A Post-Authorisation Safety Study to Evaluate the Effectiveness of VIZAMYL™ Reader Training in Europe
Conditions: Cognitive Impairment
Sponsor: GE Healthcare

GE Confidential 
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Clinical Study Protocol 
GE Healthcare 
GE067-027 
Title 
A Post-Authorisation Safety Study to Evaluate the Effectiveness of 
VIZAMYL™ Reader Training in Europe 
Protocol version identifier 
3.0 
Date of protocol 
11 December 2019 
EU PAS register number  
EUPAS24735 
Active substance  
Pharmacotherapeutic group(s): Radionuclide Imaging 
ATC code: V09AX04 
Medicinal product  
VIZAMYL™ 
Product reference  
EMEA/H/C/002557 
Procedure number  
EMEA/H/C/002557/MEA 002 
Marketing authorisation holder 
GE Healthcare Ltd, Pollards Wood, Nightingales Lane, Chalfont St 
Giles, Buckinghamshire, HP8 4SP, United Kingdom 
Joint PASS  
No 
Research question and objectives 
Research Question:  
•
How effective is the VIZAMYL™ reader training programme in
clinical practice in Europe?
Primary Objective: 
•
Assess effectiveness of the VIZAMYL™ reader training
programmes (in-person or electronic) in Europe by estimating the
diagnostic accuracy, sensitivity, specificity, positive predictive
value (PPV), and negative predictive value (NPV) of the visual
interpretation of VIZAMYL™ images obtained in clinical practice.
Secondary Objective: 
•
Evaluate the impact of demographic and other factors (such as
method of training, gap between training and reading, and country)
on diagnostic accuracy to try to identify factors that may be
associated with image interpretation errors.
Countries of study 
European countries where VIZAMYL™ is commercially available 
 
  
Author 
 
 
GE Healthcare 
100 Results Way, Marlborough, MA 01752 USA 
 
MAH contact person 
 
GE Healthcare 
Nycoveien 1, 0485 Oslo, Norway 
 
Confidentiality Statement 
This protocol is provided for conducting a clinical research study. The information contained in this document is 
confidential and, except to the extent necessary to obtain informed consent or IEC approval, cannot be disclosed 
unless required by governmental regulation. Persons to whom any portion of the contents of this document is 
disclosed must be informed that the information is confidential and may not be further disclosed by them. 
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Investigator’s Signature Page 
I have read this protocol and all associated case report forms and agree to conduct this study in 
full accordance with the stipulations of the protocol described herein. 
 
 
 
Signature 
 
 
 
Date 
Print Name 
 
 
 
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1 
TABLE OF CONTENTS 
1.1 
Overall Table of Contents 
Page Number 
1 
TABLE OF CONTENTS ............................................................................................... 3 
1.1 
Overall Table of Contents .................................................................................. 3 
1.2 
List of Tables ...................................................................................................... 4 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................ 5 
3 
RESPONSIBLE PARTIES ............................................................................................ 6 
4 
ABSTRACT ................................................................................................................... 7 
5 
AMENDMENTS AND UPDATES ............................................................................. 11 
6 
MILESTONES ............................................................................................................. 13 
7 
RATIONALE AND BACKGROUND ........................................................................ 14 
8 
RESEARCH QUESTIONS AND OBJECTIVES ........................................................ 16 
9 
RESEARCH METHODS ............................................................................................. 17 
9.1 
Study Design .................................................................................................... 17 
9.1.1 
Overall Study Design and Plan ....................................................... 17 
9.2 
Setting ............................................................................................................... 20 
9.2.1 
Selection and Replacement of Countries ........................................ 21 
9.2.2 
Selection and Replacement of Imaging Sites ................................. 21 
9.2.3 
Selection and Replacement of Subjects .......................................... 21 
9.2.4 
Inclusion and Exclusion of VIZAMYL™ Images ......................... 22 
9.2.5 
Selection and Replacement of Clinical Readers ............................. 22 
9.2.6 
Selection and Replacement of Expert Readers ............................... 23 
9.3 
Variables ........................................................................................................... 23 
9.3.1 
Demographic Data .......................................................................... 23 
9.3.2 
Exposures ....................................................................................... 24 
9.3.3 
Outcome Measures ......................................................................... 24 
9.3.4 
Risk Factors .................................................................................... 24 
9.3.5 
Co-Morbidities ............................................................................... 24 
9.3.6 
Co-Medications .............................................................................. 25 
9.3.7 
Potential Confounders and Effect Modifiers .................................. 25 
9.4 
Data Sources ..................................................................................................... 25 
9.4.1 
Strategies and Data Sources ........................................................... 25 
9.4.2 
Expert Committees ......................................................................... 25 
9.5 
Study Size ......................................................................................................... 25 
9.6 
Data Management ............................................................................................. 27 
9.6.1 
Data Collection ............................................................................... 27 
9.6.2 
Data Monitoring ............................................................................. 27 
9.6.3 
Data Retrieval from Sites ............................................................... 27 
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9.6.4 
Data Preparation ............................................................................. 27 
9.6.5 
Data Management and Statistical Hardware .................................. 27 
9.7 
Data Analysis .................................................................................................... 28 
9.8 
Quality Control ................................................................................................. 30 
9.8.1 
Mechanisms and Procedures to Ensure Data Quality and Integrity 30 
9.8.2 
Source Data Verification ................................................................ 31 
9.8.3 
Validation of Endpoints .................................................................. 31 
9.8.4 
Storage of Records including Archiving of Statistical 
Programming .................................................................................. 32 
9.8.5 
Certification and Qualifications of Supporting Laboratory or 
Research Groups ............................................................................. 32 
9.9 
Limitations of the Research Methods ............................................................... 32 
9.10 
Other Aspects ................................................................................................... 32 
9.10.1 
Overall Responsibilities of Investigators ........................................ 33 
9.10.2 
Subject Informed Consent .............................................................. 33 
9.10.3 
Protocol Deviations ........................................................................ 33 
10 
PROTECTION OF HUMAN SUBJECTS ................................................................... 34 
11 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ................................................................................................................ 35 
11.1 
Safety Assessments .......................................................................................... 35 
11.1.1 
Treatment-Emergent Adverse Events ............................................. 35 
11.1.2 
Serious Adverse Events .................................................................. 36 
11.1.3 
Other Significant Adverse Events .................................................. 36 
11.1.4 
Adverse Event and Serious Adverse Event Reporting ................... 36 
11.1.5 
Urgent Safety Measures.................................................................. 38 
11.1.6 
Pregnancy Reporting ...................................................................... 39 
12 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .. 40 
13 
REFERENCES ............................................................................................................. 41 
1.2 
List of Tables 
Table 1 
Study Milestones ...................................................................................................... 13 
Table 2 
Study Schedule of Events for Prospective Data Collection ..................................... 19 
Table 3 
Study Schedule of Events for Image Evaluation by Expert Readers ....................... 20 
Table 4 
Blinding of Persons Involved in the Study ............................................................... 20 
Table 5 
Demographic Data to Be Collected .......................................................................... 23 
Table 6 
95% Confidence Interval Width for Different Sample Sizes Assuming 90% 
Diagnostic Accuracy................................................................................................. 26 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AD 
Alzheimer’s Disease 
AE 
Adverse Event 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTECS 
Clinical Trial Emergency Contact Service 
EANM 
European Association of Nuclear Medicine 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EFNS 
European Federation of the Neurological Societies 
EMA 
European Medicines Agency 
ETP 
Electronic Training Programme 
EU 
European Union 
FDA 
Food and Drug Administration 
Flutemetamol 
INN for drug substance  
Flutemetamol (18F) 
Injection 
Generic name for VIZAMYL™. Drug product; the product 
that is injected containing drug substance and excipients 
Flutemetamol (18F) 
Active component of the drug product 
FN 
False Negative 
FP 
False Positive 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
MRI 
Magnetic Resonance Imaging 
NPV 
Negative Predictive Value 
PASS 
Post-authorisation Safety Study 
PET 
Positron Emission Tomography 
PiB 
Pittsburgh Compound B 
PPV 
Positive Predictive Value 
PRAC 
Pharmacovigilance Risk Assessment Committee 
QPPV 
Qualified Person Pharmacovigilance 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SOT 
Standard of Truth 
TN 
True Negative 
TP 
True Positive 
VIZAMYL™ 
Trade name for Flutemetamol (18F) Injection 
 
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3 
RESPONSIBLE PARTIES 
Contact information for investigators and other study personnel is provided in the standalone 
document, “VIZAMYL Study GE067-027 Study Personnel” listed in Annex 1. It is available 
upon request. 
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4 
ABSTRACT 
Title 
A Post-Authorisation Safety Study to Evaluate the Effectiveness of VIZAMYL™ Reader 
Training in Europe. Protocol Version 3.0. 11 December 2019. Main Author: 
 
