloid burden of the brain globally. 
This subject score will be assigned by the 3 independent blinded readers (for the imaging 
window 50 to 70 minutes post injection) as follows:  
1 = Scan without β-amyloid deposition:  Regional cortical tracer binding score of 1 (no 
cortical tracer uptake) in each of the 4 brain regions listed in Table 4. 
2 = Scan with β-amyloid deposition:  Regional cortical tracer binding score of 2 (cortical 
tracer uptake) in at least 1 of the 4 brain regions listed in Table 4. 
 
The on-site radiologist/nuclear medicine physician as well as the independent blinded reader 
must classify the whole brain assessment score as 1 or 2 on the basis of the individual RTUS 
scores in the 4 brain regions.  
 
8.1.8.2 
Subject Level Quantitative Assessment (Secondary Efficacy Endpoints) 
Quantitative assessment of the [18F]NAV4694 PET image data will be performed by one 
experienced nuclear medicine expert at the image core laboratory for the image data sets 
acquired from 50 to 70 minutes post injection.  Brain regions to be used for ROI sampling are 
listed in Table 5. The expert will align the T1 weighted MRI scan and each PET frame using 
a standard mutual information algorithm.  An ROI template will then be applied to the 
aligned MRI for standardized regional brain sampling and will be adjusted on the MRI for 
optimal fit to the respective individual neuroanatomy.  After transfer of the adjusted ROIs to 
the PET study, for each ROI the Bq/cc brain tissue will be extracted for calculation of the 
standard uptake values (SUVs).  For each region, the SUV will be derived from activity in a 
volume of interest (VOI) determined as described above by taking into consideration study 
participant weight and dose injected.  For the subject level assessment, acquired SUV data 


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will then be normalized to the cerebellar cortex resulting in a “region to cerebellar” ratio 
termed the SUVR. 
Table 5. 
The Regions of the Brain Used for ROI Sampling for Subject Level 
Quantitative Analysis 
frontal cortex 
orbitofrontal cortex 
temporal cortex  
lateral temporal cortex 
mesial temporal cortex 
parietal cortex 
pons 
cerebellar cortex 
occipital cortex 
anterior cingulate 
posterior cingulate 
gyrus rectus 
putamen 
caudate nucleus 
cerebellar white matter 
white matter (subcortical white matter) 
thalamus 
 
 
A more detailed description of the various quantification methods and templates used is 
provided in the IRC. 
8.2 
Pharmacokinetics 
No pharmacokinetic investigation will be performed in this study. 
8.3 
Safety 
8.3.1 
Adverse Events 
8.3.1.1 
Definition of Adverse Event 
The definitions below follow International Conference on Harmonization (ICH) – Good 
Clinical Practice (GCP) (see also ICH Guideline for Clinical Safety Data Management:  
Definitions and Standards for Expedited Reporting). 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
By definition for this study, all untoward medical occurrences beginning on the day of 
injection through the assessment 7 days post injection are to be reported as AEs.  


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Additionally, untoward medical events occurring prior to the day of injection and after the 
7 day post injection follow up will only be captured as AEs if they are related to a study 
procedure. SAEs will be reported from the time of consent through the end of participation. 
8.3.1.2 
Categories for Adverse Event Assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 8.3.1.5. 
Severity 
The intensity of an AE is classified according to the following categories, taking into account 
the possible range of the intensity of the event: 
• Mild   
The adverse event is transient and easily tolerated by the subject. 
• Moderate  The adverse event causes the subject discomfort and interrupts the subject’s 
usual activities 
• Severe  
The adverse even causes considerable interference with the subject’s usual 
activities and may be incapacitating or life-threatening. 
Investigational product action 
Any potential investigational product action to resolve the AEs is to be documented as “Drug 
discontinued.” 
Specific drug treatment 
Any specific drug treatment will be documented. 
Causal relationship to investigational product 
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of investigational product:  
Definitely related: 
Event can be fully explained by administration of the 
investigational product. 
Probably related: 
Event is most likely to be explained by administration of the 
investigational product rather than the subject’s clinical state or 
other agents/therapies. 


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Possibly related: 
Event may be explained by administration of the investigational 
product or by the subject’s clinical state or other agents/therapies. 
Probably not related: 
Event is most likely to be explained by the subject’s clinical state 
or other agents/therapies, rather than the investigational product. 
Definitely not related: 
Event can be fully explained by the subject’s clinical state or other 
agents/therapies. 
For causality assessments, events meeting the categories of definitely, probably, or possibly 
related will be considered to be related to investigational product. 
Outcome 
The outcome of the AE is to be documented as follows: 
• Resolved 
• Resolved with sequelae 
• Ongoing 
• Unknown 
• Lost to Follow-up 
• Death 
8.3.1.3 
Assessments and Documentation of Adverse Events  
Attention shall be paid to the occurrence of AEs at all stages of the PET examination.  Thus, 
the subject should be closely observed by the investigator both during and after the 
examination.   
Any AE (observed, volunteered, or elicited) should be recorded in detail in the source 
documenation. 
The following information is required: 
• The date and time of onset of any AE. 
• The duration (the entire duration of an event or symptom, calculated from date of onset 
to date of end, if not recorded directly). 
• The seriousness of the AE will be assessed by the investigator.  If the investigator deems 
that an AE qualifies as an SAE, a special form provided by the sponsor should be 
completed and the event must be immediately reported to the sponsor.  A definition of 
serious adverse events is provided below.   
• The maximum intensity (mild, moderate, or severe). 


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• Whether investigational product was discontinued   
• Specific drug treatment 
• The relationship of the AE to the investigational product and to study conduct (for 
definitions, see above). 
• The outcome of the AE (recovered/resolved, recovering/resolving, not recovered/not 
resolved, recovered/resolved with residual effects, fatal, unknown). 
AEs will be coded according to an internationally recognized dictionary (Medical Dictionary 
for Regulatory Activities or MedDRA). 
8.3.1.4 
Expected Adverse Events 
Expected Disease-Related AEs 
A worsening of the subject’s cognitive impairment and potential diagnosis of dementia will 
not be considered an adverse event. 
Expected Conduct-Related AEs 
The use of an indwelling venous cannula for the purpose of blood sampling and 
administration of investigational product may be accompanied by mild bruising and also, in 
rare cases, by transient inflammation of the vessel wall.  After initial irritation, the presence 
of an indwelling cannula is usually painless and hardly noticeable.  The same applies to 
single vein punctures for blood sampling. 
Expected Adverse Drug Reactions 
The definition below follows ICH-GCP (see also ICH Guideline for Clinical Safety Data 
Management:  Definitions and Standards for Expedited Reporting): 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not be established, all noxious and unintended 
responses to a medicinal product related to any dose should be considered as ADR.  The 
phrase ‘responses to a medicinal product’ means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility (definitely, probably, 
possibly), i.e., the relationship cannot be ruled out. 
Investigational Product-Related Risks 
No adverse effects are expected from the administration of [18F]NAV4694. 
Adverse events from the radioactive dose are not expected, since the applied radiation doses 
are far below doses that can cause acute effects in human tissues. 