 GE Healthcare. 
Rationale and background 
VIZAMYL™ (Flutemetamol (18F) Injection) was approved by the United States Food and 
Drug Administration (FDA) on 25 October 2013 and by the European Medicines Agency 
(EMA) on 22 August 2014. VIZAMYL™ is a radiopharmaceutical medicinal product 
indicated for positron emission tomography (PET) imaging of β-amyloid neuritic plaque 
density in the brains of adult patients with cognitive impairment who are being evaluated for 
Alzheimer’s disease (AD) and other causes of cognitive impairment. VIZAMYL™ is for 
diagnostic use only and should be used in conjunction with clinical evaluation. Owing to its 
radioactive nature and consequent short shelf-life, VIZAMYL™ is manufactured on demand in 
response to a valid prescription.  
GE Healthcare was asked by the EMA to conduct a post-authorisation safety study (PASS) to 
determine the rate of VIZAMYL™ image interpretation errors in clinical practice and to 
evaluate the effectiveness of the VIZAMYL™ reader training programme in Europe. This non-
interventional (observational) study, designed in response to those requests, will assess 
effectiveness of the electronic training programme (ETP) in clinical practice by determining 
the diagnostic accuracy of the visual image interpretations made by clinical readers (i.e., 
readers who mainly interpret nuclear medicine images in clinical practice rather than in 
research) in European countries where VIZAMYL™ is commercially available 
 
. Each reader will interpret images from 
his/her site, for a total of at least 200 images across all sites. The standard of truth (SOT) will 
be the majority blinded visual interpretation of 5 expert readers who will independently review 
the same ≥200 images. The majority interpretation is the image interpretation made separately 
by at least 3 of the 5 expert readers (expert readers will not be allowed to discuss images with 
each other and will be blinded to the interpretations of the other expert and clinical readers). 
Research question and objectives 
Primary Objective: 
• Assess effectiveness of the VIZAMYL™ reader training programmes (in-person or 
electronic) in Europe by estimating the diagnostic accuracy, sensitivity, specificity, positive 
predictive value (PPV), and negative predictive value (NPV), of the visual interpretation of 
VIZAMYL™ images obtained in clinical practice. 
Each recruited clinical reader will review (or will have reviewed) the VIZAMYL™ images 
obtained in clinical practice at his/her institution, for a net total of at least 200 subjects across 
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all readers. The SOT will be the majority blinded visual image interpretations of the same 
images by 5 independent expert readers. 
Secondary Objective 
• Evaluate the impact of demographic and other factors (such as method of training, gap 
between training and reading, and country) on diagnostic accuracy to try to identify factors 
that may be associated with image interpretation errors. 
Study design 
Overview 
To evaluate the effectiveness of the VIZAMYL™ reader training programme in Europe, the 
diagnostic accuracy of the visual interpretation of VIZAMYL™ images in clinical practice will 
be determined in this non-interventional PASS. Clinical readers (1 to 5 per country) will be 
recruited from European countries where VIZAMYL™ is commercially available 
 
.  
Clinical readers will interpret (or will have interpreted) VIZAMYL™ images obtained in 
clinical practice (with anatomic images when available and if part of normal practice) at his/her 
institution; a total of at least 200 images will be collected in the study. Following local 
practices at the institution, each reader will interpret (or will have interpreted) images as 
positive (significant levels of amyloid present) or negative (significant levels of amyloid 
absent); these image classifications are consistent with the VIZAMYL™ reader training 
programme, the VIZAMYL™ Summary of Product Characteristics, and the European 
Association of Nuclear Medicine (EANM) guidelines on interpretation of amyloid PET images 
[Minoshima et al. 2016].  
Data from subjects and clinical readers can be obtained prospectively, or existing data can be 
used. An obvious difference between prospective collection of images and collection of 
existing images is that the clinical reader of the existing images would likely be unaware that 
his/her image interpretation would be used in a clinical study, whereas in prospective image 
reads the clinical reader would obviously be aware that his/her interpretation will be collected 
for the study. This will not affect the study results because the clinical interpretation would still 
be conducted blinded to the expert image read (which will occur after the clinical image read in 
every case). Indeed, similar studies of other amyloid imaging agents (Amyvid (florbetapir) and 
Neuraceq (florbetaben) are designed to use existing images to test clinical readers 
[EUPAS11867],[EUPAS12145].  
Data sources will be the images and patient medical records. Image interpretations and other 
data will be recorded directly onto eCRFs; images will be provided electronically. All 
measurements are considered standard for assessment of a diagnostic test. 
Each image interpretation will be compared to the corresponding majority blinded visual 
interpretation of 5 expert readers and sub-classified as true positive (TP), true negative (TN), 
false positive (FP), or false negative (FN). Expert image reads will be obtained prospectively 
from expert readers who consent to participate.  
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Diagnostic accuracy (the percentage of all images correctly interpreted) will be determined 
based on all images. Since the maximum possible value of diagnostic accuracy is 1, one minus 
the diagnostic accuracy will give the overall rate of image interpretation errors. 
The standard measures of diagnostic test performance, sensitivity (TP rate for image 
interpretation), and specificity (TN rate for image interpretation), will also be determined based 
on all images. Other study endpoints will include PPV and NPV. 
All of the above metrics will be determined for subsets of images by country and by reader. 
Further details may be found below in the body of the protocol.  
Population 
At least 200 VIZAMYL™ images will be collected from at least 200 subjects. Subjects will be 
patients who are being (or have been) evaluated for AD and other causes of cognitive 
impairment, who are referred (or were referred) by their physician for a clinically indicated 
VIZAMYL™ PET brain scan. 
The study will be conducted in European countries where VIZAMYL™ is commercially 
available 
. Imaging sites 
that fall within the regions of VIZAMYL™ supply may participate within this study. Imaging 
sites must also meet instrumentation requirements for PET imaging, obtain Independent Ethics 
Committees (IEC) approval of the study protocol, have a reasonable probability of conducting 
amyloid PET imaging (i.e., they must serve the relevant population), agree to obtain written 
informed consent from potential study subjects when required by the IEC, and agree to collect 
and transmit subjects’ study data.  
Each potential clinical reader contacted will be asked to complete a screening survey, which 
asks, among other things, if they are willing to participate in the study, and if they are 
authorised by their institution to read VIZAMYL™ PET images. Those who meet eligibility 
criteria and are willing to participate will be included in the study, 1 to 5 clinical readers per 
country. To avoid overrepresentation of any reader, institution, or country in the study results, 
the following restrictions will apply: 
• No clinical reader may contribute more than 7.5% of the total number of images (e.g., 15 of 
200 images) 
• No institution may contribute more than 15% of the total number of images (e.g., 30 of 200 
images) 
• No country may contribute more than 25% of the total number of images (e.g., 50 of 200 
images) 
The expert readers will consist of 5 experienced nuclear medicine physicians or radiologists, 
with extensive experience in PET imaging (including VIZAMYL™ imaging), who have 
completed the VIZAMYL™ training programme. They may have participated in VIZAMYL™ 
clinical trials. The expert readers will have a minimum of 5 years of experience in nuclear 
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medicine brain imaging and must have reviewed a minimum of 100 amyloid PET images 
within the previous 5 years from the start of the study. 
Variables 
Each clinical reader’s classification of each VIZAMYL™ image as positive or negative will be 
recorded. Each image classification will then be sub-classified as a TP, TN, FP, or FN based on 
a comparison with the majority blinded visual interpretation of 5 expert readers, and the 
numbers of each sub-classification will be used to calculate diagnostic accuracy, sensitivity, 
specificity, PPV, and NPV. Clinical and expert readers will also record their certainty in the 
classification on a scale of 1 to 5 (1 = lowest, 5 = highest).  
Data sources 
Data from subjects and clinical readers can be obtained prospectively, or existing data can be 
used. The clinical interpretations of existing images collected will be obtained from the patient 
medical record. Expert reads will be obtained prospectively from expert readers who consent to 
participate. Data sources will be the images and patient medical records. Image interpretations 
and other data will be recorded directly onto electronic case report forms (eCRFs); images will 
be provided to the Sponsor electronically. All measurements are considered standard for 
assessment of a diagnostic test. 
Study size 
At least 200 VIZAMYL™ images collected from at least 200 subjects will be interpreted by 
clinical readers from the institution where the images were obtained (i.e., each reader will 
interpret only those images collected at his/her institution). The readers’ interpretations will be 
compared to the majority blinded visual interpretations of the same images made subsequently 
by 5 expert readers to determine diagnostic accuracy, sensitivity, specificity, PPV, and NPV. 
Data analysis 
Diagnostic accuracy, sensitivity, specificity, PPV, and NPV value will be determined for each 
reader, and reported as point estimates with exact 95% confidence intervals (CIs).  
Milestones 
Milestone  
Planned date  
Registration in the EU PAS register 
 
Start of data collection  
 
End of data collection  
 
Final report of study results  
 
Study progress reports 
Twice annually 
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5 
AMENDMENTS AND UPDATES 
GE 
Healthcare 
Version 
Number 
Original 
Status 
PRAC 
Version 
Date 
Key Reasons for New Version 
1.0 
Approved 
1.0 
 
Original document. 
2.0 
Approved 
1.0 
 
This document was revised to reformat the protocol to 
the PASS Protocol style. 
3.0 
Approved 
1.0 
 
This document was revised to incorporate the following 
changes: 
• Changed and clarified the number of readers per 
country to avoid overrepresentation of any reader, 
institution, or country in the study. The discussion of 
study limitations was updated to reflect these 
changes. 
• Moved sensitivity, specificity, PPV, and NPV as 
secondary objectives to a primary objective, and 
updated the endpoints and analyses to reflect this 
change. 
• Clarified the definition of positive and negative image 
results to be significant levels of amyloid present and 
absent, respectively. 
• It was added that each reader would provide his/her 
level of certainty for each image classification. 
This version was submitted to, and approved by, the 
EMA. 
4.0 
Approved 
2.0 
 
This document was revised to incorporate the following 
changes: 
• Changed and clarified the readers, countries, and 
subjects to be selected for participation in this study 
to allow for flexibility. 
• The option of classifying an image as indeterminate 
was removed. 
• A reader certainty scale was added. 
• Study milestones were updated. 
5.0 
Effective 
2.0 
 
Administrative changes to clarify the version on the title 
page as the PRAC approved version. In addition, study 
milestones were updated. 
6.0 
Effective 
3.0 
 
The percentage of total number of images allowed to be 
contributed by individual clinical readers, institutions 
and countries has been increased based on commercial 
sales of VIZAMYL™ in order to meet the target 
enrolment for the study. Study milestones have also been 
updated. Updates to text based on current Guideline on 
Good Pharmacovigilance Practices, Module VIII (Rev 3) 
have been implemented. 
This is not considered a substantial amendment, rather 
an update to the study protocol. 
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GE 
Healthcare 
Version 
Number 
Original 
Status 
PRAC 
Version 
Date 
Key Reasons for New Version 
7.0 
 
 
 
The percentage of total number of images allowed to be 
contributed by individual clinical readers, institutions 
and countries has been changed back to the original 
values based on PRAC comments. Study milestones 
have also been updated. The option of collecting existing 
data has been added.  
 
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6 
MILESTONES 
Table 1 
Study Milestones 
Milestone  
Planned date  
Registration in the EU PAS register 
 
Start of data collection  
 
End of data collection  
 
Final report of study results  
 
Study progress reports 
Twice annually 
 
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7 
RATIONALE AND BACKGROUND 
Neuropathological diagnostic criteria for Alzheimer’s disease (AD) include whether or not 
there are neuritic plaques in the brain, and if so, their relative frequency [Khachaturian, 1985]; 
[Mirra et al. 1991]; [NIA-Reagan, 1997]. Plaques can be found in aged cognitively normal 
subjects, so although plaques are necessary for a diagnosis of AD, they are not sufficient 
(neurofibrillary tangles must also be present). On the other hand, the absence of significant 
levels of amyloid plaques in the brain is sufficient to rule out AD. 
Positron emission tomography (PET) imaging using VIZAMYL™, Flutemetamol (18F) 
Injection, is a method to detect abnormal neuritic plaque density. Flutemetamol (18F), the active 
ingredient, is an analogue of Pittsburgh Compound B (PiB; 2-[4-methylamino phenyl]-1, 3-
benzothiazol-6-ol) radiolabelled with the positron-emitting isotope 18F. Both flutemetamol and 
PiB are neutral analogues of Thioflavin T, an accepted histological stain for detecting neuritic 
plaques. PiB was designed to cross the blood-brain barrier, bind to neuritic plaques with high 
affinity at low nanomolar concentrations, and clear rapidly from normal brain tissue. The PET 
imaging properties of PiB derive from the positron-emitting isotope, carbon-11 (11C), which 
has a radioactive half-life of 20 minutes, too short for commercial distribution. The longer 
radioactive half-life of fluorine-18 (110 minutes) permits fluorine-labelled PET amyloid 
imaging agents such as VIZAMYL™ to be distributed commercially, offering more flexibility 
in scheduling of PET imaging. Visual interpretation of flutemetamol (18F) PET images has high 
sensitivity and specificity for the in vivo detection of abnormal brain neuritic plaque density in 
the brain. 
VIZAMYL™ was approved by the United States FDA 25 October 2013 and by the EMA 22 
August 2014. VIZAMYL™ is a radiopharmaceutical medicinal product indicated for PET 
imaging of β-amyloid neuritic plaque density in the brains of adult patients with cognitive 
impairment who are being evaluated for AD and other causes of cognitive impairment. 
VIZAMYL™ is for diagnostic use only and should be used in conjunction with clinical 
evaluation. Owing to its radioactive nature and consequent short shelf-life, VIZAMYL™ is 
manufactured on demand in response to a valid prescription. 
The efficacy of VIZAMYL™ was established in 2 pivotal clinical studies, GE067-007 and 
GE067-026. Both studies used histopathological analysis of brain tissue as the SOT to confirm 
VIZAMYL™ PET scan findings. 
Study GE067-007 used 5 blinded independent readers to interpret VIZAMYL™ scans. These 
readers had been trained to interpret VIZAMYL™ images using an in-person training 
programme. Four of the readers showed high sensitivity and specificity, while the last reader 
showed high sensitivity but lower specificity [Curtis et al. 2015]. Analysis of reader 
performance resulted in recommendations for changes in the training programme, which were 
incorporated into an electronic training programme (ETP) which GE Healthcare developed to 
avoid the need for time-intensive, in-person training. The effectiveness of the ETP was 
evaluated in a clinical study (GE067-021) by estimating post-training sensitivity and specificity 
for each of 5 readers previously naïve to VIZAMYL™ image interpretation; each reader 
showed high sensitivity and specificity, indicating that the ETP was effective [Buckley et al. 
2017]. 
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Subsequently, GE Healthcare was asked by the EMA to analyse additional brains that had been 
collected but not yet analysed in Study GE067-007. This study, GE067-026, analysed data 
from 106 subjects for whom histopathological analyses of brain tissue were available. Five new 
readers were used to read the 106 images, and these readers were trained with the ETP, in 
contrast to Study GE067-007. This study also showed high sensitivity and specificity for all 
readers [Salloway et al. 2017].  
Few, if any, diagnostic tests are perfect, and thus, sensitivity and specificity are rarely both 
100%. This means that false-positive (FP) and false-negative (FN) results are possible. Because 
these inaccurate results may be acted on by physicians, FP and FN test results are potential 
safety issues. Image interpretation errors were thus included in the VIZAMYL™ Risk 
Management Plan, and the VIZAMYL™ Summary of Product Characteristics contains 
language recommending that all readers of VIZAMYL™ images first undergo training in the 
interpretation of VIZAMYL™ images.  
In addition, GE Healthcare was asked by the EMA to conduct a study to determine the rate of 
VIZAMYL™ image interpretation errors in clinical practice and to evaluate the effectiveness 
of the reader training programme in Europe.  
This study, designed in response to those requests, will assess effectiveness of the training 
programme (in-person or electronic) in clinical practice by determining the diagnostic accuracy 
of the visual image interpretations made by clinical readers (i.e., readers who mainly interpret 
nuclear medicine images in clinical practice rather than in research) in European countries 
where VIZAMYL™ is commercially available 
 
. Each reader will interpret (or will have interpreted) images from 
his/her site, for a total of at least 200 images across all sites. The SOT will be the majority 
blinded visual interpretation of 5 expert readers who will independently review the same ≥200 
images. The majority interpretation is the image interpretation made separately by at least 3 of 
the 5 expert readers (expert readers will not be allowed to discuss images with each other and 
will be blinded to the interpretations of the other expert and clinical readers). 
Description of the Training Programme 
The content of the training programme that is being made available to European physicians to 
support clinical practice is essentially identical to the content used in Studies GE067-021 and 
GE067-026. It contains the following modules, which include a final test. The trainee must 
correctly assess a minimum of 14 cases (93%) out of 15 to successfully complete the training. 
• Brain anatomy in magnetic resonance imaging (MRI) and PET 
• Image orientation & displaying images 
• Reviewing images 
• Pre-test cases (10) with guided reviews 
• Test cases (15) with reviews in the event of incorrect assessment and second test cases 
(15) in the event of not passing the test on the first 15 cases 
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8 
RESEARCH QUESTIONS AND OBJECTIVES 
The research question to be answered by this study is: How effective is the VIZAMYL™ reader 
training programme in clinical practice in Europe? To answer this question, the study has the 
following primary and secondary objectives. 
Primary: 
The primary study objective is to assess the effectiveness of the VIZAMYL™ reader training 
programmes (in-person or electronic) in Europe by estimating the diagnostic accuracy, 
sensitivity, specificity, PPV, and NPV, of the visual interpretation of VIZAMYL™ images 
obtained in the course of clinical practice. Diagnostic accuracy is the overall true-interpretation 
rate for all subjects. One minus the diagnostic accuracy gives the overall image interpretation 
error rate.  
At least 200 VIZAMYL™ images obtained in clinical practice will be reviewed (or will have 
been reviewed) by clinical readers recruited from European countries where VIZAMYL™ is 
commercially available 
 
. The SOT will be the majority blinded visual image interpretations of the same images 
by 5 independent expert readers. 
Secondary: 
The secondary study objective is: 
Evaluate the impact of demographic and other factors (such as method of training, gap between 
training and reading, and country) on diagnostic accuracy to try to identify factors that may be 
associated with image interpretation errors. 
Sensitivity is the true-positive (TP) image interpretation rate in subjects with brain amyloid. 
Specificity is the true-negative (TN) image interpretation rate in subjects without brain 
amyloid. Positive predictive value (PPV) is the TP image interpretation rate for subjects with 
positive VIZAMYL™ scans. Negative predictive value (NPV) is the TN image interpretation 
rate for subjects with negative VIZAMYL™ scans.  
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9 
RESEARCH METHODS 
9.1 
Study Design 
9.1.1 
Overall Study Design and Plan 
This is a non-interventional PASS with the primary objective of assessing effectiveness of the 
VIZAMYL™ reader training programmes (in-person or electronic) in Europe by estimating the 
diagnostic accuracy of the visual interpretation of VIZAMYL™ images by clinical readers 
recruited from European countries where VIZAMYL™ is commercially available 
 