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Precautionary Measures 
Special precautionary measures are not considered to be necessary for this study.  In case of 
emergency, standard emergency procedures will be employed. 
Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction is defined as an adverse reaction that in nature and 
severity is not consistent with the applicable product information (e.g., Investigator’s 
Brochure). 
Any adverse experience that is not listed in the current Investigator’s Brochure or which is, 
with regard to the specificity or severity, not consistent with the risk information shall be 
regarded as unexpected. 
Examples would be (a) acute renal failure listed in the Investigator’s Brochure with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  “Unexpected” as used in this definition refers to an adverse drug experience that 
has not been previously observed and included in the product information, rather than from 
the perspective of such experience not being anticipated from the pharmacological properties 
of the investigational product. 
8.3.1.5 
Serious Adverse Events  
Definition of Serious Adverse Events 
Definition 
The following SAE definition is based on ICH guidelines and the final rule issued by the 
Food and Drug Administration (FDA) and effective 06 Apr 1998.  It is to be applied to AEs 
(defined in Section 8.3.1.1). 
An SAE is classified as any untoward medical occurrence that at any dose 
• results in death, or 
• is life threatening, or 
• requires inpatient hospitalization or prolongation of existing hospitalization, or 
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect, or 
• is an important medical event (see paragraphs below). 
The term ‘life threatening’ in the definition refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe. 


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Medical and scientific judgment should be exercised in deciding whether it is appropriate to 
report an AE as serious also in other situations, such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  These should also usually be considered serious.  Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm or blood 
dyscrasias or convulsions that do not result in subject hospitalization. 
Actions and reporting obligations in case of serious adverse events 
The investigator should take appropriate diagnostic and therapeutic measures to minimize the 
risk to the subject.   
If any SAE occurs over the course of the study, investigators or other site personnel will 
inform Navidea Biopharmaceutical representatives within one day (i.e., within 24 hours) of 
becoming aware of the SAE. Written notification of the SAE will be faxed to Navidea 
Biopharmaceuticals at (855) 793-7501 or email to Pharmacovigilance@navidea.com. For 
fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. 
All SAEs must also be recorded on the Adverse Event eCRFs. 
Notification of the IECs/IRBs 
The sponsor and/or the investigator will notify the IECs/IRBs about all relevant events (e.g., 
Serious Adverse Events [SAEs] and Suspected, Unexpected, Serious Adverse Reactions 
[SUSARs]) according to all applicable regulations. 
Notification of the authorities 
The sponsor will process and report all relevant events (e.g., SAEs, SUSARs) to the 
authorities according to all applicable regulations. 
Sponsor’s notification of the investigators 
The sponsor will inform all investigators about reported relevant events (e.g., SAEs, 
SUSARs) according to all applicable regulations. 


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8.3.2 
Further Safety Assessments 
8.3.2.1 
Physical Examination 
Complete physical examinations will be conducted according to the Schedule of Study 
Events (see Appendix 1). 
Physical examination will be performed for the following body systems: 
• General appearance 
• Skin/dermatological 
• Eyes, ears, nose, throat 
• Head and neck (including thyroid) 
• Lungs 
• Heart 
• Abdomen (liver, kidney, spleen, gastrointestinal) 
• Lymph nodes 
• Musculoskeletal 
• Psychiatric 
• Neurologic 
 
8.3.2.2 
Vital Signs 
Vital signs comprise the measurement of systolic and diastolic blood pressure and heart rate.  
All vital signs will be measured after the subject has been in a resting position for at least 3 
minutes.  Heart rate should be measured immediately before or immediately after blood 
pressure measurement.   
Blood pressure and heart rate will be measured at baseline (10 minutes before investigational 
product injection), 10 and 30 minutes post injection, and at the 24 hour follow-up visit. 
Any clinically significant change from baseline that results in a change in subject 
management will be considered an AE. 
8.3.2.3 
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) will be obtained 10 minutes before 
investigational product injection), as well as within 10 minutes after investigational product 
injection, and at the 24 hour follow-up visit.  The ECG will be measured with the subject in a 
resting position for at least 3 minutes.  No continuous ECG monitoring will be required.  
ECG clocks should be synchronized with the time point for injection used in the eCRF.   


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On-site investigator’s responsibilities 
The immediate cardiac safety of the subject will be ensured by the on-site qualified 
physician.  Any 12-lead ECG intervals, waveform abnormalities, and rhythm changes that 
are clinically significant in that they result in a change in subject management will be 
considered an AE.  In the case of an SAE, once SAE notification is decided upon, 
investigators are required to follow the procedure described for SAE notification and 
document abnormal ECG findings (intervals and waveforms).  Any interval data or abnormal 
waveform finding that resulted in an AE (i.e., change of patient management) must be 
followed for the duration of the subject's participation in the study until normalization or 
return to baseline takes place.   
Each 12-lead ECG tracing must be signed and dated and stored in the ISF.   
Independent cardiologist responsibilities 
A dedicated ECG core laboratory will be contracted by the sponsor to perform the 
independent assessment of the ECGs. 
The original ECG from all time points will be electronically transferred and independently 
read within 14 days of the ECG examination by an independent board-certified cardiologist.  
The independent cardiologist will review, interpret, and provide a written assessment of the 
ECGs for each subject in consecutive order, determining all intervals (e.g., PR, QRS, QT, 
and RR) and waveform changes.  The reports will be signed and dated.  A  copy of the ECGs 
at each time point will be retained in the investigator’s study record for each subject 
(identified with the subject’s initials, study number, date, and time of recording).   
The QT interval will be calculated by the core laboratory cardiologist using the correction 
formulae according to Bazett (QTc = QT/RR 0.5) and Fridericia (QTc = QT/RR 0.33). 
8.4 
Other Procedures and Variables 
8.4.1 
Blood Sampling 
8.4.2 
Laboratory Data Related to Screening and Safety 
Clinical laboratory tests to be evaluated in this study include hematology, serum chemistry 
(including vitamin B12, folic acid, and thyroid function at screening), and urinalysis.  Blood 
and urine samples for safety will be obtained according to the Schedule of Study Events (see 
Appendix 1).  Table 6 shows the parameters to be assessed: 