 (each reader will interpret (or will 
have interpreted) images collected at his/her institution, for a total of at least 200 images). The 
diagnostic accuracy of image interpretation will be determined across all images as well as for 
subsets of images by country and by reader. Sensitivity, specificity, PPV, and NPV will also be 
determined and will be reported as point estimates along with exact 95% CIs. The SOT for 
classifying each image as correct (TP or TN) or incorrect (false positive or false negative) will 
be the majority blinded visual interpretations of 5 independent expert readers.  
Imaging sites will be selected according to the criteria detailed below in Section 9.2.2. Each 
imaging site will be assigned a 3-digit identifying number. The VIZAMYL™ images at each 
participating site will be obtained in clinical practice. Because VIZAMYL is approved and no 
longer investigational, the need for subject informed consent will be decided at each institution 
by the local IEC.  
All subjects must satisfy all the inclusion criteria and none of the exclusion criteria listed in 
Section 9.2.3. When required by the local IEC, signed and dated informed consent must be 
obtained from all subjects or the subject’s legally acceptable representative, if applicable, in 
accordance with local regulations, prior to collection of any study-specific data. Each subject 
will be assigned a 7-digit identifying number; the first 3 digits will be the identifying number 
for the site at which the subject’s VIZAMYL™ scan was obtained (as described in the 
preceding paragraph), and the remaining 4 digits will be assigned consecutively at each site. 
Demographic data (see Table 5) will be recorded for each subject. 
The images will be de-identified (i.e., subject identifying information will be removed) so that 
inspection of an image will not reveal the identity of the subject from whom the image was 
obtained. 
If anatomic images are used in the interpretation of the VIZAMYL™ images, they will also be 
de-identified and transmitted to the core image lab, and will be interpreted with the 
VIZAMYL™ images by the expert readers.  
The clinical reader eligibility criteria are discussed below in Section 9.2.4. Demographic data 
(see Table 5) will be recorded for each clinical reader. Each clinical reader will be assigned an 
identifying letter that starts with C (for Clinical): CA, CB, CC, etc. 
During the image interpretations, the clinical readers will not be (or were not) blinded to the 
subjects’ clinical information, but will be blinded to the interpretations of the expert readers 
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(which will not be available yet). Each clinical reader will interpret the VIZAMYL™ images 
as they are collected at his/her site. VIZAMYL™ images will be interpreted as positive 
(significant levels of amyloid present) or negative (significant levels of amyloid absent) 
according to local practices at the institution; these classifications are consistent with the 
VIZAMYL™ reader training programme, the VIZAMYL™ Summary of Product 
Characteristics, and the EANM guidelines on interpretation of amyloid PET images 
[Minoshima et al. 2016]. If anatomic images (MRI and/or computed tomography [CT]) are 
available for a subject, the normal institutional clinical practice regarding use of these images 
in PET interpretation will be followed. The clinical reader will enter his/her interpretation and 
other data into an eCRF. The site will remove identifying information (except for subject 
number) from the image and transmit the image electronically to the GE Healthcare image core 
lab.  
The image core lab will assign a randomization code to the image and will remove the subject 
number.  
The ≥200 images collected in this study will be interpreted separately by each of 5 expert 
readers, who will classify each image as positive or negative for brain amyloid. The expert 
readers will consist of 5 experienced nuclear medicine physicians or radiologists, with 
extensive experience in PET imaging (including amyloid imaging), who have completed a 
VIZAMYL™ training programme. The selection criteria for these 5 expert readers are detailed 
below in Section 9.2.6. The expert readers will be blinded to the subjects’ clinical information 
and to the interpretations of the other expert readers and clinical readers, and will not be 
permitted to discuss images or interpretations with anyone. The expert read will result in at 
least 200 x 5 = 1000 expert blinded visual interpretations, which will be analysed by subject to 
determine the majority blinded visual interpretation, as follows. Each image will have 5 expert 
interpretations, each of which will be positive or negative. The image interpretation (positive or 
negative) made by the majority of the 5 expert readers will be taken as the majority 
interpretation. For example, if 3, 4, or 5 of the expert readers interpreted a specific subject’s 
image as positive, then the majority interpretation for that image will be positive. The result of 
this analysis will be at least 200 majority interpretations (1 per image). The level of reader 
certainty will also be recorded on a scale of 1 to 5 (1 = lowest, 5 = highest).  
Using subject number, each of the ≥200 clinical image interpretations will be matched to the 
corresponding expert reader majority interpretation for the subject and the image interpretation 
will be classified as a TP, TN, FP or FN using the expert reader majority interpretation as the 
SOT. For example, if an image interpretation is “positive” and the expert reader majority 
interpretation is “positive”, the image interpretation would be classified a TP. If the expert 
reader majority interpretation were “negative”, however, then the image interpretation would 
be classified as a FP. The numbers of TP, TN, FP, and FN images among the ≥200 original 
images will be used to calculate diagnostic accuracy: 
Diagnostic accuracy = (nTP + nTN) / (nTP + nTN + nFP + nFN) 
Where nTP is the number of true-positive scans, nTN is the number of true-negative scans, nFP 
is the number of false-positive scans, and nFN is the number of false-negative scans. 
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Sensitivity, specificity, PPV, and NPV will also be calculated: 
Sensitivity = nTP / (nTP + nFN) 
Specificity = nTN / (nTN + nFP) 
PPV = nTP / (nTP + nFP) 
NPV = nTN / (nTN + nFN) 
Treatment-emergent adverse events (AEs) with onset or worsening between the start of 
VIZAMYL™ injection and subject discharge from the imaging suite will be recorded on an 
AE eCRF, along with the centre’s assessment of relationship to VIZAMYL™, severity, 
seriousness, timing, need for treatment, and outcome.  
Study procedures for prospective data collection are summarised in the Study Schedule of 
Events for Prospective Data Collection (Table 2). For collection of existing data, the activities 
in the “Subject Enrolment” and “Imaging Visit” columns in Table 2 will have occurred in the 
past and may be obtained from the medical record, including whether or not the patient meets 
the inclusion and exclusion criteria. .  
Table 2 
Study Schedule of Events for Prospective Data Collection 
Procedures 
Subject 
Enrolment 
Imaging 
Visit 
Post-
Imaging 
Responsible 
Selection of imaging sites 
 
 
 
Sponsor 
Informed consent obtained from subject (if IEC 
requires) 
X 
 
 
Centre 
Subject inclusion/exclusion criteria assessed 
X 
 
 
Centre 
Subject demographic information recorded 
X 
 
 
Centre 
VIZAMYL™ administration and PET imaging; AE 
monitoring from start of injection until discharge 
from imaging centre 
 
X 
 
Centre 
Completion of electronic case report form 
 
 
X 
 
De-identification of subject’s images 
 
 
X 
Centre 
Transmittal of subject’s images to Sponsor image 
core lab 
 
 
X 
Centre 
Preparation of images for expert readers 
 
 
X 
Sponsor 
 
The image evaluation by expert readers will be prospective; these activities are summarised in 
Table 3.  
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Table 3 
Study Schedule of Events for Image Evaluation by Expert Readers 
Procedures 
Expert 
Selection 
Expert  
Image 
Evaluation 
Responsible 
Identification of expert reader candidates 
X 
 
Sponsor 
Informed consent obtained from expert reader 
candidates 
X 
 
Sponsor 
Expert reader candidate inclusion/exclusion criteria 
assessed 
X 
 
Sponsor 
Selection of 5 expert readers 
X 
 
Sponsor 
Expert reader demographic information recorded 
X 
 
Sponsor 
Independent review of images 
 
X 
Readers 
 
The criteria for blinding are shown below in Table 4. 
Table 4 
Blinding of Persons Involved in the Study 
Personnel 
Blinded To: 
Subjects 
Expert readers’ image interpretations 
Imaging Centre Site Personnel 
Expert readers’ image interpretations 
Clinical Readers 
Other clinical readers’ image interpretations 
Expert readers’ image interpretations 
Expert Readers 
Clinical readers’ image interpretations  
Other expert readers’ image interpretations 
Subject clinical information  
 