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Table 6. 
Clinical Laboratory Parameters 
Hematology 
Leukocytes, erythrocytes, hemoglobin (Hb), hematocrit (HCT), 
red blood distribution width (RDW), mean corpuscular volume 
(MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC) platelets, mean 
platelet volume (MPV), neutrophils, eosinophils, basophils, 
lymphocytes, monocytes 
Serum chemistry 
 
Aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), gamma-glutamyl transferase (gamma-GT), alkaline 
phosphatase, total bilirubin, creatinine, chloride, potassium, 
sodium, total protein, albumin, globulin, carbon dioxide (CO2), 
blood urea nitrogen (BUN) 
Serum chemistry 
(screening only) 
Vitamin B12, folic acid, FT3/FT4, TSH, glucose (non-fasting) 
Serology 
(screening only) 
Syphilis (treponama pallidum particle agglutination assay) 
A central laboratory will be used for all blood and urine samples to be determined in this 
trial.   
The central laboratory will provide the necessary kits to collect the blood and urine samples 
and will also provide appropriate information regarding shipping of the samples.   
Care is to be taken not to potentially produce an erroneous value, e.g., by inappropriate use of 
the tourniquet or forceful withdrawal of blood.  Each original laboratory report will be 
retained in the subject files.   
All laboratory reports must be promptly reviewed by the investigator, and upon review, 
initialed and dated by the investigator.  Change(s) in post-dose test values considered 
clinically significant, which would require either additional control or therapy and, in case of 
disturbing or influencing factor(s) on values/samples, details of the appropriate value(s) and 
the source of disturbance or influence (e.g., quality of sample, co-medication etc.) are to be 
recorded.  Good clinical practice would suggest that a copy of the safety laboratory results be 
available to the subject and to the subject’s referring physician.   
The following are general guidelines and are provided in order to assist the investigator in 
evaluating changes in laboratory values after the administration of investigational product.  
Since from previous clinical experience, these changes are unexpected, in all instances 
laboratory error must be considered and ruled out.  One common cause of error is dilution of 
the blood sample, which occurs when blood is drawn through a fluid-filled catheter.   
Changes 
in 
most 
individual 
laboratory 
values 
cannot 
be 
interpreted 
without 
concomitant/concordant changes in related parameters.  For example, a decrease in 
hematocrit of approximately 5 percentage points (49% to 44%) at 24 hours post injection can 
be considered clinically significant, but without a similar change in hemoglobin and RBC, 


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laboratory error must be ruled out.  Shifts in hematocrit may also occur with changes in 
subject’s hydration status.  With comparable decreases in hematocrit, hemoglobin and RBC, 
the investigator must evaluate the subject for blood loss/hemorrhage, especially at the site of 
venepuncture.  If coagulopathy or hemolysis is suspected appropriate follow-up, including 
diagnostic tests and treatment, should be undertaken.  Decreases in platelet count by greater 
than 30% of baseline value or an absolute value of less than 50,000/µL after a normal 
baseline value should also be followed up to rule out laboratory error or an underlying 
problem, such as a coagulopathy.   
Increases in 2 or more liver function and related parameters (alkaline phosphatase, AST, 
ALT, and bilirubin) that result in values twice that of the upper limit of the normal range 
must be followed up to rule out any acute liver and/or cardiac illness.  The investigator must 
obtain the appropriate tests as indicated by the subject’s clinical status.  Changes in sodium, 
potassium and chloride that are greater than 20% of baseline value must be followed up.   
In all instances of changes in multiple parameters, regardless of the magnitude, the 
investigator must evaluate the subject in light of the clinical signs and symptoms and institute 
appropriate treatment.  There may be other abnormal laboratory changes not specifically 
noted above that the investigator may want to follow up as appropriate for a particular 
subject.   
Any change in laboratory value which results in a change in subject management (additional 
controls or treatment required) will be reported as a clinically significant change.  Clinically 
significant changes in laboratory parameters which are not the result of laboratory error are to 
be recorded as AEs. 
Any clinically significant changes in laboratory values are to be followed up with repeated 
tests at appropriate intervals (as determined by the investigator and the medical monitor) 
until the values return to baseline level or until the abnormality is explained by the 
investigator.  Such additional tests should also be done at the central laboratory and will be 
entered into the database.   
The amount of blood to be withdrawn is shown in Table 7.  
Table 7. 
Amount of Blood Withdrawn 
 
Safety 
Laboratory examination (screening) 
24 mL 
Laboratory examination (baseline, baseline follow-
up, 18 month1, 18 month follow-up1) 
4 x 8 mL 
Archival Sample (optional) 
6 mL 
 
 
Total 
62 mL  
1 
Only for the subset of 20 subjects that is imaged at 18 months 


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Blood and urine specimens will be sent to a central vendor for analysis. Specimen collection, 
packaging, and shipping instructions are provided in a separate laboratory manual. 
8.4.3 
Blood Sampling and Processing for Genetic Analyses  
Providing a sample for archival is optional.  Providing blood samples for all other laboratory 
examinations is required, including samples for genetic tests.  Results of the genetic tests will 
be shared with the subject at the discretion of the investigator and the preference of the 
subject.   
Handling of Blood Samples 
A blood specimen collected at the screening visit will be sent to a central vendor for ApoE 
genotype and other potential genetic determination.  This result will be used for purposes of 
analysis for exploratory objectives in this study.   
Evaluation of Data 
Currently apolipoprotein E4 (Apo-E4) genotyping is envisaged.  Further genes known or 
suspected to confer an increased risk of AD (e.g., APP, PSEN1, PSEN2) may be included as 
well.   
ApoE4 will be classified according to:  
- 
homozygous non-E4/non-E4 
- 
heterozygous non-E4/E4  
- 
heterozygous non-E4/E4 or homozygous E4/E4 
- 
homozygous E4/E4 