No direct benefits to subjects enrolled in this study are expected. Each subject will be referred 
for a VIZAMYL™ scan according to clinical need determined by his/her physician. The 
potential risks to subjects are described in the VIZAMYL™ Summary of Product 
Characteristics, and include adverse drug reactions and image interpretation errors.  
9.2 
Setting 
This study will allow patients and clinical readers from any healthcare setting (i.e., primary, 
secondary, and tertiary care) to participate. However, it is anticipated that referrals for 
VIZAMYL™ imaging will be made predominantly by specialists (e.g., neurologists and 
psychiatrists) rather than by primary care physicians and that a substantial proportion will be 
made by dementia specialists who may be based in tertiary care centres. It is anticipated that 
the main use of amyloid PET imaging will be to assist in the diagnosis of cases of dementia 
that are difficult because of atypical symptoms and/or early onset), as suggested by the 
European Federation of the Neurological Societies (EFNS) task force’s publication on the use 
of neuroimaging in the diagnosis of dementia [Filippi et al. 2012]. The type of medical practice 
for the referring physicians and for the readers will be collected as part of the demographic 
data. 
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9.2.1 
Selection and Replacement of Countries 
The study will be conducted in European countries where VIZAMYL™ is commercially 
available 
.  
9.2.2 
Selection and Replacement of Imaging Sites 
Because of the short radioactive half-life (~110 minutes) of the fluorine 18 isotope in 
[18F]flutemetamol (the active component of VIZAMYL™), the ability to supply VIZAMYL™ 
is limited to within a finite radius around each manufacturing site, and therefore only imaging 
sites that fall within the regions of VIZAMYL™ supply may participate.  
Imaging sites must also meet the instrumentation requirements for PET imaging, obtain 
Independent Ethics Committee (IEC) approval of the study protocol, have a reasonable 
probability of conducting amyloid PET imaging (i.e., they must serve the relevant population), 
agree to obtain written informed consent from potential study subjects when required by the 
IEC, and agree to collect and transmit subjects’ study data.  
9.2.3 
Selection and Replacement of Subjects 
Subjects who receive VIZAMYL™ as part of routine clinical practice will be eligible; patients 
scheduled for a VIZAMYL™ scan as part of a clinical study will be excluded from this study. 
When required by the local IEC, subjects must provide written informed consent before any 
study-specific data are collected. A subject will be considered enrolled in the study if he/she 
has provided written informed consent (if required) and any study-specific data have been 
collected about the subject. Subjects meeting the following criteria may be enrolled: 
1. The subject is an adult (aged 18 years or older) of any race or gender and has been referred 
for a VIZAMYL™ PET brain scan as part of the assessment of his/her cognitive 
impairment. 
2. The VIZAMYL™ scan was ordered as part of the clinical care of the subject and is not 
exclusively for a clinical trial.  
3. If informed consent is required by the local IEC, the subject, or his/her legally authorised 
representative, is willing and able to sign consent for use of their de-identified 
VIZAMYL™ PET images and associated anatomic images (brain CT and/or MRI) used in 
the interpretation of the VIZAMYL™ images as well as de-identified demographic 
information.  
Subjects must be excluded from this study if the following criterion is met: 
1. If informed consent is required by the local IEC, the subject (or representative) is not 
willing to consent to their de-identified images and other data being used in this study. 
No withdrawal criteria for this study have been formalised. In accordance with the Declaration 
of Helsinki, each consenting subject is free to withdraw from the study at any time. Subjects 
who withdraw from the study will be asked if their de-identified data may be used; if consent 
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to use their de-identified data is withdrawn, every effort will be made to exclude their data 
from analysis. Incomplete data sets from withdrawn subjects may be excluded from analysis 
even if permission has been granted for use if critical data are missing. Subjects whose data are 
excluded from analysis may be replaced. 
No termination criteria for this study have been formalised. The Sponsor reserves the right to 
terminate the study at any time. 
9.2.4 
Inclusion and Exclusion of VIZAMYL™ Images 
To be included in efficacy analyses, a subject’s VIZAMYL™ PET scan must be interpretable 
and it must be transferred to the Sponsor.  
Interpretability of the image will be determined by the nuclear medicine personnel obtaining 
the PET scan at each imaging centre. For example, if the subject moves during the scan, the 
scan may be severely blurred and therefore uninterpretable. Images that are not interpretable 
will be excluded from efficacy analyses and the subject data will be included in safety analyses 
only. Additional images may be collected to ensure a minimum of interpretable 200 images.  
Images that cannot be transferred to the Sponsor for technical reasons will not be included in 
analyses and subject data will be included in safety analyses only. Additional images may be 
collected, if necessary, to ensure a minimum of 200 images total for the efficacy analyses.  
9.2.5 
Selection and Replacement of Clinical Readers 
Potential clinical readers will be identified in each of the European countries where 
VIZAMYL™ is commercially available 
 
. They cannot be one of the readers selected to be an expert reader, and cannot 
have participated in any of the VIZAMYL™ clinical trials sponsored by GE Healthcare. They 
must consent to have demographic information collected about them.  
Each potential clinical reader contacted will be asked to complete a screening survey, which 
asks, among other things, if they are willing to participate in the study, and if they are 
authorised by their institution to read VIZAMYL™ PET images. Those who meet eligibility 
criteria and are willing to participate will be included in the study, 1 to 5 clinical readers per 
country. 
To avoid overrepresentation of any reader, institution, or country in the study results, the 
following restrictions will apply: 
• No clinical reader may contribute more than 7.5% of the total number of images (e.g., 15 of 
200 images) 
• No institution may contribute more than 15% of the total number of images (e.g., 30 of 200 
images) 
• No country may contribute more than 25% of the total number of images (e.g., 50 of 200 
images) 
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Additional clinical readers may be added as necessary to replace clinical readers who 
withdraw. In the event that a clinical reader withdraws, the reason for withdrawal will be 
recorded, and permission to use his/her data will be sought; if declined, he/she will be replaced 
and his/her data will not be used.  
9.2.6 
Selection and Replacement of Expert Readers 
The expert readers will consist of 5 experienced nuclear medicine physicians or radiologists, 
with extensive experience in PET imaging (including VIZAMYL™ imaging), who have 
completed the VIZAMYL™ training programme. They may have participated in VIZAMYL™ 
clinical trials. The expert readers will have a minimum of 5 years of experience in nuclear 
medicine brain imaging and must have reviewed a minimum of 100 amyloid PET images 
within the previous 5 years from the start of the study. 
In the event that an expert reader withdraws, the reason for withdrawal will be recorded. If the 
expert reader withdraws before reading all of the images, or withdraws permission to use 
his/her demographic information, he/she will be replaced. The replacement reader will be 
asked to read all images and his/her results will be used. The incomplete results from the expert 
reader who withdrew will not be used.  
9.3 
Variables 
9.3.1 
Demographic Data 
The demographic data listed in Table 5 will be collected about subjects and readers. In 
addition, every effort will be made to collect these data from readers who decline to participate 
as well. 
Table 5 
Demographic Data to Be Collected 
Group 
Demographic Factors 
Subjects 
• Age 
• Gender 
• Race 
• Reason for scan 
• Country 
• Imaging centre 
• Type of medical practice of referring physician (primary, secondary, tertiary) 
• VIZAMYL™ dose in MBq or mCi 
• Type of anatomic images available, if any (MRI and/or CT) 
Clinical readers 
• Age 
• Gender 
• Race 
• Country 
• Institution 
• VIZAMYL™ reading training status 
• VIZAMYL™ reading training method (electronic, in-person, or both) 
• Date(s) of VIZAMYL™ reading training (this will be used to determine the time from 
last training to the date of image interpretation) 
• Training with other amyloid PET imaging agents 
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Table 5 
Demographic Data to Be Collected 
Group 
Demographic Factors 
• Medical specialty 
• Years of experience reading PET images 
• Number of brain PET scans read in clinical practice 
• Type of medical practice (primary, secondary, tertiary) 
• Prior experience (clinical or research) with any amyloid PET imaging agent (including 
VIZAMYL™)  
 
9.3.2 
Exposures 
Subjects will receive (or will have received) VIZAMYL™ intravenously prior to PET imaging, 
according to clinical practice. 
Clinical readers may or may not have completed any training in reading VIZAMYL™ images, 
and some may have completed 1 or more VIZAMYL™ reader training programmes. They also 
may or may not have prior experience in reading VIZAMYL™ images.  
Expert readers will have been trained in reading VIZAMYL™ images and will have 
experience in reading amyloid PET images. 
9.3.3 
Outcome Measures 
The primary outcome measure will be diagnostic accuracy (point estimates and exact 95% CIs) 
determined across all images (at least 200 images), as indicators of the collective proficiency of 
the clinical readers at interpreting VIZAMYL™ PET images. Diagnostic accuracy will give an 
indication of the overall image interpretation error rate (1 minus diagnostic accuracy). 
Additional outcome measures will be sensitivity, specificity, PPV, and NPV.  
9.3.4 
Risk Factors 
Demographic variables about the clinical readers will be analysed to try to determine reader-
associated variables associated with image interpretation errors.  
9.3.5 
Co-Morbidities 
Except for structural abnormalities of the brain (which can be detected on MRI and/or CT and 
possibly adjusted for during PET image interpretation), there are no known co-morbidities that 
would affect PET image interpretation.  
The AE profile in patients with renal impairment and/or hepatic impairment is currently 
unknown. In accordance with the current risk management plan for VIZAMYL™, a history of 
renal impairment and/or hepatic impairment will be captured in the eCRF. For documentation 
of AEs in these patients see Section 11.1.4. 
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9.3.6 
Co-Medications 
There are no known drug interactions that would affect image interpretation and so data on co-
medications will not be collected.  
9.3.7 
Potential Confounders and Effect Modifiers 
Potential factors that may affect image interpretation are brain atrophy, enlarged ventricles, and 
intracranial masses (which may distort brain anatomy). These can be detected on MRI and/or 
CT scans (which should be available for most if not all subjects as they are a standard 
component of patient workup for cognitive impairment) and taken into account during PET 
image interpretation.  
9.4 
Data Sources 
9.4.1 
Strategies and Data Sources 
Data from subjects and clinical readers can be obtained prospectively, or existing data can be 
used. Expert image reads will be obtained prospectively from expert readers who consent to 
participate. Data sources will be the images and patient medical records. Image interpretations 
and other data will be recorded directly onto eCRFs; images will be provided electronically. 
All measurements are considered standard for assessment of a diagnostic test. 
Consenting eligible clinical readers (1 to 5 per country) will be selected and demographic 
information about them will be collected. They will each read VIZAMYL™ PET images 
obtained in clinical practice to generate the primary data that will be used to determine 
diagnostic accuracy. 
Participating subjects will have been administered VIZAMYL™ intravenously and will have 
subsequently undergone PET brain imaging. Demographic information about the subject will 
be obtained from the imaging site where the subject is/was scanned. All VIZAMYL™ PET 
images (at least 200 images) and any associated anatomic images (brain CT and/or MRI) in 
this study will be acquired as part of clinical practice in Europe. 
9.4.2 
Expert Committees 
Five consenting expert readers will each be asked to separately and independently read the 
images obtained in clinical practice from the subjects, and their majority image interpretations 
will be used as the SOT for determining diagnostic accuracy, sensitivity, specificity, PPV, and 
NPV. The interpretation of the images by the expert readers may be split up into multiple small 
reads for convenience as well as to accrue data steadily throughout the study.  
9.5 
Study Size 
Number of Subjects 
This study has no formal hypothesis and no statistical tests will be performed. The endpoints of 
accuracy, sensitivity, and specificity will be summarised descriptively with point estimates and 
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95% CIs. Although no formal hypothesis will be tested, the sample size is determined to 
achieve the desired precision in estimating the primary endpoint of the percentage of subjects 
whose images are correctly classified as positive or negative (accuracy). Assuming that 
VIZAMYL™ images from 90% of subjects are read correctly by readers who have taken the 
VIZAMYL™ training programme, 200 subjects will achieve a 95% CI width of less than 10%.  
The endpoints of sensitivity and specificity will also be summarised descriptively. This study 
aims to characterise reader performance in clinical practice so the number of positive and 
negative images will not be controlled. However, it is expected that most patients who are 
referred for a VIZAMYL™ scan will have dementia, and most cases of dementia are AD. 
Since brain amyloid is present in AD, it is expected that the majority of patients in this study 
will have brain amyloid. It is assumed that the majority blinded interpretation of the expert 
readers will be SOT-positive for approximately 65% of scans, giving a total of approximately 
130 scans for sensitivity, with the remaining 70 scans being SOT-negative and therefore usable 
for calculating specificity. Assuming a sensitivity of 90% and a specificity of 90%, these 
sample sizes should give reasonably precise 95% CIs for estimating sensitivity and specificity 
in this scenario (95% CI width of approximately 15% or less). 
Accuracy, sensitivity, and specificity will also be calculated by country where all study images 
from sites within a given country will be pooled for analysis. No country may contribute more 
than 25% of the total number of images. Because the number of subjects per country is smaller 
than the overall number of subjects, the level of precision and the width of the CI will be 
impacted. Again, since the aim of the study is to characterise reader performance in clinical 
practice, the exact number of images obtained per country and per site is unknown. Table 6 
provides examples of 95% CI widths for accuracy assuming a few different sample sizes per 
country to illustrate the change in precision. 
Table 6 
95% Confidence Interval Width for Different Sample Sizes Assuming 90% 
Diagnostic Accuracy 
Sample Size 
Actual 95% CI Width 
Lower Confidence 
Limit 
Upper Confidence 
Limit 
30 
24.4% 
73.5% 
97.9% 
40 
20.9% 
76.3% 
97.2% 
50 
18.5% 
78.2% 
96.7% 
60 
16.7% 
79.5% 
96.2% 
 