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9 
STATISTICAL METHODS  
9.1 
Introduction 
This study is an open-label, non-randomized, multi-center study to investigate whether 
[18F]NAV4694 PET scan findings have the ability to distinguish subjects with MCI who 
progress to AD from those who do not.  The study will be conducted at approximately 15 
study centers in the US and Germany.  Subjects will be enrolled in the trial for a period of 
approximately 36 months.  The objectives of the statistical analyses are to investigate the 
ability of the study procedure (PET scan findings using [18F]NAV4694) to distinguish 
between subjects who progress to AD from MCI and those who do not and to establish the 
safety and tolerability of [18F]NAV4694 in subjects with MCI. 
A study center is defined as a treatment administration site under the control and supervision 
of the same Principal Investigator. 
9.2 
Randomization Methods 
This is a non-randomized clinical trial where each subject will undergo PET imaging using 
[18F]NAV4694 and a battery of neurocognitive testing. 
9.3 
Pooling of Study Centers 
Study centers will be pooled for all statistical analyses.  
9.4 
Efficacy Variables 
9.4.1 
Primary Efficacy Variables 
The primary efficacy variables of this study are the diagnostic result from the PET imaging 
after administration of [18F]NAV4694 at baseline and the SoT diagnosis of transition from 
MCI to AD made by the investigator at the study site at the 18- and 36-month time points.  
The diagnostic results for both entities are that the subject has/has not transitioned to AD. 
Each subject will undergo brain imaging that will be read by 3 independent readers blinded 
to clinical information.  Each reader will score each region of the brain and then follow the 
scoring algorithm described in Section 8.1.8.1 of the protocol to arrive at a final classification 
(AD vs. no AD) for the subject.  The final overall subject level classification (AD vs. no AD) 
will be made by a majority rule of the individual reader classifications.           
At the 18- and 36-month time points, the investigator will determine the SoT diagnosis of 
transition from MCI to AD based on a review all of the clinical and neuro-cognitive data 
gathered for each subject over the course of the trial. 


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9.4.2 
Secondary Efficacy Variables 
The secondary efficacy variables for this study are: 
• the diagnostic result from the PET imaging after administration of  [18F]NAV4694 at 18 
months 
• neuro-cognitive test battery scores at screening and/or baseline, 6, 12, 18, 24, 30, and 36 
months (CDR Domains (Memory, Orientation, Judgment & Problem Solving, 
Community Affairs, Home & Hobbies, and Personal Care), CDR-Global, ADCS-MCI-
ADL, MMSE, RAVLT,ADAS-Cog) 
• subject-level neocortical SUVR at baseline and 18 months (computed as the average of 
the SUVRs from the frontal, lateral temporal, parietal, occipital and posterior and anterior 
cingulate cortices) 
 
9.5 
Pharmacokinetic Variables 
Not applicable. 
9.6 
Safety Variables 
9.6.1 
Primary Safety Variables 
The primary safety variables for this study are: 
• Physical exams (screening, pre and 24 hours post injection at baseline, day 1, and pre and 
post 24 hours post injection for all subjects, and at month 18 for a subset of 20 subjects ) 
• Vital signs (screening, pre- and post-injection at baseline, pre- and post-injection for all 
subjects, and at month 18 for a subset of 20 subjects)  
• Laboratory parameters (screening, pre and 24 hours post injection at  baseline, day 1 and 
pre and 24 hours post injection for all subjects, and at 18 months for a subset of 20 
subjects) 
• Adverse events 
• ECG parameters (baseline, pre, post and 24 hours post injection at baseline and pre, post 
and 24 hours post injection for all subjects, and at 18 months for a subset of 20 subjects) 
9.7 
Sample Size Justification 
Approximately 120 evaluable subjects will be enrolled in the study.  It is expected that 40% 
of the patients will progress to AD over the 36 month study period. Taking a drop-out rate of 
30% into account, the study will provide 34 MCI patients progressing to AD vs. 50 who will 
not progress at the 36 month timepoint. As no preliminary data exists for this compound in 
MCI, accurate sample size calculations are not possible. The sample size is consistent with 
that employed in most early phase PET studies. 


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9.8 
Handling of Missing Data 
In the statistical analysis of the primary efficacy endpoints of the study, only subjects with 
evaluable endpoint values for both the blinded read and the SoT diagnosis will be used in the 
statistical analysis, i.e., a complete case analysis.  The handling of missing values for all 
other study endpoints will be described in the Statistical Analysis Plan (SAP) for the study. 
9.9 
Statistical Analysis  
9.9.1 
Analysis Populations 
The following analysis populations will be defined:  
Intent-to-Diagnose (ITD) Population – All subjects in whom any PET imaging with 
[18F]NAV4694 was performed, with valid standard of truth for the subject-level brain 
assessment, will be included in the ITD population. 
Per Protocol (PP) Population – All subjects belonging to the ITD population who do not 
have protocol deviations predefined as leading to non-evaluability of the subject for the 
primary efficacy variable. Such predefined protocol deviations may include, but are not 
restricted to:  
• no PET acquisition during the 50 to 70 minute imaging window 
Protocol deviations leading to non-evaluability will be listed in a separate document that will 
be finalized before the first image is read. 
Safety Population – All subjects who received any amount of [18F]NAV4694 will be 
included in the safety analysis set. 
The analysis of the primary efficacy endpoints will be conducted on ITD and PP populations.  
The primary analysis set will be the PP analysis set.  All safety analyses will be conducted on 
the safety population.   
9.9.2 
Analysis of Baseline and Demographic Characteristics 
Baseline and demographic characteristics, including clinically relevant covariates, will be 
summarized for all subjects in the safety population.  Continuous variables will be displayed 
via summary statistics (mean, median, sample size, standard deviation, minimum, and 
maximum).  Categorical variables will be summarized via counts and percentages. 
9.9.3 
Analysis of Primary Variables 
The analysis of the primary efficacy variables will consist of calculating sensitivity, 
specificity, false negative rate (FNR), false positive rate (FPR), positive predictive value 
(PPV), negative predictive value (NPV) and accuracy of the baseline [18F]NAV4694 PET 
scan reader evaluation findings  relative to the 18- and 36-month SoT clinician diagnosis of 


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transition from MCI to AD.  Exact 95% binomial confidence intervals will be constructed for 
all computed parameters. 
9.9.4 
Analysis of Secondary Variables 
In order to compare the results obtained using blinded readers to results obtained from the 
imaging device (specifically, subject level SUVRs), a receiver operating characteristics 
(ROC) curve analysis will be conducted using the subject level SUVRs from the baseline 
[18F]NAV4694 PET scan and the 18- and 36-month SoT clinician diagnosis of transition 
from MCI to AD.  An empirical ROC curve will be constructed and graphically displayed 
using each SUVR in the dataset as the cut point to compute sensitivity and specificity of the 
[18F]NAV4694 PET scan relative to the SoT clinician diagnosis.  A nonparametric estimate 
of the area under the ROC curve (ROC) will be computed along with the DeLong variance 
estimate and a 95% confidence interval on the AUC.  The optimal cut point will be obtained 
by visual inspection of the ROC curve.  Once the optimal cut point has been determined, all 
diagnostic parameters (sensitivity, specificity, FNR, FPR, PPV, NPV and accuracy) will be 
calculated using the optimal cut point for SUVRs and the 18- and 36-month SoT diagnosis.  
The 95% exact binomial confidence intervals for each parameter will also be calculated. 
These same parameters (sensitivity, specificity, FNR, FPR, PPV, NPV and accuracy) will 
also be computed using a pre-determined cut point based on historical data. 
In order to assess changes in amyloid burden over time in subjects with reader evaluated 
positive or negative scans, summary statistics (n, mean, median, standard deviation, 
minimum and maximum) will be computed on the subject level SUVRs change from 
baseline to 18 month data (for a subset of 20 subjects) by baseline reader evaluation status 
(positive or negative for AD) and overall. 
To assess correlation of change over time in the subject level SUVRs to neurocognitive test 
results, Pearson correlation coefficients will be computed on the change from baseline 
subject level SUVRs at 18 months (for a subset of 20 subjects) and all change from baseline 
neurocognitive test results at the 6-, 12-, 18-, 24-, 30-, and 36-month time points. 
In order to predict the probability of transition from MCI to AD, a logistic regression model 
will be fit using the subject level SUVRs at baseline as the independent variable and the SoT 
clinician diagnosis as the dependent variable.  Model fit parameters will be obtained as well 
as the predicted probability of transition from MCI to AD for each subject.  The odds ratio of 
transition from MCI to AD based on the logistic regression model will be computed in two 
ways: 
• For a one unit difference in subject level SUVR 
• For a difference in the median subject level SUVR for each quintile of the observed 
subject level SUVR distribution (these results will be displayed in a two way tabular 
form) 


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Other exploratory statistical analyses may be conducted on the primary and secondary 
efficacy variables and will be described in the SAP for the study. 
9.9.5 
Safety Analyses 
All AEs will be observed for each subject from enrollment until termination from the study.  
Prior to analysis, all AEs will be coded using MedDRA. Based on these coded terms, AEs 
will be summarized using system organ class and preferred terms.  All AEs will be listed.      
The analysis of all other safety variables for this study will be described in the Statistical 
Analysis Plan document. 
9.10 Interim Analyses 
No formal interim analyses will be conducted during this study.  In order to make a 
regulatory submission for this product that will include results from this study, an analysis of 
the data collected up to and including the 18-month time point will be conducted.  This will 
not be considered a statistically-based interim analysis and will not need alpha level 
adjustment for the following reasons: 
• The summary will not be conducted until all subjects who remain in the study have 
reached the 18-month time point. 
• The database will be “soft locked” so that no 36-month data is unblinded at the time of 
the 18-month analysis. 
• This study is exploratory and there will be no hypothesis testing. 
 


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10 DATA HANDLING AND QUALITY ASSURANCE 
10.1 Data Recording 
The investigator will document in the file of the study participant at least the items listed in 
Section 10.2 
Data required according to this protocol are to be entered into the eCRFs (provided by the 
sponsor) as soon as possible. 
10.1.1 
Electronic CRF design 
Electronic data capture with the sponsor’s eCRF will be used for collecting all data generated 
during the study.  The eCRF application has a built-in plausibility check, forcing the 
investigators to answer the questions in the appropriate manner, and auto-checks for missing 
data.  The system type and eCRF details will be documented in a separate document that will 
be provided by the sponsor and maintained in the TMF. 
10.2 Monitoring 
This study will be monitored regularly by a clinical research associate (CRA) from the 
sponsor or a contract research organization (CRO).  Monitoring procedures include one or 
more visits designed to clarify all prerequisites before the study starts.  Interim monitoring 
visits will take place on a regular basis according to a schedule fixed by mutual agreement.  
During these visits, the CRA will check for completion of the entries on the eCRFs, their 
compliance with the protocol and with GCP, and will compare the eCRF entries with the 
source data. 
All data recorded in the eCRF will be captured in the source documentation. 
The CRA will verify the correct use of the investigational product.  The investigational 
product will not be supplied to the investigator site prior to a favorable opinion from the 
IRB/IEC and the regulatory authority and, if appropriate, from the radiation protection 
authorities. 
In addition, the CRA will determine whether all AEs and SAEs have been appropriately 
reported (including adherence to the time periods required for SAEs). 
10.3 Data Processing 
Study data documentation will be maintained specifying all relevant aspects of data 
processing for the study (including data validation, cleaning, correcting, releasing).  This 
documentation will be stored in the TMF. 


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For data coding (e.g., AEs, medication, medical/surgical history), internationally recognized 
and accepted dictionaries will be used.  These and the processes used for coding will be 
specified in the SAP. 
10.4 Auditing 
A member of the sponsor’s (or a designated CRO) quality assurance unit may arrange to visit 
the investigator in order to audit the performance of the study at the study site and the study 
documents originating there.  The auditor(s) will usually be accompanied by a CRA or the 
study team lead.  The investigator will be informed about the outcome of the audit. 
In addition, inspections by health authority representatives and IEC(s)/IRB(s) are possible at 
any time.  The investigator is to notify the sponsor of any such inspection immediately. 
10.5 Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that 
they are readily available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution, or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period. 
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g., relocation or transfer of ownership). 
The investigator site file is not to be destroyed without the sponsor’s approval. 
The investigator’s contract will contain all regulations relevant for the study center. 
10.6 Premature Termination of the Study  
Termination by the Sponsor 
The Sponsor may terminate the study at any time for any of the following reasons: 
1. Failure to enroll subjects 
2. Protocol violations 
3. Inaccurate or incomplete data 
4. Unsafe or unethical practices 
5. Questionable safety of the investigational product 
6. Suspected lack of efficacy of the investigational product 
7. Administrative decision 
 


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Termination by the Investigator 
If the Investigator terminates the study prematurely, the Investigator must do the following: 
• Return all unused investigational products and related study materials to the Sponsor. 
• Provide the IRB/IEC and the Sponsor with a written statement describing why the study 
was terminated prematurely. Prompt compliance with this requirement is essential so that 
the Sponsor may comply with its regulatory obligations. 
 