When calculating sensitivity and specificity per country, precision will again be impacted 
because the sample size per country will be further divided into SOT-positive and SOT-
negative scans. For example, if a country enrols 40 subjects and 65% of the scans are SOT-
positive (n = 26) then the width of the 95% CI for sensitivity would be 26.4% (lower 
confidence limit = 71.8%) and the width for specificity would be 37% (lower confidence limit 
= 62.4%).  
Accuracy by reader will also be presented in a tabular form, though it may be expected that 
some institutions will have very few scans per reader. 
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Number of Clinical Readers 
The number of clinical readers (1 to 5 per country) was chosen to allow each European country 
where VIZAMYL™ is commercially available 
 
 to be represented.  
Number of Expert Readers 
The number of expert readers (5) was chosen based on precedent set in prior clinical studies of 
VIZAMYL™.  
9.6 
Data Management 
9.6.1 
Data Collection 
Non-imaging data will be collected directly from sites, clinical readers, and expert readers 
using eCRFs. Images will be transferred from imaging sites to the Sponsor using electronic 
transfer protocols.  
9.6.2 
Data Monitoring 
Data will be monitored for completeness and logic using electronic edit checks, manual data 
listing review, and source data verification.  
9.6.3 
Data Retrieval from Sites 
This is described above in Section 9.6.1.  
9.6.4 
Data Preparation 
When necessary, the Sponsor or a designee will remove identifying information from the ≥200 
VIZAMYL™ PET images, which thereafter will be designated only by subject number.  
The images received by the GE Healthcare core lab will have been transferred by a system 
which de-identifies the images. This will be confirmed in a quality control step when images 
are received.  
9.6.5 
Data Management and Statistical Hardware 
An electronic data capture (EDC) system will be used to collect data. A single data 
management contract research organization (CRO) will oversee the data collection at all sites. 
The data management CRO will be responsible for developing the database, training site 
personnel to enter data, data cleaning, and query resolution. The handling of data, including 
data quality control, will comply with all applicable regulatory guidelines. Appropriate access 
controls will be built into the database to ensure image blinding is maintained. The data 
management process will be outlined in more detail in the Data Management Plan.  
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9.7 
Data Analysis 
The data will be analysed by the sponsor-designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to the Sponsor before publication or 
presentation. 
Data from participating centres in this protocol will be combined so that an adequate number of 
subject images will be available for analysis. The data will be summarised with respect to 
demographic characteristics and efficacy observations and measurements. 
General Statistical Considerations 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed using SAS software, Version 9.3 or higher. Descriptive statistics for continuous 
data in summary tables will include the number of subjects in the analysis (n), mean, standard 
deviation, median, and range (minimum, maximum). Descriptive statistics for categorical data 
in summary tables will include counts and percentages. All data entered into the database will 
be provided in separate data listings showing individual subject values. The planning and 
reporting of statistical analysis will be carried out as described in the Sponsor and CRO’s 
standard operating procedures (SOPs) governing clinical studies. Details of the analysis will be 
provided in the Statistical Analysis Plan. 
Missing values will not be substituted by estimated values, but treated as missing in the 
statistical evaluation. All data from all subjects enrolled and imaged in the study will be 
included in all listings, plots, summary tables, and statistical analyses when appropriate. 
Subjects who do not meet the definition of the evaluable population will be excluded from the 
analyses. This will be determined prior to database freeze and image unblinding.  
Any deviations from the statistical analysis outlined in this protocol will be described, and 
reasons for the deviations listed, in the final Clinical Study Report. 
Populations for Analysis 
The safety population will consist of all subjects who were enrolled in the study and received a 
dose of VIZAMYL™.  
The efficacy subject population will consist of all subjects who have an interpretable image 
that has an available expert majority image interpretation. 
The efficacy clinical reader population will consist of each clinical reader who has interpreted 
the images included from his/her institution and has had their image interpretations classified 
as TP, TN, FP, or FN through comparison with the SOT (the expert reader majority 
interpretation).  
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Subject Demographics/Other Baseline Characteristics 
A table will be provided with the following information: 
• 
Number of subjects enrolled. 
• 
Number of subjects in the safety population. 
• 
Number of subjects with VIZAMYL™ images included in the efficacy analysis. 
Demographic information (Table 5 above) will be summarised using descriptive statistics.  
Study Treatments 
All subjects will have received VIZAMYL™ as part of routine clinical practice. The dose and 
volume administered will be summarised across all subjects.  
Clinical Reader Demographics/Other Baseline Characteristics 
A table will be provided with the following information: 
• 
Number of clinical readers participating. 
• 
Number of clinical readers’ image interpretations included in the efficacy analysis. 
Demographic information (Table 5 above) will be summarised using descriptive statistics. 
Demographic information will be reported for readers who are randomly chosen to participate 
as well as the complete pool of potential readers who agreed to participate in addition to 
readers who decided not to participate where data are available.  
Primary Analysis 
The primary analysis will be the determination of diagnostic accuracy, sensitivity, specificity, 
PPV, and NPV across readers based on all evaluable images (at least 200 images) (point 
estimates and exact 95% CIs).  
Secondary Analyses 
The numbers and percentages of images for which 5 expert readers agree, 4 expert readers 
agree, and 3 expert readers agree will be summarised. In addition, results will be analysed by 
the following variables: 
• Country 
• Time from training to image interpretation (<6 months, >6 months) 
• Specialty of the reader 
• Training method(s) used by the clinical reader (in-person, electronic, or both) 
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• Number of scans read by the clinical reader in practice prior to the study (<50, >50) 
• Reader classification certainty (1 to 5) 
The by-variable summaries will include estimates of diagnostic accuracy, sensitivity, 
specificity, PPV, and NPV along with 95% CIs for data pooled within each category. They will 
also show the number of clinical readers in each category and the number and percentage of 
clinical readers in each category with diagnostic accuracy <70%, >70% to ≤80%, >80% to 
≤90%, and >90%.  
The certainty of image classification will be summarised.  
Safety Analyses 
The number and percentage of subjects with 1 or more treatment-emergent AEs will be 
summarised. Additionally, treatment-emergent AEs will be coded and summarised by system 
organ class and preferred term. Treatment-emergent AE summaries will be provided by 
relationship to study drug and severity. Treatment-emergent serious AEs (SAEs) will also be 
summarised. 
Interim Analysis 
No formal interim analyses of the data are planned for this study. Interim progress reports of 
enrolment and safety will be provided annually.  
Analyses of Study Limitations 
Please see Section 9.9 below. 
Evaluation of Impact of Study Results on Marketing Authorisation 
The Sponsor will evaluate whether the study results have an impact on the marketing 
authorisation and will, if necessary, submit to the EMA an application to vary the marketing 
authorisation. 
9.8 
Quality Control 
9.8.1 
Mechanisms and Procedures to Ensure Data Quality and Integrity 
For eCRFs, data will be entered by trained site personnel with reasons given for any missing 
data. Any errors should be corrected within the electronic system. The audit trail will record all 
changes made, the date and time of the correction, and the person correcting the error. The 
appropriate electronic signature will be provided. Any data recorded directly in the eCRF, for 
which no other written or electronic record will be maintained in the subject’s medical record, 
will be considered source data and should be signed by the investigator(s). Data collected from 
sites via eCRFs will be subject to source verification and edit checks for completeness, 
consistency, and logic.  
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Audit and Inspection 
The Sponsor will ensure that the analytical dataset and statistical programmes used for 
generating the data included in the final study report are kept in electronic format and are 
available for auditing and inspection. 
According to International Conference on Harmonization (ICH) E6-Good Clinical Practice 
(GCP), the Sponsor or regulatory authorities may audit the investigational site. The Sponsor’s 
Quality Assurance Unit, independent of the Clinical Research and Development Department, is 
responsible for auditing the study. 
The investigator(s) must accept that regulatory authorities may conduct an inspection to verify 
compliance of the study with GCP. 
Confidentiality Regarding Study Subjects 
The investigator(s) must assure that the privacy of the subjects, including their personal 
identity and all other personal medical information, will be maintained at all times. In eCRFs 
and other documents or image material (including materials from all examinations, e.g., CT, 
PET, and MRI examinations) submitted to the Sponsor/CRO, subjects will not be identified by 
their names, but by an identification code (e.g., study subject number). 
Personal medical information may be scrutinised for the purpose of verifying data recorded in 
the eCRF. This may be done by the monitor(s), properly authorised persons on behalf of the 
Sponsor, the quality assurance unit, or regulatory authorities. Personal medical information will 
always be treated as confidential. 
9.8.2 
Source Data Verification 
Source data verification will be conducted by the CRO. The monitor(s), auditor(s), authorised 
personnel of the Sponsor/CRO, health authority inspector(s) or their agents, and authorised 
members of the IECs will be given direct access to source data and documentation 
(e.g., medical charts/records, laboratory results, printouts, videotapes, etc.) for source data 
verification, provided that subject confidentiality is maintained in accordance with local 
requirements. Image evaluation data from the clinical readers and expert readers will be 
entered directly into the eCRF and so no source verification is required. 
9.8.3 
Validation of Endpoints 
The endpoints (diagnostic accuracy, sensitivity, specificity, PPV, and NPV) are well accepted 
for assessing diagnostic test performance. The endpoints of inter-reader agreement and intra-
reader reproducibility will not be possible because each reader will interpret only the images 
collected at his/her institution, and it is assumed that each reader will interpret each image only 
once.  
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9.8.4 
Storage of Records including Archiving of Statistical Programming 