10.6.1 
Study as a Whole 
The sponsor retains the right to prematurely terminate the study as a whole at any time.  
Reasons for such premature termination may include the following: 
At the discretion of the sponsor, the entire study may be canceled for medical reasons.  In 
addition, the sponsor retains the right to end the study at any time if the study cannot be 
carried out as agreed upon in the protocol.  
In case of premature termination or suspension of the study, the principal 
investigator/sponsor will promptly inform the investigator/institutions, regulatory authorities, 
and IRB/IEC of the termination or suspension and the reason for that. 
10.6.2 
Center 
At any time, the trial may be terminated at an individual center if:  
• The center cannot comply with the requirements of the protocol. 
• It is not possible for the center to comply with GCP standards. 
10.6.3 
Study Participant 
Individual subjects may be withdrawn from the study according to the criteria specified in 
Section 4.3. 


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11 ETHICAL AND LEGAL ASPECTS 
11.1 Ethical and Legal Conduct of the Study 
The planning and conduct of this clinical study are subject to national laws. Only when all of 
the requirements of the appropriate regulatory authority have been fulfilled will the study 
begin. The study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and the ICH-GCP Guidelines of 17 Jan 1997. At the 
discretion of the investigator, the entire study may be canceled for medical reasons. In 
addition, the sponsor retains the right to end the study for medical-scientific or GCP-relevant 
reasons. In case of premature termination the investigators, IRB/IECs and Regulatory 
Authorities will be informed by the Study Manager. As required by local law, current safety-
relevant information will be provided to the IEC / IRB and the regulatory authorities by the 
sponsor. The sponsor will also inform all investigators about relevant safety events according 
to the applicable regulations. 
11.2 Subject Information and Consent 
All relevant information on the study will be summarized in the subject consent form and 
additionally as required by the investigator’s institution in an integrated subject information 
and consent sheet. A sample informed consent form is provided as a document separate to 
this protocol. 
Based on this subject informed consent form, the investigator will explain all relevant aspects 
of the study to each subject, before his/her entry into the study (i.e., before examinations and 
procedures associated with selection for the study are performed).  
The investigator will also mention that written approval of the IRB/IEC has been obtained.  
Each subject will have ample time and opportunity to ask questions and will be informed 
about the right to withdraw from the study at any time without any disadvantage and without 
having to provide reasons for this decision.  
Following this informative discussion, the subject will be asked if he/she is willing to sign 
and personally date a statement of informed consent. Only if the subject voluntarily agrees to 
sign the informed consent form and has done so, may he/she enter the study. Additionally, 
the investigator or his nominated designee will personally sign and date the form, too. The 
subject will receive a duplicate of the signed and dated form.  
The investigator will record in the source documentation the time and date of obtaining 
informed consent. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject's clinical record must clearly show that informed 
consent was obtained prior to these procedures.  


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The informed consent form and any other written information provided to subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol which necessitates a change to the 
content of the subject information and/or the written informed consent form. The investigator 
will inform the subject of changes in a timely manner and will ask the subject to confirm 
his/her participation in the study by signing the revised informed consent form. Any revised 
written informed consent form and written information must receive the IRB/IEC's 
approval/favorable opinion in advance of use. 
11.3 Financing/Financial Disclosure 
Each investigator (including principal and/or any subinvestigators; as well as their spouses 
and dependent children) who is directly involved in the treatment or evaluation of research 
subjects has to provide a financial disclosure according to all applicable legal requirements. 
All relevant documentation will be filed in the TMF and/or ISF, as appropriate. 
11.4 Publication Policy 
The Sponsor will be responsible for determining when any trial results should be published. 
The Sponsor will work jointly with the investigator(s) to publish information in a timely 
manner. The investigator(s) shall not submit any information gleaned under the direct 
support or sponsorship of the Sponsor to journals or professional societies without the prior 
written approval of the Sponsor.  A "publication" is meant to include any abstract, letter, 
manuscript or public announcement in any form or length that contains information gleaned 
under the direct support or sponsorship of the Sponsor. 
11.5 Subject Injury 
In general, if a subject is injured as a direct result of the investigational product but not due to 
medical negligence on the part of the Principal Investigator or study staff, the Sponsor will 
pay for reasonable and necessary medical treatment for the injury, to the extent the expenses 
are not covered by the subject’s medical insurance, a government program, or other 
responsible third party.  If laws or regulations of the locality in which the trial is taking place 
require additional payment of expenses, the sponsor shall comply with such law or 
regulation.  Where applicable, the Sponsor has taken specific national insurance. 