All study documentation will be archived in accordance with ICH E6- GCP and the 
Sponsor/CRO’s quality standards and SOPs. 
The Sponsor will ensure that all study information is handled and stored to allow for accurate 
reporting, interpretation and verification of that information and shall ensure that the 
confidentiality of the records of the study subjects remains protected. 
9.8.5 
Certification and Qualifications of Supporting Laboratory or Research Groups 
Not applicable to this study.  
9.9 
Limitations of the Research Methods 
The main limitations of this study are: 
1. Not all countries and sites can be represented because of restrictions due to approval and 
manufacturing locations.  
2. Readers who participate may not be fully representative of the population of readers in 
clinical practice (e.g., untrained readers may be unwilling to participate, and there may not 
be a balanced split among clinical readers for subgroups such as training type, specialty, 
etc. since we are not controlling these factors). 
The potential for bias from the first limitation cannot be assessed in this study. The potential 
for bias from the second limitation will be assessed by reporting demographic data (see 
Table 5) for readers who are randomly chosen to participate as well as the complete pool of 
potential readers who agreed to participate in addition to readers who decided not to 
participate, where data are available. 
9.10 
Other Aspects 
Before starting this study, the protocol (authorised by the Sponsor) will be submitted to the 
regulatory bodies/local health authorities (in accordance with local regulations) and to the IEC 
for evaluation. The protocol will also be signed by the principal investigator before submission 
to the IEC. The study will not start before the IEC gives written approval or a favourable 
opinion in accordance with ICH E6-GCP and all applicable regulatory bodies/local health 
authorities give approval or a favourable opinion as required. 
No changes from the final approved (authorised) protocol will be initiated without the IEC’s 
prior written approval or favourable opinion of a written amendment, except when necessary to 
eliminate immediate hazards to the subjects or when the change involves only logistics or 
administration. The Sponsor will authorise and the principal investigator(s) will sign the 
protocol amendment prior to submission to the IEC. Protocol amendments should be submitted 
to the IEC without delay. 
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9.10.1 
Overall Responsibilities of Investigators 
The investigators are responsible for conducting the study in full accordance with the Protocol 
and the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guideline, approved 
by the ICH, and any applicable national and local laws and regulations. Information regarding 
any investigational centres participating in this study that cannot comply with these standards 
will be documented. 
9.10.2 
Subject Informed Consent 
When informed consent is required by the local IEC, written and oral information about the 
study in a language understandable by the subject will be given to all subjects. Each subject’s 
willingness to participate in the study will be documented in a signed and dated informed 
consent form before any procedures or assessments are done and after the aims, methods, 
anticipated benefits, potential hazards, and insurance arrangements in force are explained. It 
will also be explained to the subjects that they are free to refuse entry into the study and free to 
withdraw from the study at any time without prejudice to future treatment. The informed 
consent process will be documented in the subject's medical record and the investigator will 
sign, date and time the informed consent form after the subject has signed, dated, and recorded 
the time. The investigators will keep the original consent forms and copies will be given to the 
subjects. 
9.10.3 
Protocol Deviations 
Any deviation from the protocol when no approved amendment exists must be documented as 
a protocol deviation and reported according to local requirements. If appropriate, corrective 
and preventative action must be implemented to avoid repetition. Protocol deviations and any 
potential impact on the study results will be discussed during the reporting of the study. 
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances. 
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10 
PROTECTION OF HUMAN SUBJECTS 
The study protocol will be reviewed by an IEC at each imaging site. Each participating subject 
and clinical reader must provide informed consent prior to participation.  
Subject and clinical reader confidentiality will be maintained in accordance with local 
requirement. The legislation applicable to this study on data protection with regard to the 
processing of personal data and on the free movement of such data will be followed. 
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11 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
11.1 
Safety Assessments 
The imaging agent VIZAMYL™ is approved and non-investigational in this study. It will be 
ordered and used in the course of everyday clinical practice. For the purposes of this study it is 
not considered to be an intervention. The collection of safety data is therefore aimed at post-
approval supplementation of the safety profile described in the VIZAMYL™ Summary of 
Product Characteristics.  
The investigator(s) and the Sponsor will review the data on treatment-emergent events (AEs 
and SAEs). 
The Sponsor will periodically monitor the data generated during study conduct and consider 
any implications for the risk-benefit balance of VIZAMYL in Global Pharmacovigilance safety 
signal management. 
11.1.1 
Treatment-Emergent Adverse Events 
Study personnel must remain vigilant for the occurrence of AEs, particularly those that may be 
life-threatening. Personnel who are trained in the acute management of anaphylaxis and other 
emergencies and who have access to appropriate clinical supplies must be immediately 
available for 30 minutes after dosing. Treatment of SAEs should be primarily supportive of 
vital functions. 
AE Definition: An AE is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a study drug, whether or not considered related to that product. Only 
symptoms/signs that begin or worsen in severity and/or frequency after study drug 
administration/use will be recorded as AEs in the eCRF.  
The subjects will be closely observed and questioned for any kind of AE during the study 
procedures and at follow-up appointments throughout the study period with non-leading 
questioning (e.g., “How do you feel?”). The subjects will be instructed to immediately report 
any symptoms and signs to the study staff (i.e., between formal observations). 
Both the investigator(s) and Sponsor will perform a causality assessment on any AE, to assess 
whether or not there is a reasonable possibility (evidence to suggest) that the study drug caused 
the event.  
Expectedness of an AE/reaction will be assessed against the approved VIZAMYL™ Summary 
of Product Characteristics. 
Adverse Reaction: An AE that is caused by the study drug. 
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Suspected Adverse Event: A reasonable possibility exists for causality between the study 
drug and the AE. 
11.1.2 
Serious Adverse Events 
An SAE is defined as any AE that: 
• 
Results in death. 
• 
Is life-threatening. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is another important medical event.* 
*Other important medical events are those that may not result in death, be life threatening, or 
require hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardise the subject and may require medical intervention to prevent one 
of the outcomes listed above. 
11.1.3 
Other Significant Adverse Events 
Clinical laboratory abnormalities that qualify as AEs (other than those meeting the definition 
for serious) and any events that lead to an intervention (including premature discontinuation of 
study drug, dose reduction or significant additional concomitant therapy), other than those 
reported as SAEs, will be reported and evaluated as other significant AEs. 
11.1.4 
Adverse Event and Serious Adverse Event Reporting 
All AEs should be recorded using acceptable diagnoses, if possible. If an AE has already been 
reported it is not necessary to report each individual sign and symptom of that AE as a separate 
AE. For example, if myocardial infarction is reported as an AE, there is no need to report 
elevated creatine kinase and abnormal ECG, or other related signs, symptoms, or laboratory 
values as separate AEs. However, if both occurred in isolation and myocardial infarction was 
not diagnosed, then each event would be reported as an AE. 
The intensity of all AEs will be graded as mild, moderate, or severe using the following 
definitions: 
Mild: 
Tolerable. 
Moderate: 
Interferes with normal activity. 
Severe: 
Incapacitating (causes inability to perform usual activity or work). 
The investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the study drug or not) until the outcome of the AE has been determined. 
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In addition to the investigator’s own description of the AEs, each AE will be encoded by the 
Sponsor according to a well-recognised dictionary of medical codes. 
AEs will be recorded in the eCRF if they occurred as follows: 
• 
From start of injection until discharge from imaging centre, whether or not considered 
related to the study drug, and 
• 
After discharge from imaging centre, and for which a causal relationship to the study 
drug is a reasonable possibility. 
All serious and non-serious AEs must be followed for a final outcome until the end of the 
follow-up period. An outcome of “unknown” is not considered to be an acceptable final 
outcome. An outcome of “not yet resolved” is an acceptable final outcome for non-serious AEs 
at the end of a subject’s participation in a study, and for SAEs at database lock. 
Additional information required in cases of hypersensitivity reactions or AEs in patients 
with renal and/or hepatic impairment. 
In accordance with the Risk Management Plan for VIZAMYL™, hypersensitivity-type adverse 
reactions (both serious and non-serious) and AEs in patients with renal impairment and/or 
hepatic impairment (both serious and non-serious) need to be carefully documented. 
Investigators are requested to fill out the questionnaire (see Annex 1) together with the 
AE/SAE form. 
Study centres are instructed to report all AEs to GE Healthcare Global 
Pharmacovigilance within 3 days by sending an email to gpv.drugsafety@ge.com.  
Individual case safety reports of valid serious and non-serious adverse drug reactions will be 
classified as solicited reports. The Sponsor will report adverse drug reactions (i.e., AEs for 
which a causal relationship is at least a reasonable possibility) to health authorities in 
accordance with applicable postmarketing reporting requirements and Sponsor SOPs.  
Reports of causally unrelated AEs will be summarised as part of any interim safety analysis 
and in the final study report, where applicable. 
Adverse reactions to medicines other than VIZAMYL™ will be handled according to GE 
Healthcare Global Pharmacovigilance SOPs. 
Events which affect the known risk-benefit balance of VIZAMYL™ and/or impact on public 
health will be notified to competent authorities and the Agency, in accordance with GE 
Healthcare Global Pharmacovigilance SOPs. 
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The centre should also notify the Qualified Person Pharmacovigilance (QPPV) of the SAE at 
one of the contact numbers below. For any protocol or safety-related questions please contact 
the QPPV: 
 
GE Healthcare 
Nycoveien 1 
0485 Oslo, Norway 
 
 
Subjects will be provided with a Clinical Trial Participant card at the time of study drug 
administration. This card will list contact details for the investigator and for GE Healthcare 
medical emergency cover services (Clinical Trial Emergency Contact Service [CTECS]). The 
CTECS provides 24-hour, 7-day-a-week emergency cover service for advice on trial–related 
medical questions or problems should a medical emergency arise and the investigator is not 
available. 
For collection of existing data, the medical record will be reviewed and any AEs that occurred 
between the start of injection and discharge from the imaging suite will be recorded in the 
eCRF and recorded/summarised in the final study report but not reported as individual case 
safety report to competent authorities.  
11.1.5 
Urgent Safety Measures 
In accordance with the principles of GCP as laid out in ICH E6, the investigator(s) has/have 
primary responsibility for assuring subject safety throughout the performance of study 
procedures. An urgent safety measure is defined as any measure which an investigator may 
need to implement which is a deviation from, or a change in, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IEC approval/favourable opinion. 
The investigator may take appropriate urgent safety measures in order to protect the subjects of 
a clinical trial against any immediate hazards to their health or safety. However, the 
investigator must inform the Sponsor within 24 hours of having taken such measures. 
The Sponsor in turn shall immediately, and in any event no later than 3 days from the date the 
measures are taken, give written notice to the licensing authority and the relevant IEC of the 
measures taken and the circumstances giving rise to those measures. 
All urgent safety measures must be reported to the Medical Director using the contact 
information provided in Section 11.1.4 within 24 hours of having to take such a measure(s). 
Such reports can be initiated by telephone but must be officially documented by the 
investigator (by email) and must include details of what measures were taken and the 
circumstances giving rise to those measures. If there is an associated AE, this should be 
reported as described in Section 11.1.4.  
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11.1.6 
Pregnancy Reporting 
This process is aimed at ensuring the appropriate monitoring of the potential risk related to 
study drug exposure of pregnant women and/or foetuses as well as the risks associated with 
exposure of a father, regarding congenital abnormalities or birth defects in their offspring. It 
also ensures compliance with applicable international and local regulations. 
The requirements are applicable to all subjects following exposure to study drug. 
Female trial subjects: The trial subject must be advised by the investigator to inform him/her 
immediately if she suspects she may be pregnant within 30 days after receiving VIZAMYL™. 
Male trial subjects: The trial subject must be advised by the investigator to inform him/her 
immediately if they suspect their partner became pregnant within 30 days after the subject was 
administered with study drug. 
When a trial subject reports a pregnancy (post-study drug administration) to the investigator, a 
pregnancy test should be arranged for the trial subject (or their partner) by the investigator 
within 7 days of the pregnancy being reported. 
The investigator must inform the Sponsor within 24 hours of receiving positive pregnancy test 
results using either a copy of the relevant eCRF page (demography or AE) or via email. The 
investigator should include an estimated date of conception when communicating with the 
Sponsor. 
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12 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
Annual progress reports will be submitted to the EMA.  
The Sponsor will submit a final study report to the EMA PRAC within 12 months of the end of 
data collection or will submit a request for a waiver. 
The Sponsor may submit the results of the study for publication in a peer-reviewed journal. 
Abstracts and/or oral presentations of the results at medical professional meetings may also be 
planned. 
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13 
REFERENCES 
[Buckley et al. 2017] 
Buckley CJ, Sherwin PF, Smith AP, et al. Validation of an electronic image reader training 
programme for interpretation of [18F]flutemetamol β-amyloid PET brain images. Nucl Med 
Commun. 2017 Mar;38(3):234-241. doi: 10.1097/MNM.0000000000000633. 
[Curtis et al. 2015] 
Curtis C, Gamez JE, Singh U, et al. Phase 3 trial of flutemetamol labeled with radioactive 
fluorine 18 imaging and neuritic plaque density. JAMA Neurol. 2015 Mar;72(3):287-94. doi: 
10.1001/jamaneurol.2014.4144. 
[EUPAS11867] 
The European Union electronic Register of Post-Authorisation Studies (EU PAS Register). EU 
PAS Register Number EUPAS11867. “Evaluation of Effectiveness of Amyvid Reader Training 
(I6E-AV-AVBE)”. Last updated 2017. 
[EUPAS12145] 
The European Union electronic Register of Post-Authorisation Studies (EU PAS Register). EU 
PAS Register Number EUPAS12145. “A prospective observational study to assess 
effectiveness of the training and risk minimisation measures recommended for the usage of the 
diagnostic agent NeuraCeq™ in the post-authorisation clinical situation: A post-authorisation 
safety study (PASS)”. Last updated 2017. 
[Filippi et al. 2012] 
Filippi M, Agosta F, Barkhof F, et al. EFNS task force: the use of neuroimaging in the 
diagnosis of dementia. Eur J Neurol. 2012;19:1487-1511. 
[Khachaturian, 1985] 
Khachaturian ZS. Diagnosis of Alzheimer’s Disease. Arch Neurol. 1985;42:1097-1105. 
[Minoshima et al. 2016] 
Minoshima S, Drzezga AE, Barthel H, et al. SNMMI Procedure Standard/EANM Practice 
Guideline for Amyloid PET Imaging of the Brain 1.0. J Nucl Med. 2016 Aug;57(8):1316-22. 
doi: 10.2967/jnumed.116.174615. 
[Mirra et al. 1991] 
Mirra SS, Heyman A, McKeel D. The Consortium to Establish a Registry for Alzheimer’s 
Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s 
disease. Neurology. 1991;41:479-486. 
[NIA-Reagan, 1997] 
NIA-Reagan 1997. National Institute on Aging, and Reagan Institute Working Group on 
Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Consensus 
recommendations for the postmortem diagnosis of Alzheimer’s disease. Neurobiol Aging. 
1997;18:(4 suppl):S1–S2. 
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[Salloway et al. 2017] 
Salloway S, Gamez JE, Singh U, et al. Performance of [18F]flutemetamol amyloid imaging 
against the neuritic plaque component of CERAD and the current (2012) NIA-AA 
recommendations for the neuropathologic diagnosis of Alzheimer's disease. Alzheimers 
Dement (Amst). 2017 Jul 1;9:25-34. doi: 10.1016/j.dadm.2017.06.001. eCollection 2017. 
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GE-067-027 C
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6,*1$785(3$*(
Date / Name
Justification / Role
Signed By: 
Date of signature: 18-Jun-2020 16:37:45 GMT+0000
Justification: Approved
Role: Head of Biometrics
Signed By: 
Date of signature: 19-Jun-2020 06:12:38 GMT+0000
Justification: Approved
Role: Head of Clinical Development
Signed By: 
Date of signature: 19-Jun-2020 11:36:02 GMT+0000
Justification: Approved
Role: Safety
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