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12 REFERENCE LIST 
(D2750C0001). Open label Positron Emission Tomography Study with [18F]AZD4694 and 
[11C]AZD2184, Candidate Radioligands for Aβ Amyloid, to Determine and 
Compare in vivo Brain Uptake and Distribution in Healthy Volunteers and Patients 
with Alzheimer’s Disease. 
(D2750C00002). Open-Label Positron Emission Tomography Study with the Selective β-
Amyloid Radioligand [18F]AZD4694 to assess the Effects of Varying Mass of 
AZD4694 on Radioligand Binding Parameters in Healthy Volunteers and Patients 
with Alzheimer's Disease  
(D2750N00006). A Phase II, Open Label, Non-Randomized Study of [18F]AZD4694 to 
Compare PET Measurements of Fibrillar Amyloid Burden Obtained Using Different 
Scanning Parameters, Reference Region Procedures and to Assess Test-retest 
Reliability in Patients with Alzheimer’s Disease and Healthy Adult Volunteers. 
ADNI. "Alzheimer’s Disease Neuroimaging Initiative (ADNI) 2009 ", from 
http://www.fnih.org/work/areas/chronic-disease/adni. 
Albert M, DS, Dickson D, Dubois D, Feldman H, Fox N, Gamst A, Holtzman D, Jagust W, 
Peterson R, Snyder P. (2010). Criteria For Mild Cognitive Impairment Due to AD: 
11. 
Albert, MS, DeKosky, ST, Dickson, D, et al. The diagnosis of mild cognitive impairment due 
to Alzheimer's disease: recommendations from the National Institute on Aging-
Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimers Dement (2011);7(3): 270-279. 
Andersson, C, Lindau, M, Almkvist, O, et al. Identifying patients at high and low risk of 
cognitive decline using Rey Auditory Verbal Learning Test among middle-aged 
memory clinic outpatients. Dement Geriatr Cogn Disord (2006);21(4): 251-259. 
Barthel, H, Gertz, HJ, Dresel, S, et al. Cerebral amyloid-beta PET with florbetaben (18F) in 
patients with Alzheimer's disease and healthy controls: a multicentre phase 2 
diagnostic study. Lancet Neurol (2011);10(5): 424-435. 
Berg, L, Miller, JP, Baty, J, et al. Mild senile dementia of the Alzheimer type. 4. Evaluation 
of intervention. Ann Neurol (1992);31(3): 242-249. 
Braak, H and Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta 
Neuropathol (1991);82(4): 239-259. 
Dubois, B. 'Prodromal Alzheimer's disease': a more useful concept than mild cognitive 
impairment? Curr Opin Neurol (2000);13(4): 367-369. 
Flicker, C, Ferris, SH and Reisberg, B. Mild cognitive impairment in the elderly: predictors 
of dementia. Neurology (1991);41(7): 1006-1009. 
Folstein, MF, Robins, LN and Helzer, JE. The Mini-Mental State Examination. Arch Gen 
Psychiatry (1983);40(7): 812. 
Forsberg, A, Engler, H, Almkvist, O, et al. PET imaging of amyloid deposition in patients 
with mild cognitive impairment. Neurobiol Aging (2008);29(10): 1456-1465. 
Galasko, D, Edland, SD, Morris, JC, et al. The Consortium to Establish a Registry for 
Alzheimer's Disease (CERAD). Part XI. Clinical milestones in patients with 
Alzheimer's disease followed over 3 years. Neurology (1995);45(8): 1451-1455. 


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Amendment 2 Effective Date: 13 May 2014  
 
 
 
 
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Gauthier, S, Reisberg, B, Zaudig, M, et al. Mild cognitive impairment. Lancet 
(2006);367(9518): 1262-1270. 
Hughes, CP, Berg, L, Danziger, WL, et al. A new clinical scale for the staging of dementia. 
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Klunk, WE, Engler, H, Nordberg, A, et al. Imaging brain amyloid in Alzheimer's disease 
with Pittsburgh Compound-B. Ann Neurol (2004);55(3): 306-319. 
Larrieu, S, Letenneur, L, Orgogozo, JM, et al. Incidence and outcome of mild cognitive 
impairment in a population-based prospective cohort. Neurology (2002);59(10): 
1594-1599. 
McKhann, G, Drachman, D, Folstein, M, et al. Clinical diagnosis of Alzheimer's disease: 
report of the NINCDS-ADRDA Work Group under the auspices of Department of 
Health and Human Services Task Force on Alzheimer's Disease. Neurology 
(1984);34(7): 939-944. 
Mohs, RC, Knopman, D, Petersen, RC, et al. Development of cognitive instruments for use 
in clinical trials of antidementia drugs: additions to the Alzheimer's Disease 
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Study. Alzheimer Dis Assoc Disord (1997);11 Suppl 2: S13-21. 
Morris, JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology (1993);43(11): 2412-2414. 
Morris, JC, McKeel, DW, Jr., Fulling, K, et al. Validation of clinical diagnostic criteria for 
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Perneczky, R, Pohl, C, Sorg, C, et al. Impairment of activities of daily living requiring 
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(2006);21(2): 158-162. 
Petersen, RC. Mild cognitive impairment as a diagnostic entity. J Intern Med (2004);256(3): 
183-194. 
Petersen, RC. Early diagnosis of Alzheimer's disease: is MCI too late? Curr Alzheimer Res 
(2009);6(4): 324-330. 
Petersen, RC, Doody, R, Kurz, A, et al. Current concepts in mild cognitive impairment. Arch 
Neurol (2001);58(12): 1985-1992. 
Petersen, RC and Negash, S. Mild cognitive impairment: an overview. CNS Spectr 
(2008);13(1): 45-53. 
Petersen, RC, Smith, GE, Waring, SC, et al. Mild cognitive impairment: clinical 
characterization and outcome. Arch Neurol (1999);56(3): 303-308. 
Reitz, C and Mayeux, R. Use of genetic variation as biomarkers for mild cognitive 
impairment and progression of mild cognitive impairment to dementia. J Alzheimers 
Dis (2010);19(1): 229-251. 
Ritchie, K, Artero, S and Touchon, J. Classification criteria for mild cognitive impairment: a 
population-based validation study. Neurology (2001);56(1): 37-42. 
Rosen, WG, Mohs, RC and Davis, KL. A new rating scale for Alzheimer's disease. Am J 
Psychiatry (1984);141(11): 1356-1364. 
Rountree, SD, Waring, SC, Chan, WC, et al. Importance of subtle amnestic and nonamnestic 
deficits in mild cognitive impairment: prognosis and conversion to dementia. Dement 
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Rowe, CC, Ackerman, U, Browne, W, et al. Imaging of amyloid beta in Alzheimer's disease 
with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol 
(2008);7(2): 129-135. 
Schmidt, M (2010). Rey Auditory Learning Test: A Handbook. USA, Western Psychological 
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Stabin, MG, Sparks, RB and Crowe, E. OLINDA/EXM: the second-generation personal 
computer software for internal dose assessment in nuclear medicine. J Nucl Med 
(2005);46(6): 1023-1027. 
Vandenberghe, R, Van Laere, K, Ivanoiu, A, et al. 18F-flutemetamol amyloid imaging in 
Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol 
(2010);68(3): 319-329. 
Villemagne, VL, Pike, KE, Darby, D, et al. Abeta deposits in older non-demented individuals 
with cognitive decline are indicative of preclinical Alzheimer's disease. 
Neuropsychologia (2008);46(6): 1688-1697. 
 


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Appendix 1 
Schedule of Events 
 
Screening Baseline 
Baseline Day 1 
24 hr follow-up Telephone follow-
up 
 
Day -56 to 
0 
Day -7 to 
0 
Prior to 
injection 
10 min before 
injection 
Injection 
Within 10 min
post- injection 
30 ± 5 min 
post injection 
50-70 min 
post injection 
Day 2 (24 ± 4 hr) 
post- injection 
Day 8 (7 [+3]) days 
post injection 
Consent 
X 
 
 
 
 
 
 
 
 
 
Interview (subject specific 
characteristics) 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
 
X 
 
X 
X 
 
X 
 
Physical exam1 
X 
X 
 
 
 
 
 
X 
 
Body weight 
X 
 
X 
 
 
 
 
 
 
 
Neurological exam 
X 
 
 
 
 
 
 
 
 
 
Screening neuro-cog battery2 
X 
 
 
 
 
 
 
 
 
 
Baseline neuro-cog battery3 
 
X 
 
 
 
 
 
 
 
 
MRI brain scan4 
X 
 
 
 
 
 
 
 
 
 
Urine collection for urinalysis 
X 
X 
 
 
 
 
 
X 
 
Blood draw   
X5 
X6 
 
 
 
 
 
 
X6 
 
Electrocardiogram 
 
 
 
X 
 
X 
 
X 
 
Insertion and test of catheter 
 
 
X 
 
 
 
 
 
 
 
Measure [18F] activity in syringe 
 
 
 
 
X 
 
 
 
 
 
Investigational product injection 
 
 
 
 
X 
 
 
 
 
 
Measure [18F] activity  
 
 
 
 
X 
 
 
 
 
 
PET scan imaging procedure 
 
 
 
 
 
 
 
X 
 
 
On-site PET image analysis  
 
 
 
 
 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
 
X 
X 
Telephone contact 
 
 
 
 
 
 
 
 
 
X 
1 Document height and weight of subject at screening 
2 Screening assessments: CDR, MMSE, DSM-IV-TR criteria for dementia, DSM-IV-TR criteria for major depressive disorder, recurrent  
3 Baseline assessments: RAVLT, ADAS-cog, ADCS-MCI-ADL 
4 MRI is required unless scan with adequate acquisition sequences is available from previous 6 months 
5 Screening blood draw: routine blood hematology and chemistry parameters, genetic analysis, laboratory tests related to cognitive impairment; optional archival 
sample  
6 Blood draw: routine blood hematology and chemistry parameters 
 


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6, 12, 181, 24, 
30, and 36 
Month Visits 
182 Month or Early Withdraw Assessments 
 
Neuro-cog 
exam (± 30 
days) 
Day - 30 to 0 
Day -7 to 0 
prior PET 
imaging 
Prior to 
injection 
10 min 
before 
injection 
Injection Within 10 min 
post injection 
30 ± 5 min 
post 
injection 
50-70 min 
post injection 
24 hr (+ 4 
hr) follow-
up 
Telephone 
follow-up 
Consent 
 
 
 
 
 
 
 
 
 
 
 
Interview (subject specific characteristics) 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
 
 
 
X 
 
X 
X 
 
X 
 
Physical exam 
 
 
X 
 
 
 
 
 
 
X 
 
Body weight 
 
 
 
X 
 
 
 
 
 
 
 
Neurological exam 
 
 
X 
 
 
 
 
 
 
 
 
6, 12, 18, 24, 30, 36 m neuro-cog battery3 
X 
X 
 
 
 
 
 
 
 
 
MRI brain scan 
 
X 
 
 
 
 
 
 
 
 
 
Urine collection for urinalysis 
 
 
X 
 
 
 
 
 
 
X 
 
Blood draw4 
 
 
X 
 
 
 
 
 
 
X 
 
Electrocardiogram 
 
 
 
 
X 
 
X 
 
X 
 
Insertion and test of catheter 
 
 
 
X 
 
 
 
 
 
 
 
Measure [18F] activity in syringe 
 
 
 
 
 
X 
 
 
 
 
 
Investigational product injection 
 
 
 
 
 
X 
 
 
 
 
 
Measure [18F] activity  
 
 
 
 
 
X 
 
 
 
 
 
PET scan imaging procedure 
 
 
 
 
 
 
 
 
X 
 
 
On-site PET image analysis  
 
 
 
 
 
 
 
 
X 
 
 
Documentation of subject diagnosis and 
progression status5 
X 
 
X 
 
 
 
 
 
 
 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
 
 
X 
 
 
 
 
 
 
X 
X 
Telephone contact 
 
 
 
 
 
 
 
 
 
 
X 
1 Excluding the subset of 20 subjects imaged at 18 months 
2 18 month assessments for the subset 20 subjects imaged at 18 months 
3 All cognitive assessments to be performed at 6, 12, 18, 24, 30 and 36 month follow up visit 
4 Blood draw: routine blood hematology and chemistry parameters 
5 DSM-IV-TR criteria will be used to determine whether a subject has dementia and if so, which type.  Probable AD will be confirmed using criteria from NINCDS-ADRDA. 


Navidea Biopharmaceuticals 
Protocol Number: NAV4-04 
Amendment 2 Effective Date: 13 May 2014 
Appendix 2 
Sponsor Signatures 
Study Title: 
Beta-Amyloid Imaging With [1HF]NAV4694 Positron Emission 
Tomography (PET) in Predicting Progression to Alzheimer's 
Disease (AD) in Subjects with Mild Cognitive lmpainnent (MCI) 
Study Number: 
Original Protocol 
Date: 
Amendment 1 Date: 
Amendment 2 Date: 
This clinical study p 
sponsor. The fl 
· 
NAV4-04 
06 February 2013 
Navidea B~9p~armaceutic 
Signed: (J 
/ __t....:. 
__.,. 
Cornelia Reininger, MD,' hD 
Senior VP and Chief Medical Officer 
Navidea Biophannaceuticals 
/ ~v.
. ~ 
Signed:_.....::..?V-=-..:... 
~- -'----'-'-=7<--'--------
William Regan 
Senior VP, Glob' I Regulatory Strategy 
Navidea Biophannaceuticals 
Page 82 of83 
Proprietary and Confidential 
Date: /'-j //!Ill'( 
;}oj l..f 
_..!:...--..;~_;_,.:_,.,__ __ 
Date: 


Navidea Biopharmaceuticals 
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Appendix 3 
Investigator’s Signature 
Study Title: 
Beta-Amyloid Imaging With [18F]NAV4694 Positron Emission 
Tomography (PET) in Predicting Progression to Alzheimer’s 
Disease (AD) in Subjects with Mild Cognitive Impairment (MCI) 
Study Number: 
NAV4-04 
Original Protocol 
Date: 
06 February 2013 
Amendment 1 Date: 
07 June 2013 
Amendment 2 Date: 
13 May 2014 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol. 
 
 
Signed: 
 
 
Date:  
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 
<enter address> 
<enter phone number>